Clinical trials for various myeloma vaccines have been completed within the last several years. The following is a summary of the most recently reported results from completed clinical trials for multiple myeloma vaccines, starting with the most promising results.

Phase 2 Clinical Trial Shows Cell-Based Antibody Fragment Myeloma Vaccine Improves Survival

In October 2009, researchers at the Mayo Clinic in Rochester, Minnesota, reported the results of a Phase 2 myeloma vaccine trial. According to their findings, a vaccine developed from the cells of myeloma patients was associated with prolonged survival.

Patients were immunized with unique fragments created from their monoclonal (M)-protein combined with cells that activate the immune system.

This trial was conducted in patients directly following autologous stem cell transplantation. A total of 27 patients were given the vaccine, 17 of whom were relapsed/refractory and 10 of whom were in a response or plateau phase.

Responses in patients receiving the vaccine were compared to 124 patients who underwent stem cell transplantation without vaccination.

To qualify for the trial, patients had to have quantifiable M-protein present in the serum, which was frozen and stored for vaccine preparation prior to stem cell transplantation.

Myeloma patients were vaccinated intravenously with their unique M-protein/immune cell vaccine in weeks 0, 2, 4, and 16 following their stem cell transplants.

Ninety-six percent of patients achieved an objective response following stem cell transplantation. Following vaccination, 22 percent of patients achieved improvement to complete response, and 7 percent improved to partial response. The remaining patients experienced prolonged stabilized disease.

There was no statistical difference in time-to-progression or progression-free survival between patients who received the vaccine and those who did not. Overall survival, however, of 5.3 years for patients receiving the vaccine was significantly better than overall survival of 3.4 years for patients who did not receive the vaccine.

For more information, please see the research article in the American Journal of Hematology (abstract).

Phase 1 Trial Shows Treatment With Natural Killer Cells From A Related Donor Can Cause Complete Remission

In December 2008, researchers at the Myeloma Institute for Research and Therapy in Arkansas, lead by Dr. Frits van Rhee, published results from a Phase 1 trial investigating another type of cell-based therapy for high-risk or relapsed multiple myeloma.

According to Susann Szmania, a researcher involved in the study, once this type of therapy has been proven effective in the high-risk disease setting, it could be used as an upfront therapy for multiple myeloma patients.  She also noted that it would be a useful addition to stem cell transplantation and/or novel therapies.

To generate anti-myeloma responses in patients, researchers collected natural killer cells from a family member of each participant and used these cells to vaccinate the myeloma patients. Natural killer cells are one part of the immune system primarily responsible for defense against viral infection. However, they can also recognize and kill tumor cells.

Ten patients with relapsed multiple myeloma after single or double autologous stem cell transplantation were enrolled in the study.  Patients were treated with chemotherapy, and then the natural killer cells were administered over two days.  Two weeks later, the patients underwent another autologous stem cell transplant.

Researchers found that 50 percent of study participants achieved complete remission or near complete remission.  The researchers noted that the complete response rate in their study was better than a 40 percent complete response rate seen in a similar group of patients who did not receive natural killer cells, but the results were not statistically different.

No patients experienced graft-versus-host disease, which is a serious side effect associated with stem cell transplants using cells from a donor.

In email correspondence with The Beacon, Ms. Szmania revealed that a similar Phase 2 study has recently been activated.  The trial, designed by Dr. van Rhee and led by Dr. Bijay Nair, will enroll 30 patients over the next 3 years.

For more information on the results of the Phase 1 trial, see the study in the British Journal of Haematology (abstract).

Phase 1/2 Clinical Trial Of Cell-Based Antibody Fragment Vaccine Can Stabilize Myeloma

In October 2007, researchers in Italy reported the results of a Phase 1/2 clinical trial that demonstrated a myeloma vaccine was safe and produced an anti-myeloma immune response.

The vaccine was created by combining unique fragments created from each patient’s M-protein with dendritic cells, a type of cell responsible for activating the immune system.

Myeloma patients were enrolled in the trial if, following double stem cell transplantation, they could not tolerate maintenance therapy or progressed during maintenance therapy.

A total of 15 symptomatic multiple myeloma patients were enrolled in the trial. The patients received five injections of the vaccine at two week intervals. If stable disease was achieved and enough vaccine was available, monthly injections were continued.

Following immunization, one patient achieved partial remission after 40 months. Seven patients had stable disease after an average follow-up of 26 months, and seven patients progressed.

For more information, see the research article in the British Journal of Haematology (abstract)

Phase 1 Trial Shows Cell-Based Vaccine Can Stabilize Myeloma

In October 2010, researchers from Beth Isreael Deaconess Medical Center and Dana Farber Cancer Institute published results of a Phase 1 trial demonstrating that a multiple myeloma vaccine produced disease stabilization in the majority of enrolled myeloma patients with advanced disease (see related Beacon news).

The researchers designed an anti-myeloma vaccine by combining myeloma tumor cells with dendritic cells, a type of cell that helps activate the immune system. When administered to patients, the vaccine stimulates the immune system to form a response against the tumor cells.

A total of 18 multiple myeloma patients were enrolled. After vaccination, 61 percent of patients achieved stable disease.  The longest duration of ongoing stable disease without evidence of progression was 41 months.

The vaccine was well tolerated and did not result in decreased blood cell counts or autoimmunity, a condition in which the patient’s immune system attacks the patient’s own cells and tissues. The most common side effects were redness and pain at the vaccine injection site.

The researchers suggested future trials investigate the use of the vaccine in multiple myeloma patients who undergo vaccination soon after stem cell transplantation.

For more information, please see the article in the journal Blood (abstract).

Phase 1/2 Clinical Trial Shows Myeloma Vaccination Regimen Is Ineffective And Poorly Tolerated

In October 2010, researchers at the University of Maryland reported the results of a Phase 1/2 clinical trial demonstrating that a complex myeloma vaccination regimen was not as effective or safe as autologous stem cell transplantation followed by maintenance therapy.

A total of 56 myeloma patients were enrolled in the study.  Patients were divided into two groups; one group received the myeloma vaccine prior to stem cell transplantation, while the other only underwent transplantation.

Prior to stem cell transplantation, half of the patients received a series of myeloma vaccinations comprised of the human telomerase reverse transcriptase (hTERT) and survivin proteins, which are overproduced in myeloma cells.

Those patients’ white blood cells were then collected and activated to divide so they would have more immune cells to specifically target hTERT and survivin.  Two days after stem cell transplantation, the white blood cells were injected into patients.

Researchers found patients who were vaccinated had inferior event-free survival compared to those patients who did not receive vaccination, with 25 percent and 65 percent, respectively, predicted to be event free at two years.  Furthermore, there was no statistical difference in the overall survival between groups.

Researchers attributed the inferior event-free survival in the vaccinated group to decreased use of maintenance therapy following transplantation rather than the myeloma vaccine.

Additionally, patients who received the myeloma vaccinations were at increased risk for developing diarrhea, possibly due to an immune reaction in the colon following vaccination.

For more information, please see the research article in Blood (abstract).

The authors of the study suggested that patients with very low counts of blood forming stem cells on day one of collection should be treated with Mozobil (plerixafor), a drug used to mobilize stem cells from the bone marrow into the blood stream where they can be collected, or undergo collection using a process known as large-volume apheresis.

“In taking care of transplant patients, I know that the period of stem cell mobilization and collection can be very challenging,” said Dr. Hien Duong, lead investigator of the study.  “If we can find ways to improve upon this and intervene when needed in order to ensure that enough stem cells can be collected, this can significantly help our patients.”

Despite the use of stem cell mobilization therapy, up to half of all patients fail their first attempt to collect enough stem cells for transplantation.  Collection failure may be due to a number of factors, including extensive bone marrow involvement in the cancer, older age, and prior radiation, chemotherapy, or Revlimid (lenalidomide) therapy.

The ability to predict early in the collection procedure which patients will fail to collect enough stem cells for transplantation would prevent further futile collections.  Furthermore, it would allow physicians the opportunity to modify treatment prior to future collection procedures to improve stem cell yield.

The purpose of this study, conducted at the Cleveland Clinic Foundation in Ohio, was to determine whether the number of stem cells collected during the first day of collection could predict the success of collecting enough stem cells within five days of collection.

Researchers analyzed the medical records of 172 multiple myeloma patients who had undergone mobilization treatment and stem cell collection procedures between 2001 and 2008.

Of the patients included in the study, 13 percent failed to achieve adequate stem cell counts after five days of collection.

The researchers determined that patients who did not collect more than 0.7 million stem cells/kg on their first day of collection were unlikely to successfully collect enough stem cells during five days of collection.

Among the patients who failed to collect enough stem cells throughout the entire collection process, all but one collected less than 0.7 million stem cells/kg on the first day.

The median five-day total number of stem cells collected from patients achieving 0.7 million stem cells/kg or fewer on the first day was one-fifth the median total number of stem cells collected by those achieving greater than 0.7 million cells/kg on the first day of collection.

The researchers observed collection failure in three-quarters of patients who did not collect more than 0.7 million stem cells/kg on the first day or 1.54 million/kg by the end of the second day.

Researchers confirmed that older age and prior Revlimid treatment were associated with lower stem cell collection numbers.

Of the patients who failed to reach adequate stem cell numbers after five days of collection, 61 percent eventually achieved numbers that allowed them to proceed to transplantation.  To collect enough stem cells, 21 percent went beyond five days of collection and 79 percent underwent a second mobilization regimen.

The investigators believe that the identification of patients who are likely to fail to collect adequate stem cell counts for transplantation can be achieved with this prediction method, which they describe as “simple and practical.”  Furthermore, they suggest that this individualized approach can be cost-effective and efficient.

According to Dr. Duong, the Cleveland Clinic Foundation is now conducting a study to determine whether patients previously treated with Revlimid are more likely to collect enough stem cells if they are treated with growth factor alone or in combination with Mozobil.

For more information, see the study in the Journal of Clinical Apheresis (abstract).

As described in Part 1 of this series, there are a number of challenges associated with cancer vaccines.  Therefore, a variety of strategies are currently being explored for the development of an effective myeloma vaccine.  The following are some of the strategies being tested in laboratory and clinical research.

Protein Vaccines

Many current preventative vaccines, such as the hepatitis B virus (HBV) vaccine, are protein vaccines.  These vaccines are comprised of proteins that are contained within a pathogen or toxin. Similarly, the protein-based vaccines currently being explored for multiple myeloma are comprised of proteins unique to cancerous cells.

It is thought that these vaccines work when specialized cells in the immune system ingest the vaccine proteins.  These cells can then activate other components of the immune system, which produce antibodies and help fight disease.

Wilm’s tumor gene (WT1) and human telomerase reverse transcriptase (hTERT) are proteins found in a variety of malignancies, including myeloma. The overproduction of these proteins allows cells to rapidly divide and become cancerous. Protein vaccines are currently being developed with WT1 and hTERT for a variety of therapeutic cancer vaccines.

Abnormal production of another protein called Mucin1 (MUC1) also plays a role in the development of multiple myeloma. The use of this protein in a multiple myeloma vaccine has shown promise in preclinical trials and is currently in Phase 1/2 clinical testing.

In addition to finding the correct protein to use for vaccination, much research is focused on compounds that help activate the immune system at the time of vaccination. These compounds, called adjuvants, are currently used in preventative protein vaccines, such as the HBV vaccine, to help stimulate a more potent immune response to the selected protein.

Finding the optimal adjuvant and protein combination to stimulate the most potent immune response will continue to be investigated in laboratories and clinical trials.

Cell-Based Vaccines

Many researchers believe that combining protein vaccines with dendritic cells, a type of cell that activates the immune system, may result in more optimal immune responses. In a cell-based vaccine therapy, dendritic cells are collected from a myeloma patient and loaded with cancer-specific proteins, either manufactured proteins or ones from the patient’s blood. These modified cells are then used to vaccinate the patient.

This technique harnesses the patient’s own immune system for potent responses.  When the dendritic cells loaded with cancer-specific proteins are injected back into the patient, they can activate other components of the immune system to recognize and destroy cancerous cells.

Cell-based vaccines have shown promise for a variety of cancers. In fact, the currently-approved therapeutic vaccine for prostate cancer is a dendritic cell-based vaccine.

Recently, a Phase 1 clinical trial of a myeloma vaccine that combined myeloma patients’ cancerous cells with dendritic cells yielded favorable results (see related Beacon news).

Antibody Fragment Vaccines

Multiple myeloma is characterized by the overproduction of monoclonal (M)-protein, a type of abnormal antibody. The type of overproduced M-protein, known as the idiotype, is unique to each patient.

Antibody fragment vaccines, known as idiotype vaccines, are custom-designed from a patient’s M-protein in order to stimulate his or her immune system to recognize it.  Protein and cell-based formulations of these vaccines are currently being explored.

Idiotype vaccination is one of the most active research areas for multiple myeloma vaccine development to date. Half of all the recently completed clinical trials for multiple myeloma vaccines involve idiotype strategies.

Donor Vaccination And Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation, in which a healthy donor’s stem cells are transplanted to a myeloma patient, has long been considered a possible cure for multiple myeloma because the healthy donor cells can destroy myeloma cells.

However, graft-versus-host disease (GVHD) remains a serious and life-threatening complication of the procedure, which limits its clinical use. GVHD occurs when the donated cells view healthy cells in the recipient’s body as foreign and attack them.

One strategy currently being explored to enhance the anti-myeloma effect of allogeneic stem cell transplantation and reduce the severity of GVHD is to target the donor cells to destroy patient cancer cells more selectively.

Therefore, the donor is vaccinated with M-protein fragments isolated from the myeloma patient prior to bone marrow harvest. When the bone marrow is harvested, there will be an increased proportion of cells that target the myeloma patient’s cancerous cells.  The resulting transplantation should also result in less severe GVHD.

A Search For The Cure

Multiple myeloma is the second most prevalent blood cancer in the United States. Despite advances in drug combination therapies and stem cell transplantation techniques, multiple myeloma is still considered an incurable disease (see related Beacon news).

While options for the management of myeloma continue to improve, disease relapse remains common. With the emergence of many novel therapies, developing treatments that cure myeloma is the research goal of many scientists.

One treatment strategy that has attracted attention from researchers is therapeutic vaccination, a form of “immunotherapy” that harnesses the immune system to fight and destroy cancer cells.

The goal of therapeutic vaccination is to activate cells in the immune system to recognize tumor cells as “foreign,” ultimately resulting in their destruction.

Dr. Maurizio Bendandi, a physician currently conducting myeloma vaccine research at the University of Navarra in Spain, believes that the development of a safe and effective vaccine could ultimately be used as an alternative maintenance option for myeloma patients.

Preventative Versus Therapeutic Vaccination

People are typically familiar with preventative vaccines, which as their name suggests are used to prevent a disease.  Therapeutic vaccines, however, are used to treat or cure an already existing disease.  Therapeutic vaccines are the type being studied for the treatment of multiple myeloma.

Preventative vaccines work by exposing patients to a safe form of a disease-causing agent (pathogen), most often a weakened or killed form of a virus. The immune response to the safe form of the pathogen is often enough to completely protect patients from disease caused by the active form of the pathogen years after the person receives the vaccine.

Since the late eighteenth century, preventative vaccination has forever changed medicine and its practice.  Diseases such as polio and smallpox have essentially been eradicated due to preventative vaccination.  In 2009, the FDA approved Gardasil, a vaccine against human papillomavirus, making it the first vaccine available for the prevention of cancer.

Although the development, production, and distribution of preventative vaccines exploded during the 20^th century, the development of therapeutic vaccines, which can be used to treat already existing disease, remains a challenging area of research.

Therapeutic cancer vaccines have been intensely researched for more than a decade. So far, only one has been approved for use in the United States.  Provenge (sipuleucel-T) received FDA approval in April of last year for the treatment of certain men with advanced prostate cancer.

Unlike preventative vaccination, which stimulates a protective immune response before disease occurs, therapeutic vaccination must stimulate an immune response against an already established disease, a process that has proven to be very difficult to initiate and sustain.

Pathogens differ greatly from human cells, and are therefore more easily recognized by the immune system as “foreign.”

Cancer, on the other hand, arises from mutations in human cells. When developing therapeutic vaccines for myeloma, researchers must vaccinate against components that are present in cancerous cells but not normal cells. If the vaccine component is not specific enough to the cancerous cells, the immune system may not respond at all, or it may begin to recognize normal cells as “foreign,” resulting in their destruction.

Dr. Ravi Vij, a myeloma expert and researcher from Washington University in St. Louis, said that myeloma vaccines could conceivably lengthen progression-free survival with minimal side effects.  However, he also said that there are several hurdles that must be overcome, including finding the right targets to generate the vaccine as well as making the vaccine elicit a strong enough immune response.

Based on these findings, the study authors recommended avoiding the administration of intermittent high-dose dexamethasone with the vincristine-doxorubicin-dexamethasone regimen in myeloma patients at high risk for infection. 

The combination treatment of vincristine (Oncovin), doxorubicin (Adriamycin), and dexamethasone (Decadron) plus high-dose pulses of dexamethasone (referred to as VAD-HD) was first approved as a treatment for advanced multiple myeloma.

It is currently also used in newly diagnosed multiple myeloma patients and can result in a high response rate of up to 80 percent in this patient population.  Additionally, VAD-HD has few effects on blood stem cells and is therefore often used as treatment for patients who plan to undergo stem cell transplantation.

Despite its efficacy, the VAD-HD regimen is associated with an increased risk of bacterial infections in multiple myeloma patients.  High doses of glucocorticoids, such as the dexamethasone included in VAD-HD, can suppress the immune system, making it more difficult for patients to fight off infections. 

In their retrospective analysis, the Japanese researchers sought to determine whether the omission of high-dose dexamethasone pulses from the VAD regimen could lower the rates of infection among multiple myeloma patients.

They analyzed data of 77 multiple myeloma patients who had been treated with either VAD or VAD-HD at their institution between July 1999 and October 2009. Of the 77 patients, 37 had received VAD alone, and 40 had received VAD-HD. 

Patients who were treated with VAD alone received 2-4 cycles of the drugs on days 1-4 of a 21-day cycle.  The VAD dosing schedule was identical for patients in the VAD-HD treatment group, with the addition of intravenous dexamethasone on days 9-12 and 17-20 of each 28-day cycle. 

The researchers found that there were no statistically significant differences in the overall response rates between the two treatment groups. Of the patients who received VAD without HD, 62.9 percent responded compared to 50 percent of patients who received VAD-HD. 

The researchers did find, however, that the VAD-HD treatment was associated with a higher risk of bacterial infection than the VAD treatment. They documented 26 bacterial infections in the patient group treated with VAD-HD, compared to 13 in the patient group treated with VAD.

Patients with more advanced stages of multiple myeloma were also at a higher risk of bacterial infection. The researchers documented 28 bacterial infections in patients with advanced stages of myeloma, compared to 11 in patients with early-stage disease.

The most commonly observed bacterial infections included pneumonia, urinary tract infections, and staphylococcus infections. 

For more information, please see the full study in the International Journal of Hematology (abstract).

Although multiple myeloma remains an incurable disease, the introduction of novel agents, such as thalidomide (Thalomid), Velcade (bortezomib), and Revlimid (lenalidomide) has lead to significant improvements in disease outcomes.

In their analysis, the Canadian researchers sought to determine the effect of these novel agents on the outcomes of multiple myeloma patients who had relapsed after stem cell transplantation.

They also sought to determine if novel agent therapy has improved the outcomes for a subset of patients considered high-risk due to early relapse (less than 12 months) following transplantation.

The Canadian researchers analyzed data collected from 460 multiple myeloma patients who received an autologous stem cell transplant in British Columbia, Canada, between June 1988 and June 2008.

The novel therapeutic agents administered in the event of a relapse following transplantation (post-relapse, or salvage, therapy) were developed during the 20 year study period, which allowed the researchers to compare the relative efficacy of each drug.

Prior to 1999, post-relapse therapy in British Columbia was comprised of various chemotherapy regimens. Thalidomide was first available for post-relapse therapy in 1999, followed by Velcade in 2004, and Revlimid in 2005.

Of the 460 patients included in the study, 306 experienced relapse following stem cell transplantation. Among these relapsed patients, the overall survival was 59.6 months, and the median post-relapse survival was 31 months.

The analysis showed that there was little difference in the post-relapse survival between patients who received conventional chemotherapy and those who received thalidomide as post-relapse therapy.

The researchers therefore divided the relapsed patients into two groups: (1) those who relapsed prior to 2004 and received post-relapse chemotherapy or thalidomide, and (2) those who relapsed in 2004 or later and received the novel agents Velcade or Revlimid as part of post-relapse therapy.

Overall survival significantly improved for patients who relapsed in 2004 or later (71.8 months), compared to patients relapsing prior to 2004 (32 months).

Likewise, the post-relapse survival also improved in the more recently relapsed group, with a median of 42.8 months compared to 15.2 months in those relapsing prior to 2004.

Progression-free survival after transplantation was similar for the two groups (19.9 months versus 14.6 months), which according to the study authors is an indication that any potential changes that were made to transplantation procedures over time did not have an impact on outcome.

When researchers analyzed the relationship between early relapse following transplantation, overall survival, and post-relapse survival, they found that patients who relapsed early had lower overall survival times (26.8 months) compared to those with a later relapse (75 months).

Patients who relapsed early also had lower post-relapse survival times (16.3 months) than patients who relapsed later (37.2 months).

Early relapse patients who relapsed in 2004 or later did, however, experience an improvement in post-relapse survival time (33.4 months) compared to those who relapsed prior to 2004 (9.1 months).

For more information, see the research article in Leukemia & Lymphoma (abstract).

Total body irradiation is commonly used prior to stem cell transplantation to destroy cancerous cells in the bone marrow. The bone marrow is then repopulated with healthy transplanted cells.

A technique known as helical tomotherapy is an image-guided procedure that allows physicians to concentrate the radiation on affected areas, protecting surrounding organs.

When undergoing helical tomotherapy, patients lie on a table that is moved through a donut-shaped machine. Radiation sources then move around the patient in a spiral, or helical, pattern. This allows for delivery of radiation to the cancer source from many different directions.

The goal of this study, conducted by researchers at City of Hope Cancer Center, was to determine the safety and efficacy of total marrow irradiation delivered by helical tomotherapy in multiple myeloma patients undergoing stem cell transplantation.

A total of 22 myeloma patients enrolled in the study and underwent tandem stem cell transplantation. In a tandem stem cell transplant procedure, a patient undergoes two consecutive transplantations. The second transplant is performed once the patient has recovered from the first stem cell transplant.

Patients received high-dose melphalan (Alkeran) to prepare their bone marrows for the first transplant. An average of 63.5 days following melphalan administration, patients underwent irradiation using helical tomotherapy in preparation for their second transplant.

Different doses of radiation were administered to subsets of patients in order to determine the safest dose.

Thirty days after irradiation, 23 percent of patients achieved a complete response and an additional 50 percent had a very good partial response.

Maximum responses were typically seen around 10 months after transplantation, while patients were on maintenance therapy with dexamethasone (Decadron) and thalidomide (Thalomid). Response rates increased to 55 percent of patients achieving a complete response and 27 percent achieving a very good partial response.

After 35 months of follow-up, progression-free survival was 53 percent, and overall survival was 84 percent.

At the highest radiation dose of 1800 cGy, patients experienced severe side effects, such as congestive heart failure, abnormally low blood pressure, and inflammation of the lungs and small intestine. The maximum-tolerated radiation dose was therefore 1600 cGy.

The estimated radiation dose to normal organs ranged from 11 percent to 81 percent of the full dose administered to the bone marrow. The radiation exposure to normal organs increased with higher doses, but remained below what would have been expected for the same dose administered during standard full body irradiation.

Researchers noted that, in general, the side effects of total marrow irradiation given by helical tomotherapy were similar to those seen following high-dose melphalan therapy.

For more information, please see the research article in Clinical Cancer Research (abstract).

Dr. Irene Ghobrial of the Dana-Farber Cancer Institute presented the results at the 2010 annual American Society of Hematology (ASH) conference held in Orlando last month.

Dr. Ghobrial said the trial results were promising in heavily pretreated myeloma patients and that the combination of Torisel (temsirolimus) and Velcade (bortezomib) warrants further evaluation.

Torisel is marketed by Pfizer and is currently approved for the treatment of advanced kidney cancer. It works by inhibiting a protein essential for cancer cell growth and division.  A previous study showed that the overall response rate with Torisel alone is 43 percent in myeloma patients.

This study was designed to determine the safety and efficacy of Torisel in combination with Velcade in previously treated myeloma patients.  Phase 1 of the study included 20 patients, and Phase 2 included 43 patients.  Most participants were heavily pre-treated, and 63 percent had relapsed or were resistant (refractory) to their last Velcade treatment.

In Phase 1 of the trial, patients received 1.3 or 1.6 mg/m² Velcade weekly for 4 out of 5 weeks as well as 15 or 25 mg Torisel weekly.  Both drugs were tolerated at the maximum doses tested.

In Phase 2 of the trial, 47 percent of patients responded to treatment, which included 5 percent complete responses, 9 percent very good partial responses, 19 percent partial responses, and 14 percent minimal responses. Two-thirds of patients who had previously been treated with Velcade achieved stable disease, and 20 percent achieved a minimal response or better.

“If we had used twice-a-week Velcade instead of once-a-week Velcade or added dexamethasone [Decadron] in this combination, potentially we could have had an even higher response in [Velcade-refractory] patients,” said Dr. Ghobrial.

Progression-free survival was 5.6 months, and overall survival was 18.8 months.

Almost all patients experienced side effects, especially low platelet counts, which were associated with both Velcade and Torisel. Other types of low blood cell counts were common as well.

Of note, 34 percent of participants experienced peripheral neuropathy (tingling in the arms and legs), but there were no reported cases of severe peripheral neuropathy in this study.  Dr. Ghobrial hypothesized that the reduced peripheral neuropathy in this study compared to what is normally seen with Velcade administration may have been due to the once-weekly dose of Velcade or a protective effect conferred by Torisel.

For more information, see abstract 990 on the ASH Meeting website.

Dr. Suzanne Lentzsch, of the University of Pittsburgh School of Medicine and Cancer Institute, presented the results of the study at the American Society of Hematology (ASH) 2010 annual meeting in Orlando.

Based on the safety of the Treanda, Revlimid, dexamethasone regimen observed in this study, Dr. Lentzsch believes that this combination may be particularly well suited for older patients or those with a history of peripheral neuropathy (tingling in the arms and legs).

Treanda (bendamustine) is an alkylating agent, which causes cancer cell death by damaging the cancer cells’ DNA.  The drug, developed by Cephalon, is currently approved to treat certain types of leukemia and lymphoma. 

The goal of this study was to determine the maximum tolerated doses of both Treanda and Revlimid (lenalidomide) when administered with dexamethasone (Decadron) for patients with relapsed/refractory multiple myeloma.

A total of 26 patients were enrolled in the study. The patients had received a median of three prior therapies.

During the study, they received 75 mg/m² Treanda on days 1 and 2 of a 28 day cycle, which was later escalated to 100 mg/m². Revlimid was administered at 5 mg on days 1 to 21 and was later escalated to 10 mg.  Oral dexamethasone was administered at a fixed dose of 40 mg on days 1, 8, 15, and 22 of each 28-day cycle.  Patients received a maximum of eight treatment cycles. 

Among the evaluated participants, 9 percent achieved a very good partial response and 57 percent achieved a partial response, for an overall response rate of 66 percent. 

Dr. Lentzsch described the time to response as rapid, with half of the patients achieving their best response within 1.8 months.

Median time to progression was 4.3 months.  As of the time of the ASH meeting, Dr. Lentzsch reported that the median overall survival was 10.9 months. However, she noted that the trial is still ongoing and, thus, overall survival could still change.

Low blood cell counts were common with this regimen.  Forty eight percent of patients experienced low white blood cell counts, 28 percent low platelet levels, and 20 percent low red blood cell counts.

Dr. Lentzsch pointed out that she and her colleagues did not observe any severe non-blood related side effects. The most common side effect that was not blood-related was fatigue. The study authors did not observe any case of severe peripheral neuropathy in this trial.

Based on the observed side effects at each dosing regimen, the maximum tolerated dose, when administered with dexamethasone, was determined to be 75 mg/m² Treanda and 10 mg Revlimid.

For more information, please see abstract 989 on the American Society of Hematology meeting website.

Zolinza (vorinostat) is manufactured by Merck Pharmaceuticals.  It is currently approved for a certain type of lymphoma and is being investigated as a treatment for multiple myeloma (see related Beacon news).  Zolinza is a histone deacetylase inhibitor and works by altering the production of proteins in cancer cells, thereby slowing growth of cancer cells and inducing cell death.

Zolinza With Revlimid And Dexamethasone For Relapsed/Refractory Myeloma

The results of a Phase 1 clinical trial of Zolinza with Revlimid (lenalidomide) and dexamethasone (Decadron) in relapsed or treatment-resistant (refractory) myeloma patients indicate that it is a well-tolerated and promising therapeutic option for this subset of patients.

A total of 31 patients have been treated in the trial as of July 2010.  Patients were placed into one of five treatment groups and received Zolinza (300 or 400 mg on days 15 to 21), Revlimid (10, 15, 20, or 25 mg on days 1 to 21), and dexamethasone (40 mg on days 1, 8, 15, and 22 of a 28-day cycle).

A complete response was achieved by 7 percent of patients, while very good partial and partial responses were achieved by 10 percent and 37 percent of patients, respectively.   Additionally, 17 percent achieved a minimal response and 17 percent achieved stable disease.

Of note, stable disease or better was achieved in 60 percent of patients who were previously relapsed, refractory, or intolerant to Revlimid treatment.

The median time to progression was 5 months.

Most observed side effects were mild to moderate, though 61 percent of patients experienced at least one severe side effect.  These included low white and red blood cell counts, low platelet levels, and diarrhea.  All doses tested were tolerated.

Researchers plan to continue studying this regimen in future trials.

Zolinza And Velcade For Relapsed/Refractory Myeloma

Two ongoing clinical trials, a Phase 2b trial called Vantage 095 and a Phase 3 trial called Vantage 088, are currently investigating the use of Zolinza with Velcade (bortezomib) for relapsed/refractory myeloma patients.

The Phase 2 trial will include 142 relapsed and refractory myeloma patients.  Data presented at the meeting showed that the first 108 participants were heavily pre-treated with a median of 5 prior treatments. Patients in this study received 21-day cycles of Velcade (1.3 mg/m² on days 1, 4, 8, and 11) and Zolinza (400 mg on days 1 to 14).  Patients who did not respond to Velcade and Zolinza alone could have dexamethasone added to their regimen (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12).

Interim results suggest that the regimen is effective in Velcade-refractory patients.  Final results are expected to be available in 2011.

In the Phase 3 trial, the same Velcade-Zolinza regimen is being compared to Velcade alone.  A total of 349 patients, who received one to three prior treatment regimens, have been enrolled.  Planned enrollment is 742 participants.

For more information, or to enroll in the Phase 3 trial, please see the clinical trial webpages for Vantage 095 and Vantage 088.

Zolinza With Doxil And Velcade For Relapsed/Refractory Myeloma

A Phase 1 study of Zolinza in combination with Doxil (doxorubicin liposomal) and Velcade for relapsed/refractory myeloma patients was designed to determine the maximum-tolerated dose of Zolinza when used in this combination regimen.

A total of 20 patients have been enrolled in the study thus far.  Patients were placed in one of four treatment groups receiving 21-day cycles of doxorubicin (30 mg/m² on day 4), Velcade (1.3 mg/m² on days 1, 4, 8 and 11), and Zolinza (200, 300, or 400 mg on days 4 to 11 or 1 to 14).

Thirty-eight percent of patients achieved a very good partial response or better, and an additional 23 percent achieved a partial response. Of note, 70 percent of patients with relapsed disease, 50 percent of patients with relapsed and refractory disease, and 33 percent of Velcade-refractory patients achieved a partial response or better.

Common side effects included low white blood cell and platelet levels, diarrhea, nausea, peripheral neuropathy (nerve damage in the limbs), fatigue, constipation, vomiting, and loss of appetite.

Two dose-limiting toxicities were observed at the highest dose level and one was observed at the next highest level, thus establishing the maximum-tolerated dose of Zolinza in this regimen at 400 mg administered on days 4 to 11.

Researchers believe the results of this study support further clinical testing of Zolinza with Doxil and Velcade.

Zolinza With Revlimid, Velcade, and Dexamethasone In Newly Diagnosed Myeloma

The initial results of a Phase 1 clinical trial for Zolinza with Revlimid, Velcade, and dexamethasone as frontline therapy for multiple myeloma suggest that the regimen is effective and tolerable.

To date, 11 patients have been enrolled in the study and placed into one of three patient groups.  All patients received the current standard Revlimid-Velcade-dexamethasone regimen in addition to 100, 200, 300, or 400 mg of Zolinza on days 1 to 14 of a 21-day cycle.  Participants could receive a stem cell transplant after 4 cycles.

All evaluable patients responded to the regimen, with 38 percent achieving complete response, 12 percent achieving very good partial response, and 50 percent achieving partial response.

Fifty-five percent of patients experienced the onset of peripheral neuropathy during the trial, and one patient discontinued therapy after experiencing severe peripheral neuropathy.  One dose-limiting toxicity occurred at 100 mg and another at 200 mg, but the maximum-tolerated dose of Zolinza has not yet been reached.

The study will continue to accrue patients to determine the maximum-tolerated dose of Zolinza in this regimen.  For more information or to enroll, see the clinical trial webpage for the study.

Zolinza Combinations In Relapsed/Refractory Myeloma

In this retrospective study, researchers sought to determine whether the addition of Zolinza to myeloma treatment combinations could overcome resistance to those combinations in relapsed/refractory myeloma patients.

The researchers analyzed the efficacy of Zolinza-Revlimid-dexamethasone in patients refractory to Revlimid-dexamethasone as well as the efficacy of Zolinza-Revlimid-Velcade-dexamethasone in patients refractory to Revlimid-Velcade-dexamethasone.

The study included 18 patients who had received Zolinza (300 or 400 mg) on days 1 to 7 and 15 to 21 of a 28-day cycle in combination with Revlimid and dexamethasone.  An additional 10 patients also received Velcade.

Partial responses or better were noted in 43 percent of patients, which included 14 percent very good partial responses and 29 percent partial responses. The duration of response ranged from 2 to more than 23 months.

The most common side effects were diarrhea and abdominal cramping.  Some patients experienced low red blood cell and platelet levels, but the rate was similar to that seen in patients treated with Revlimid-based therapy without Zolinza.

The results demonstrate Zolinza’s ability to overcome resistance to Revlimid, Velcade, and dexamethasone regimens.

For more information, please see abstracts 1951 (Zolinza, Revlimid, dexamethasone), 1952 (Zolinza and Velcade), 1955 (Zolinza, Doxil, Velcade), 3034 (Zolinza, Revlimid, Velcade, and dexamethasone), and 3065 (Zolinza analysis in refractory patients) on the American Society of Hematology Meeting website.

These results further underscore carfilzomib’s activity in multiple myeloma.  Several studies with promising results were also reported in poster sessions during the annual meeting (see related Beacon news).

Like Velcade (bortezomib), carfilzomib, which is being developed by Onyx Pharmaceuticals, is a proteasome inhibitor.  It prevents the break down of important proteins in cancerous cells, thereby causing cell death.

Carfilzomib, Revlimid, Dexamethasone Combination In Newly Diagnosed Multiple Myeloma

Dr. Andrzej Jakubowiak of the University of Michigan presented the results of a Phase 1/2 clinical trial investigating the safety and activity of carfilzomib in combination with Revlimid (lenalidomide) and dexamethasone (Decadron) for newly diagnosed multiple myeloma patients.

“We hypothesize that the carfilzomib, Revlimid, dexamethasone combination has potential for even higher activity in newly diagnosed myeloma [than in relapsed/refractory myeloma]. It could produce higher complete response/near complete response rates than currently available regimens,” explained Dr. Jakubowiak at the start of his talk.

To date, researchers have enrolled 24 patients in the trial.  Patients were placed into one of three treatment groups receiving 20 mg/m², 27 mg/m², or 36 mg/m² of carfilzomib to determine the maximum tolerated dose.  Carfilzomib was administered intravenously on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.

All treatment groups received Revlimid, 25 mg orally on days 1-21, and low-dose dexamethasone orally once per week. After completion of eight cycles, patients received 28-day maintenance cycles with Carfilzomib on days 1, 2, 15, and 16; Revlimid on days 1-21; and dexamethasone weekly at the doses tolerated at the end of eight cycles.

After four months of treatment, 95 percent of patients achieved a partial response or better, with 55 percent of patients achieving a complete or near complete response.

According to Dr. Jakubowiak, response to treatment was rapid, with 89 percent of patients achieving partial responses after one cycle.  He added that all patients showed improvement in responses with continued treatment.  After eight cycles, all patients achieved at least a partial response with 67 percent of patients achieving a complete response or near complete response.

At a follow-up time of six months, no patients experienced disease progression, and all patients were still alive.

According to Dr. Jakubowiak, side effects were mostly mild and included low white blood cell, red blood cell, and platelet counts, which were reversible.  Other side effects included blood clots, fatigue, mood swings, and blood sugar elevations.  Of note, clinically significant peripheral neuropathy (pain and tingling in extremities) as a result of carfilzomib was not observed, even after prolonged treatment.

“It’s still early, but these response rates appear to compare favorably to the current best regimens in newly diagnosed myeloma. Importantly, the regimen is by-and-large well tolerated, allowing for extended treatment,” concluded Dr. Jakubowiak.

He added that the results of this study provide additional support for the evaluation of the combination treatment in newly diagnosed multiple myeloma.  A Phase 3 trial will be comparing the carfilzomib, Revlimid, dexamethasone combination with Revlimid and dexamethasone alone in patients with relapsed multiple myeloma.

The results were well received by physicians in attendance at the meeting.  During the question and answer session following the talk, several people expressed that the results were “wonderful” and “encouraging.”  Another attendee said that these were unprecedented complete response rates.

Single Agent Carfilzomib For Relapsed/Refractory Multiple Myeloma

Dr. David Siegel from the Hackensack University Medical Center in New Jersey presented the results of a Phase 2b trial investigating the safety and efficacy of carfilzomib as a single agent in patients with relapsed multiple myeloma whose disease was refractory to their last treatment regimen.

The study enrolled 266 patients who had received two or more prior therapies including Velcade and either thalidomide (Thalomid) or Revlimid as well as an alkylating agent, such as melphalan (Alkeran). According to Dr. Siegel, the patients were heavily pretreated with a median of four prior therapies.

Patients received carfilzomib at 20 mg/m² on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.  After the first cycle, the dose was increased to 27 mg/m² on the same schedule for up to 12 cycles.

A total of 24 percent of patients achieved a partial response or better. Dr. Siegel added that 10 percent of patients achieved a minimal response.

“The reason I point out the 10 percent of minimal responders,” explained Dr. Siegel, “is that the duration of response was 8.3 months, and this 8.3 months was maintained in both the partial response or better population and the minimal response or better population.”

Dr. Siegel pointed out that the number of prior therapies, plasma involvement in the bone marrow, unfavorable chromosomal abnormalities, and pre-existing peripheral neuropathy were not predictive of response to carfilzomib.

For patients who were refractory to Velcade in their last line of therapy, 19 percent of patients achieved a partial response or better, which according to Dr. Siegel is similar to the overall patient population in the study.

Among patients with unfavorable chromosomal abnormalities, 28 percent responded to treatment.

The median progression-free survival was 3.7 months, and 32 percent of patients achieved stable disease for at least six weeks.

The median overall survival was 15.5 months. Median overall survival for responding patients has not yet been reached, though researchers predict based on current data that it will exceed 19 months.

The most common severe side effects included low platelet counts (27 percent), low red blood cell counts (22 percent), and low white blood cell counts (10 percent), which Dr. Siegel described as surprisingly low.

Despite the fact that 77 percent of patients had mild to moderate peripheral neuropathy prior to enrolling in the trial, new onset peripheral neuropathy resulting from carfilzomib treatment was rare, with severe cases presenting in less than one percent of participants.

Eighty-two percent of patients discontinued therapy, mostly due to progression of disease. However, Dr. Siegel pointed out that none of the patients discontinued therapy due to emerging peripheral neuropathy.

Nine percent of patients died while on the study, half due to disease progression.

“Carfilzomib is a very well tolerated drug in an extremely heavily pretreated patient population at very low incidence of peripheral neuropathy,” concluded Dr. Siegel.

For more information, please see abstracts 862 (carfilzomib, Revlimid, dexamethasone combination) and 985 (single-agent carfilzomib) on the American Society of Hematology meeting website as well as the Onyx press release (single-agent carfilzomib).

The findings were presented at the American Society of Hematology (ASH) annual meeting in Orlando last week.

Elotuzumab is a new drug being developed by Facet Biotech and Bristol-Myers Squibb as a potential treatment for multiple myeloma. It recognizes and binds to unique proteins on the surface of multiple myeloma cells. The immune system can then target and destroy the cancerous cells.

Elotuzumab In Combination With Velcade

Dr. Andrzej Jakubowiak, from the University of Michigan, presented a poster with updated results from a Phase 1 clinical trial studying elotuzumab in combination with Velcade in relapsed and refractory myeloma patients.

A total of 28 myeloma patients with an average of two prior therapies were enrolled in the study.  Of the 28 patients, 11 had received prior Velcade treatment and four of the 11 were resistant to Velcade.

The patients received escalating doses of elotuzumab (from 2.5 mg/kg to 20 mg/kg) on days 1 and 11 and a fixed-dose of Velcade (1.3 mg/m²) on days 1, 4, 8, and 11 of a 21-day cycle. Dexamethasone was added for patients who experienced disease progression early in the trial. 

Forty-eight percent of patients achieved a partial response or better, 7 percent of whom achieved a complete response.  Notably, a partial response was also observed in 50 percent of Velcade-resistant patients.

The median time to disease progression was 9.5 months, both for the overall study group and the Velcade-resistant group.

All administered doses of elotuzumab were well tolerated.  The most common severe treatment-related side effects were fatigue, diarrhea, nausea, pneumonia, low platelet counts, constipation, low red blood cell counts, peripheral neuropathy (pain and tingling in the legs, arms, hands, and feet), and low white blood cell counts.

Preliminary study results were presented at the American Society of Clinical Oncology meeting this summer (see related Beacon news).

Elotuzumab In Combination With Revlimid And Low-Dose Dexamethasone – Phase 1 Trial

Dr. Sagar Lonial, from the Emory Winship Cancer Institute, presented a poster with updated results from an ongoing Phase 1 clinical trial studying elotuzumab in combination with Revlimid and low-dose dexamethasone in relapsed and refractory myeloma patients.

The study included 29 advanced myeloma patients who had undergone an average of three prior treatments.  They received 5, 10, or 20 mg/kg elotuzumab weekly for the first two treatment cycles and then every other week for subsequent cycles. Patients also received Revlimid (25 mg) on days 1 to 21 of a 28-day cycle and low-dose dexamethasone (40 mg) once a week.

Patients received a median of 8.5 treatment cycles. 

Dr. Lonial and his colleagues found that 82 percent of patients achieved a partial response or better. Of the patients who had not received prior Revlimid treatment, 96 percent achieved a partial response or better. Overall response rates were also high in patients who had received prior thalidomide (Thalomid) treatment or were refractory to their most recent therapy, 94 percent and 82 percent, respectively. 

Among all the treatment groups, 53 percent of patients had not progressed at 16 months.  Of the patients who received the highest dose of elotuzumab (20 mg), 66 percent had not progressed at 16 months.  The median time to disease progression has not yet been reached.

The most common severe side effects were low white blood cell and platelet levels, experienced by 36 percent and 21 percent of study participants, respectively. In addition, two patients experienced serious infusion-related reactions.

Preliminary study results were presented at the American Society of Clinical Oncology meeting this summer (see related Beacon news).

Elotuzumab In Combination With Revlimid And Low-Dose Dexamethasone – Phase 2 Trial

Dr. Paul Richardson, from the Dana-Farber Cancer Institute, presented interim results of the Phase 2 study of elotuzumab in combination with Revlimid and low-dose dexamethasone in relapsed/refractory patients.

“What was particularly important [about this Phase 2 trial] is that the high overall response rates that had been seen in Phase 1 were reproduced in this larger, multicenter trial, with a remarkable overall response rate and very high quality response rate,” said Dr. Richardson.

A total of 63 relapsed/refractory multiple myeloma patients have been enrolled in the study.  Patients previously treated with Revlimid were excluded from the trial.

Half of the study participants received 10 mg/kg elotuzumab, and the other half received 20 mg/kg.  Patients received treatment once a week for the first two 28-day cycles and once every other week for all subsequent cycles.

Patients were premedicated with anti-inflammatory drugs prior to elotuzumab infusion in an attempt to control infusion-related side effects, which had been observed in the Phase 1 trial. 

Ninety percent of patients receiving the 10 mg/kg dose achieved at least a partial response, compared to 72 percent for those receiving the 20 mg/kg dose.  According to Dr. Richardson, time to response was very rapid, at a median of two months.

The median progression-free survival was not reached during the 4.9 months of follow-up, which according to Dr. Richardson is very encouraging for this patient population. He added that it was more than one year in the Phase 1 trial.

Side effects were manageable in the majority of patients and were predominantly side effects seen with Revlimid and dexamethasone. 

The most common elotuzumab-related side effects included fatigue and fever. Dr. Richardson added that the updated premedication prior to elotuzumab infusion helped to control infusion-related side effects.

There were no treatment-related deaths in the study.

Based on these findings, Dr. Richardson and his colleagues recommended the 10 mg/kg dose of elotuzumab be used in trials going forward. “Ten mg/kg of elotuzumab is now the Phase 3 recommended dose.  Recognizing there are no major differences between the two doses, one therefore takes the lower dose going forward,” explained Dr. Richardson. 

Dr. Richardson added that a large Phase 3 trial with Revlimid and low-dose dexamethasone in combination with elotuzumab in patients with relapsed/refractory myeloma patients is anticipated to start in early 2011.

For more information about the three elotuzumab studies, please refer to abstract 3023, abstract 1936, and abstract 986 on the American Society of Hematology Meeting website.

Dr. Gareth Morgan of the Royal Marsden Hospital in London presented the results, recently published in The Lancet (abstract), at the American Society of Hematology (ASH) annual meeting in Orlando today.

“I think it is incredibly compelling that the Zometa-treated group has a statistically significantly longer overall survival that amounts to about 5.5 months, which I think is clinically significant,” stated Dr. Morgan.

According to Dr. Morgan, the increase in overall survival observed in Zometa patients are a result of inherent anti-cancer effects of Zometa rather than a decrease in skeletal-related events. He added that an analysis demonstrated that there was no relationship between a reduction in skeletal-related events and patient survival. Additionally, patients without myeloma bone disease experienced a survival benefit when treated with Zometa.

Multiple myeloma is commonly associated with a number of skeletal complications, including fractures, spinal cord compression, elevated calcium levels in the blood, and severe bone pain.

These complications arise as a result of skeletal weakening due to bone lesions. Bone lesions are the result of an under activity or absence of cells responsible for bone formation paired with the over activity of cells that degrade bone (see related Beacon news). Up to 90 percent of multiple myeloma patients may develop bone lesions over the course of their disease.

Zometa (zoledronic acid) and Bonefos (clodronate) are both bisphosphonates, which reduce bone loss and fractures by inhibiting the specialized cells that breakdown bone. Zometa is approved for use in the United States, and Bonefos, while not approved for use in the United States, is currently approved in Canada, the United Kingdom, and Italy.

Previous pre-clinical and clinical trials have indicated that Zometa may have anti-cancer effects, in addition to preventing bone loss and related complications. However, no clinical trials have shown that Zometa has anti-myeloma effects.

Dr. Morgan and his colleagues compared the anti-myeloma effects of Zometa to Bonefos by evaluating the effect of the two drugs on overall survival and progression-free survival in myeloma patients. They also evaluated the drugs’ effects on skeletal-related events.

A total of 1,960 newly diagnosed multiple myeloma patients participated in the study. Each participant received either Zometa or Bonefos following induction therapy. Patients followed intensive or non-intensive pathways, which differed in terms of the induction regimen used and whether or not patients underwent a stem cell transplant.  After bisphosphonate treatment, all patients also had the option of receiving maintenance treatment with thalidomide (Thalomid).

In the intensive treatment group, the patients who received thalidomide (Thalomid) had a statistically significant higher percentage of complete responses and very good partial responses than those who did not. 

Though it was not statistically significant, Dr. Morgan noted that a higher percentage of patients in the intensive treatment group receiving Zometa achieved complete and very good partial responses (36 percent) than those receiving Bonefos (34.7 percent).

In the non-intensive treatment group, however, there was a statistically significant improvement in response rates for patients receiving Zometa compared to those receiving Bonefos.

At a median follow-up of 3.7 years, patients taking Zometa had a 16 percent reduced risk of death compared to those on Bonefos.  Likewise, Zometa improved progression-free survival by 12 percent compared with Bonefos.

Of the patients taking Zometa, 27 percent experienced a skeletal-related event, compared to 35 percent taking Bonefos. The reduction in skeletal-related events was observed regardless of whether or not patients had bone disease when they enrolled in the trial.

Dr. Morgan also noted that for elderly patients in the non-intensive treatment group, the risk of bone disease was further reduced in those patients who received thalidomide as part of their induction therapy. 

Side effects were minimal for both treatments, and there was no difference in kidney function deterioration among the Bonefos and Zometa groups. However, the rate of osteonecrosis of the jaw, a condition that is associated with a loss of blood supply to the jaw resulting in jawbone death, was higher in the Zometa group (4 percent) compared to the Bonefos group (>1 percent).

For more information, please see abstract 311 on the American Society of Hematology meeting website and the Novartis press release.

Chromosomal abnormalities result from structural changes of the chromosome.  These changes may occur through deletions, insertions, duplications, or movement of chromosomal regions. Chromosomal abnormalities are considered high-risk factors in multiple myeloma and have been an area of intensive research because they may render patients less responsive to certain treatments.

A series of prior studies have investigated the outcome of myeloma patients with certain chromosomal abnormalities who received Revlimid (lenalidomide)-dexamethasone (Decadron) therapy (see related Beacon news).

The findings of these studies have not, however, been conclusive with regard to the significance of each abnormality. They also have not addressed the outcome of patients with chromosome 1 abnormalities, which are among the most common in myeloma patients.

In their study, the Canadian researchers evaluated the impact of chromosomal abnormalities on patient response to Revlimid-dexamethasone therapy.

They retrospectively analyzed data of 143 relapsed and refractory (treatment resistant) myeloma patients. Laboratory tests were conducted to determine the presence of chromosomal abnormalities.

Overall, the researchers found that 83 percent of patients responded to treatment, with 16 percent achieving a complete or near-complete response.

The researchers also found that only prior thalidomide (Thalomid) treatment, rather than chromosomal abnormalities, had a negative impact on the response rate. The overall response rate among previously thalidomide-treated patients was 76 percent, while 96 percent of patients who did not previously receive thalidomide responded to Revlimid-dexamethasone treatment.

At the median follow-up time of 22 months, 76 percent of patients showed disease progression.  The median time to disease progression was 11 months.

The researchers found that two chromosomal abnormalities were associated with shorter time to disease progression. Patients with del(1p21) had an average time to progression of 4.6 months compared to 13.9 months for patients without del(1p21).  Similarly, patients with del(17p) also had shorter times to progression (2.1 months) than those without it (12 months).

They also found that prior Velcade (bortezomib), thalidomide, and more than three previous therapies led to shorter time to disease progression.

At the last follow-up, the overall survival rate was 48 percent, with an average survival time of 28.2 months.

While patients with del(1p21) or del(17p) generally had shorter survival times (13.6 months and 7.1 months, respectively), the differences were not found to be statistically significant.

The researchers also found that prior Velcade therapy was associated with shorter survival.

The study authors pointed out that larger prospective studies are necessary to confirm their findings.

For more information, please see the article in Leukemia and Lymphoma (abstract).

Phase 2 Trials Of IPH 2101 Are Recruiting Myeloma And Smoldering Myeloma Patients – Several Phase 2 clinical trials are now recruiting multiple myeloma and smoldering multiple myeloma patients to receive the experimental agent IPH 2101 (anti-KIR). IPH 2101 is an antibody drug being developed by Innate Pharma. It helps activate cells of the immune system to destroy cancer cells. IPH 2101 is being studied in patients with smoldering myeloma to see if it delays and/or prevents progression to multiple myeloma (trial description). It is also being studied in multiple myeloma patients in stable partial response after a first line therapy (trial description) and in combination with Revlimid (lenalidomide) in myeloma patients experiencing their first relapse (trial description). To participate in the smoldering myeloma trial at the National Institutes of Health, please contact the research nurse, Mary Ann Yancey, at (301) 435-9227 or .

Phase 3 Double Transplant Trial Is Currently Recruiting Myeloma Patients – Myeloma patients are now being recruited by the Hackensack University Medical Center in New Jersey to participate in a Phase 3 trial of tandem stem cell transplants with melphalan (Alkeran) followed by melphalan and Velcade (bortezomib). The purpose of this trial is to determine if the addition of Velcade to the second transplant will increase remission times. For more information, please see the clinical trial description.

Based on the findings, the study investigators suggested that Velcade (bortezomib) treatment may be beneficial in patients with destructive bone disease.

However, in correspondence with the Myeloma Beacon, Dr. Chang-Ki Min, lead author of the study noted, “I believe that the incidental findings require additional studies. For example, clinical results such as response to Velcade or skeletal-related events [in this patient population] should be investigated.”

Dr. Kristy Weber, professor of orthopedics and oncology at the Johns Hopkins School of Medicine also cautioned that no serious conclusions could be drawn from such a small study.

Bone disease is a major complication associated with multiple myeloma. It is the result of two simultaneous events: an increase in activity of cells that degrade bone and also a decrease in activity of cells that form bone.

Many myeloma patients receive bisphosphonates as treatment for bone disease while undergoing anti-myeloma therapy. Bisphosphonates prevent further degradation of the bone. They do not, however, help reform lost bone mass.

Recent studies in mice have demonstrated that Velcade enhances the function of bone-forming cells. Furthermore, bone formation markers in the blood have been shown to increase in myeloma patients treated with Velcade.

The goal of this study was to determine the effect of Velcade on bone lesions resulting from multiple myeloma.

The study was comprised of two myeloma patients, both 61 year old males with bone disease in their spines.

The patients had varying treatment histories. The first was treated with vincristine (Oncovin), doxorubicin (Adriamycin), and dexamethasone (Decadron) prior to autologous stem cell transplantation. He achieved a very good partial response and maintained therapy with interferon and prednisone, but relapsed 18 months later. At this point, he developed additional bone lesions, was switched to Velcade therapy, and was monitored for bone formation.

The second patient was initially treated with Velcade, doxorubicin, and dexamethasone and achieved complete response after three cycles of therapy. He was monitored for bone formation prior to receiving an autologous stem cell transplant and maintenance therapy with thalidomide (Thalomid) and dexamethasone.

Bone scans were performed on both patients to determine the effect of Velcade on their lesions. After three cycles of Velcade treatment, both patients showed increased bone formation at the site of their lesions.

When asked if bisphosphonate treatment in addition to Velcade may reverse bone degradation, Dr. Min noted that some patients have shown reversal of bone lesions after Velcade and bisphosphonate treatment. However, Dr. Min has not performed any studies to confirm this observation.

For more information, see the study in the European Journal of Haematology (abstract).

According to Dr. Morie Gertz, myeloma expert at the Mayo Clinic in Rochester, Minnesota and lead author of the study, the difference in the repopulation of white blood cells was not clinically significant. “None of the critically important end points were affected” he told The Myeloma Beacon.

Based on their results, Dr. Gertz and his colleagues concluded that the administration of growth factors is no longer necessary following stem cell transplantation.

“We just don’t see a role for it. It’s just another medicine that can cause a side effect, and I’m not sure what the benefit is,” he said. “They were using growth factors 25 to 30 years ago, at the start of transplants. Now things have changed, and I think it’s no longer necessary.”

Growth factor administration is the current standard of care for multiple myeloma patients who have undergone stem cell transplantation. Growth factors, such as Neupogen (filgrastim), are used to increase the production of white blood cells following transplantation.

The use of Neupogen after transplantation procedures was established by studies performed 20 years ago. Since that time, transplantation methods and technologies have changed considerably.

In early transplant procedures, stem cells were collected directly from the bone marrow. Currently, they are collected from the circulating blood by less invasive and more efficient procedures. In addition, the introduction of better antibiotic, antifungal and antiviral treatments has effectively prevented the emergence of infections following transplantation.

In addition to procedural changes that may eliminate the need for Neupogen, there are also several rare but serious side effects associated with its administration. These side effects include acute respiratory distress syndrome, allergic reactions, hemorrhage in the lung, and rupture of the spleen.

Despite transplantation procedural improvements and the serious risks associated with growth factor administration, recommendations made as recently as 2006 still support the use of growth factors in the transplantation setting.

In a previous study, researchers at the Mayo Clinic found that the elimination of growth factor administration after stem cell transplantation in amyloidosis patients resulted in very little difference in white blood cell recovery rate.

Based on these results, the researchers at the Mayo Clinic stopped administrating Neupogen to multiple myeloma patients after stem cell transplantation.

Their current study reports the comparison between myeloma patients with or without Neupogen as part of their supportive care following stem cell transplantation.

The researchers compared data of 498 patients who received Neupogen following transplantation to 166 patients who did not.

They found that white blood cells were repopulated in an average of 12.5 days following transplantation for patients who received Neupogen compared to 13.5 for those who did not. Optimal platelet levels were achieved in an average of 14.5 days for both groups.

Furthermore, 52 percent of patients who did not receive Neupogen were never hospitalized compared to 38 percent of patients who received Neupogen. Patients who did not receive Neupogen had an average hospital stay of zero days compared to 3.5 days for patients who received Neupogen.

According to Dr. Gertz, the most common causes of hospitalization were nutritional failure, weakness that inhibited the patients to come to the outpatient facility every day, and fever that could not be controlled with outpatient antibiotics.

Bacterial infection was also more common in the Neupogen-treated group, with 39 percent testing positive for bacteria compared to 27 percent in the untreated group.

The researchers noted that in addition to improving the safety of the transplantation procedure, the elimination of Neupogen would also result in substantial cost savings.

For more information, please see the research article in Bone Marrow Transplantation (abstract).

Researchers from Beth Isreael Deaconess Medical Center and Dana Farber Cancer Institute designed an anti-myeloma vaccine by combining myeloma tumor cells with dendritic cells, a type of cell that helps activate the immune system. When administered to patients, the vaccine stimulates the immune system to form a response against myeloma proteins. As a result, the immune system recognizes myeloma cells as “foreign” and will destroy them. This form of cancer treatment, known as “immunotherapy,” may one day provide an alternative to chemotherapy or stem cell transplantation.

A total of 18 multiple myeloma patients were enrolled in the trial. Patients had received an average of four prior treatment regimens. Fourteen patients had previously undergone high-dose chemotherapy and autologous stem cell transplantation.

The dendritic cells used to create the vaccine were grown from a subset of white blood cells collected from each patient. Tumor cells were collected from the bone marrow of patients and combined with the dendritic cells prior to vaccination.

Patients were divided into three groups, each of which received a vaccination with a different concentration of dendritic and tumor cells.

Following vaccination, 11 patients demonstrated at least a two-fold increase in the percentage of tumor-reactive white blood cells. Researchers also found that vaccination generated antibodies to several proteins produced by the tumor cells.

Stable disease was achieved in 11 patients following vaccination.  The longest duration of ongoing stable disease without evidence of progression was 41 months, which was achieved by one patient. The shortest observed duration was 2.5 months and was seen in four patients.

The vaccine was well tolerated and did not result in decreased blood cell counts or auto-immunity, a condition in which the patient’s immune system attacks the patient’s own cells and tissues. The most common side effects were redness and pain at the vaccine injection site.

The researchers suggested future trials investigate the use of the vaccine in multiple myeloma patients who undergo vaccination soon after stem cell transplantation.

For more information, please see the article in the journal Blood (abstract).

Multiple myeloma is commonly associated with a number of skeletal complications, including fractures, spinal cord compression, elevated calcium levels in the blood, and severe bone pain.

These complications arise as a result of skeletal weakening due to bone lesions. Bone lesions are the result of an under activity or absence of cells responsible for bone formation paired with the over activity of cells that degrade bone (See related Beacon news). Up to 90 percent of multiple myeloma patients may develop bone lesions over the course of their disease.

Myeloma-associated bone lesions typically do not heal, even in patients who have been in remission for years. Skeletal complications may, therefore, create permanent disabilities, require surgical intervention, and even affect survival.

According to a recent review, fractures caused by bone lesions have been associated with a 44 percent increased risk of death in myeloma patients (for more information, see Seminars in Oncology).

Since the introduction of bisphosphonate treatment for bone disease, the number of myeloma patients requiring surgical intervention for skeletal complications has dropped below 10 percent, according to Dr. James Berenson of the Institute for Myeloma & Bone Cancer Research.

“Most commonly performed procedures are minimally invasive procedures for vertebral compression fractures including kyphoplasty or vertebroplasty, procedures for femoral [hip] or humeral [upper arm] fractures including rod placement,” explained Dr. Berenson.

For myeloma-related skeletal complications, surgical therapy is a form of palliative care.  It reduces the severity of disease symptoms and may improve quality of life, but does not necessarily stop disease progression or provide a cure.

“Patients who undergo these procedures have a marked improvement in their pain and mobility,” stated Dr. Berenson.

In this study, researchers determined which factors were associated with improved survival following palliative surgical treatments for skeletal complications.

The study included a total of 75 multiple myeloma patients who required surgical intervention for myeloma-related skeletal complications. Those who received surgery had, or were at risk for, bone lesion-associated fractures or were suffering from neurological impairment due to spine lesions.

For most of the study participants, lesions were located in the spine, thigh, and upper arm.

Before the procedure, all patients reported pain, 65 percent reported fractures, and 31 percent reported neurological impairment. Patients had experienced these symptoms for an average of 7.5 months.

A number of surgical procedures were performed, including removal of the lesion, implantation of prosthetic devices, vertebroplasty, kyphoplasty, and cement stabilization of the bone.

Follow up was performed between one and 25 years after surgery.

A total of 87 percent of patients survived more than one year after surgery. Five years post-surgery, 37 percent of patients were alive. The median survival was 4.7 years.

Patients who experienced symptoms of myeloma bone lesions for more than six months had shorter survival periods following surgery (2.2 years) than those who experienced symptoms for less than 6 months (4.9 years).

Patients with a single bone lesion survived 9.5 years compared to 3.7 years for patients with multiple lesions.

Similarly, patients with negative bone marrow biopsies survived longer (10 years) than those with positive biopsies (3.8 years).

Although patients diagnosed with advanced myeloma (Durie-Salmon stages II and III) had nearly identical survival times (3.66 and 3.33 years, respectively), patients diagnosed with early-stage myeloma (Durie-Salmon Stage I) survived significantly longer, an average of 9.5 years.

Patients with normal M-protein levels survived significantly longer (8.8 years) than patients with elevated M-protein levels (3.3 years). In multiple myeloma, the M-protein is overproduced by plasma cells and cannot effectively fight infections.

Location of bone lesions did not have a statistically significant impact on survival times following surgery.

For more information, please see the study in International Orthopaedics (abstract).

“Proliferation has long been known to be an adverse prognostic factor in myeloma, but it is quite laborious to measure it in the laboratory, and is thus not routinely measured in the large European trial groups,” explained Dr. Dirk Hose, lead author of the study, in correspondence with The Myeloma Beacon. His study showed that a procedure called gene expression profiling could help identify patients with rapidly growing plasma cells.

Factors that are currently used to differentiate multiple myeloma patients based on disease prognosis include the International Staging System (ISS), beta-2 microglobulin, lactate dehydrogenase (LDH), and chromosomal abnormalities.

The ISS is used to categorize patients’ disease statuses as stage I, stage II, or stage III. Each stage is given a median survival time. Stage I has a median survival time of 62 months, stage II is 44 months, and stage III is 29 months (see related Beacon news).

The ISS is based primarily on the serum beta-2 microglobulin test. High levels of beta-2 microglobulin, a protein found on the surface of white blood cells, indicate greater disease progression (see related Beacon news).

Measurement of LDH levels is another common blood test. LDH is a molecule present in the blood when tissues in the body are damaged.  Higher levels of LDH indicate a poorer prognosis (see related Beacon news).

Multiple myeloma is also associated with chromosomal abnormalities, which evolve with disease progression. Specifically, the chromosomal abnormalities del(13), t(4;14) or del(17p) are associated with a poorer prognosis in response to traditional chemotherapy (see related Beacon news).

Rapid cell growth has never been used as a prognostic factor in a large patient study because it was assumed that the conventional prognostic factors described above were able to account for all possible prognosis groups.

In this study, researchers were the first to demonstrate that a procedure called gene-expression profiling can be used to determine the growth of patient myeloma cell samples in a clinical setting. They showed the importance of rapid cell growth as a prognostic factor and identified a patient group that may have previously been overlooked using conventional prognostic factors. 

Two groups of 298 and 345 previously untreated, newly diagnosed multiple myeloma patients were studied. Myeloma cell samples obtained from patients were assessed for rapid cell growth using genetic profiling.

Of the two groups, 43.3 percent and 39.4 percent of myeloma cell samples had higher cell growth rates than normal plasma cells.

Myeloma cells from patients in advanced stages of disease or patients with the chromosomal abnormalities 1q21 gain or del(17p) had significantly higher cell growth rates. Patients with gains of chromosome 9, 15, or 19, however, had significantly lower cell growth rates.

Rapid cell growth was significantly predictive for event-free and overall survival in both patient groups and also allowed for risk differentiation. Patients with more rapidly growing cells had lower overall and event-free survival rates and were considered a high-risk group. The associated risk was found to be independent of conventional risk factors such as serum beta-2 microglobulin, ISS-stage, and high-risk associated chromosomal abnormalities.

Based on their findings, the authors suggested that detection of cell growth should be used in clinical settings. They indicated that rapid cell growth is a prognostic factor that can allow for targeted and more personalized treatment. 

Rapid cell growth can be stopped or slowed using anti-proliferative drugs that disrupt cell division. “We hope that the use of an additional anti-proliferative (add-on) treatment would overcome the adverse prognosis of patients with (highly) proliferating myeloma cells,” stated Dr. Hose.

Dr. Hose and his team are developing a novel anti-proliferative drug known as ELR510444 that has been shown to be active for myeloma in preclinical trials. “We hope to begin a Phase 1/2 trial in the fall of next year.” 

For more information, please see the study in Haematologica (pdf).

“Our findings underline the risk of VTE [blood cots] in the monoclonal gammopathies in general and might in this way serve to increase the awareness of this complication in myeloma patients,” stated Dr. Henrik Gregersen, of the Aalborg Hospital in Denmark and lead author of this study.

While some of the increased risk may be an innate feature of the disease, the researchers concluded that the numbers were not big enough to justify the use of medication to prevent clotting, such as aspirin or heparin, in patients with the precursor disease. Instead, they suggested patients be monitored for coexisting medical conditions that warrant the use of preventative medications.

Monoclonal gammopathy of undetermined significance (MGUS) is a blood disorder characterized by elevated levels of monoclonal protein. It is often found during testing for other disorders. Evidence suggests that MGUS may be a precursor of most cases of multiple myeloma (see related Beacon news). 

Three percent of Americans over the age of 50 are diagnosed with MGUS, 1 percent of whom are likely to develop multiple myeloma or other similar diseases.  The International Myeloma Working Group recently identified myeloma risk factors for patients with MGUS, including the amount of monoclonal protein, the type of monoclonal protein, the number of bone marrow plasma cells, and the free light chain ratio (see related Beacon news).

Recently, blood clots, or venous thromboembolism (VTE), have been identified as a complication of multiple myeloma.

Ten percent of newly diagnosed myeloma patients develop VTE while undergoing chemotherapy treatment. The risk of VTE is even higher for patients who receive a combination regimen of chemotherapy, steroids, and immunomodulatory agents, such as Revlimid (lenalidomide) and thalidomide (Thalomid) (see related Beacon news).

Several studies have been conducted to determine if MGUS patients share a similar increased risk of VTE as myeloma patients, but results have been inconsistent so far. 

Results are further complicated by the fact that most MGUS patients have additional medical conditions (called comorbidities) that may increase their risk of VTE.

“The comorbidity is high in patients with MGUS and many coexisting clinical conditions and diseases have been reported, including non-hematological cancers, chronic infections, neurological disorders, osteoporosis and fracture risk. All these diseases are also potential risk factors for VTE,” explained Dr. Gregersen.

As such, the goal of this study was to compare the risk and complications of VTE in a much larger and broader group of MGUS patients to the general population. 

A total of 1610 MGUS patients were enrolled in the study. The patients were followed until VTE occurred, their MGUS transformed into a cancerous condition or until they died. 

Researchers found that compared to the general population, MGUS patients enrolled in this study had a 37% higher risk of developing VTE.

The average time to VTE from the start of follow up was 5.6 years for MGUS patients and 6.2 years for the general population.

Among the MGUS patients, those with low B cell (cells that produce antibody), M-protein, monoclonal protein or light chain lambda (both proteins overproduced by B cells) levels were at increased risk for VTE.

Researchers also found that VTE was associated with poor survival in MGUS patients.  These finding confirmed those of a separate study while, in contrast, VTE has been found not to effect survival time in multiple myeloma patients.

For more information, please see the research article in the European Journal of Haematology (abstract).

Based on their findings, the researchers recommended 30 mg Aredia be administered to multiple myeloma patients for the prevention of bone disease.

“I believe that our study can lead to a reduction in the cost of treatment and maybe more importantly a reduction in the risk of long-term toxicity (e.g. osteonecrosis of the jaw and renal [kidney] failure),” said Dr. Peter Gimsing, professor at Copenhagen University and lead author of the study.

Dr. Gimsing pointed out that the minimal effective dose may be even lower than 30 mg.  To his knowledge, however, there are no studies being conducted to test this hypothesis.

Bone disease is frequently associated with multiple myeloma and can cause pain and fractures (see related Beacon news). While the symptoms of bone disease can be treated with radiation therapy and surgical fractures, bisphosphonates are currently the only available treatment that prevents bone disease.

Bisphosphonate therapy can decrease bone pain and prevent the development of fractures. Bisphosphonates do not, however, have antitumor effects and, therefore, do not treat the underlying causes of multiple myeloma.

Bisphosphonate treatment is associated with a number of severe side effects, including kidney damage and the loss of blood supply to the jaw (osteonecrosis), which can lead to death of the jawbone.

Due to kidney damage associated with bisphosphonate use, Dr. Gimsing noted that they should be used cautiously for limited periods of time in patients with kidney failure.

Aredia (pamidronate) is a commonly used bisphosphonate in multiple myeloma. It is administered intravenously once a month.

The dosage of Aredia that provides the maximum preventative effect against bone disease in multiple myeloma patients has not yet been determined. Prior Phase 3 trials of Aredia were conducted with the currently recommended dose of 90 mg.

In order to avoid side effects associated with Aredia treatment, the authors of this study felt that research needed to be done to determine the lowest effective dose.

To address this issue, the researchers compared the effect of a high (90 mg) and a low (30 mg) dose of Aredia in newly diagnosed multiple myeloma patients.

A total of 504 newly diagnosed multiple myeloma patients were enrolled in the study. Half of the patients received 90 mg of intravenous Aredia monthly, while the remaining participants received 30 mg monthly.

Patients were evaluated using a questionnaire. Physical function, fatigue, and pain were scored on a scale from 0 to 100. Radiological assessments were also carried out.

Following 12 months of Aredia treatment, both 30 mg and 90 mg treatment groups reported a similar improvement in physical function.

Prior to treatment, patients reported physical function scores close to 50 points. After 12 months of Aredia treatment, scores increased to 68 points and 66 points for 30 mg and 90 mg treatment groups, respectively.  These improvements were maintained for up to 36 months of Aredia treatment.

Both treatment groups also reported comparable improvements in pain, fatigue, and quality of life. Radiological findings were also consistent between the two groups.

Although patients in the 90 mg treatment group experienced skeletal events sooner (9.2 months) than those in 30 mg treatment group (10.2 months), these differences were not considered statistically significant.

While both doses of Aredia were equally effective, the severity of side effects varied between the two treatment groups. Fifteen patients in the 90 mg group were forced to stop treatment due to kidney damage associated with treatment, compared to seven patients in the 30 mg group.

Results also indicate an increased risk of osteonecrosis of the jaw for patients who received the 90 mg dose of Aredia. Eight patients in the 90 mg group developed osteonecrosis of the jaw, compared to two patients in the 30 mg group.

For more information, please see the study in The Lancet Oncology (abstract).

Istodax (romidepsin) is a cyclic peptide that inhibits an enzyme in cancer cells known as histone deacetylase (HDAC). By inhibiting HDAC, Istodax disrupts the cell cycle and causes cancer cell death. Istodax is marketed by Celgene Corporation and was approved by the FDA in November 2009 as a treatment for cutaneous T-cell lymphoma.

The clinical efficacy of HDAC inhibitors as single treatment agents for multiple myeloma has not been very promising so far. Dr. Ruben Niesvizky, the lead investigator of the Phase 2 Istodax trial, noted in email correspondence with The Myeloma Beacon that no HDAC inhibitor has previously shown clinical activity as a single agent.

This Phase 2 trial sought to evaluate the safety and efficacy of Istodax as a single agent therapy. It was also designed to provide a basis for Istodax’s integration into standard multiple myeloma therapies, such as Velcade (bortezomib), in the future.

Thirteen patients with recurrent and therapy-resistant (refractory) multiple myeloma were enrolled in the study.  Each had received at least two prior lines of therapy, including stem cell transplantation, Velcade, and thalidomide. 

Patients received 13 mg/m² of Istodax on days 1, 8, and 15 of a 28-day cycle. After one cycle, patients with progressive disease were excluded from the study while the remaining patients proceeded to the next treatment cycle.

The researchers found that Istodax did not produce any anti-cancer responses.

However, four patients (31 percent) exhibited stabilization of monoclonal (M) protein production during treatment. In multiple myeloma, the M-protein is overproduced by plasma cells and cannot effectively fight infections.

Istodax treatment also resolved high calcium levels in five patients and improved bone pain in two others. 

The only severe side effect caused by Istodax treatment was lowered platelet levels, experienced by 23 percent of patients. Other commonly experienced side effects were mild and included nausea and fatigue. 

While HDAC inhibitors may not be clinically effective on their own, previous studies have shown that other HDAC inhibitors enhance the effectiveness of standard multiple myeloma therapies, including Velcade and thalidomide (Thalomid).

Further studies are currently underway to evaluate the combination of HDAC inhibitors and Velcade for multiple myeloma.

“We are anxiously awaiting the results of the first randomized trial of [the HDAC inhibitor] Zolinza (vorinostat) and Velcade,” said Dr. Niesvizky. “This will dictate approval and future usage of the drug. Currently, these drugs are seldom used in relapsed and refractory patients, with mixed results.”

A Phase 1/2 trial evaluating the combination of Velcade and Istodax in relapsed multiple myeloma is currently recruiting patients. For more information, please see the clinical trial description. 

For more information on the Istodax single agent study, please refer to the journal Cancer (abstract) and the clinical trial description.

The researchers recommended that multiple myeloma patients receiving both Velcade (bortezomib) and itraconazole (Sporanox) be closely monitored for Velcade-induced side effects throughout the duration of their treatment. 

However, according to Dr. Paul Richardson of the Dana-Farber Cancer Institute in Boston the results of the study should be interpreted cautiously. “Patients from Japan can have unique toxicities,” he explained in an email to The Myeloma Beacon.

Itraconazole is used for the treatment of fungal infections. These infections most often begin in the lungs and may spread through the body. In addition to treating fungal infections in the lungs, itraconazole is also used to treat infections of the fingernails and toenails and yeast infections of the mouth and throat.

Fungal infections can occur in multiple myeloma patients. According to Dr. Craig Hofmeister of the Ohio State University Medical Center, however, fungal infections are “rare except for patients given higher doses of dexamethasone that have an increased risk of oral thrush (oral candida).  Invasive fungal infections are rare.”

Both Dr. Richardson and Dr. Hofmeister indicated to The Myeloma Beacon that they currently do not use itraconazole for the treatment of fungal infections.

Itraconazole works by inhibiting an enzyme needed for fungi to grow properly.  However, it also inhibits liver enzymes responsible for breaking down Velcade for excretion. 

The inhibition of these enzymes can cause Velcade to accumulate in the body, resulting in an increase in the severity of its side effects. This study sought to determine if the co-administration of itraconazole with Velcade worsened Velcade-induced side effects in relapsed myeloma patients.

Six Japanese patients were included in the study. All six patients received intravenous Velcade and oral dexamethasone (Decadron) as part of a 21-day treatment cycle. Half of the patients also received itraconazole in addition to Velcade and dexamethasone. 

Only the patients who received both Velcade and itraconazole experienced worsened nerve damage to the extremities (peripheral neuropathy). Velcade treatment was stopped for two of these patients, which was followed by an improvement in the damage.

All three patients who received both Velcade and itraconazole had severely low platelet levels (thrombocytopenia). They needed platelet transfusions before they could continue therapy. The patients who did not receive itraconazole did not experience as severe a loss of blood platelets.

The effect of other antifungal medications on Velcade-induced side effects has been investigated in at least two American studies.

One study investigated the use of ketoconazole (Nizoral) with Velcade in patients with solid tumors. Another study determined the side effects resulting from co-administration of omeprazole (Losec) with Velcade in patients with a variety of cancers, including multiple myeloma. Although these medications all treat fungal infections, they each inhibit different enzymes involved in the breakdown of Velcade.

Researchers in the first study found that ketoconazole slowed the clearance of Velcade from the liver. This resulted in a 35 percent increase in exposure to Velcade for patients who received both drugs.

Unlike the Japanese study, however, neither study found that the antifungals increased the severity of Velcade-induced side effects.

“It would be ideal if a group, such as Mayo Clinic, that has a clinical database with concomitant medications could analyze for an association between peripheral neuropathy, thrombocytopenia, and itraconazole or other medications interacting with [the enzyme] CYP3A4,” said Dr. Hofmeister.

For more information, please see the Pharmacotherapy (abstract).

Weakening of the vertebrae, the bones that make up the spine, can result in vertebral compression fractures. Though the most common cause of vertebral compression fractures is osteoporosis, they may also be caused by multiple myeloma tumors.

Patients with vertebral compression fractures often suffer from debilitating pain and may experience changes in their height. Non-surgical treatments for vertebral fractures include radiation, pain medication, short periods of bed rest, calcium and vitamin D supplementation, as well as the use of external back braces. Patients whose compression fractures do not respond to medical treatment can undergo surgical procedures to treat their fractures.

ArthroCare’s Contour device uses a movable, curved needle to displace soft bone, creating a space into which bone cement can be delivered to stabilize the fracture. It is used with vertebroplasty or kyphoplasty procedures, in which physicians use image guidance to inject bone cement through a hollow needle into the fractured bone.

The Contour device would most likely be used as an alternative to balloon kyphoplasty, in which an inflatable balloon is inserted through a needle into the fractured bone, creating a space for bone cement to be delivered after removal of the balloon.

Leakage of the cement out of the vertebrae is a potential complication of these procedures. In a new procedure, known as vesselplasty, a small bag is placed inside the vertebra before the addition of the bone cement to reduce the risk of cement leakage.

For more information, please see the ArthroCare press release.

Description:
BT-062 (news articles) is a toxic drug bound to an antibody that helps deliver the treatment to myeloma and other cancer cells. When the compound enters a cancer cell, it releases the toxic drug that ultimately kills the cell. In a Phase 1 trial, BT-062 demonstrated an acceptable and manageable safety profile as well as evidence of clinical efficacy.

Clinical Trials:
For a list of clinical trials studying BT-062 for the treatment of multiple myeloma, see ClinicalTrials.gov.

Website for BT-062: http://www.biotest.de/ww/en/pub/biotherapeutics/bt___062/multiple_myeloma/biotherapeutic_agent_bt_062.cfm

The researchers suggested that medication for the prevention of blood clots is not needed in newly diagnosed multiple myeloma patients receiving the combination treatment. However this recommendation was limited to Chinese patients only because the study was conducted in a population of Chinese patients.  

The findings cannot be conclusively applied to other ethnicities because the rate of complications resulting from blood clots varies greatly among different ethnicities.

African American patients are at the greatest risk for blood clot-related events, followed by Caucasians and Hispanics. 

Asians and Pacific Islanders, however, have a significantly lower risk of blood clot-related events. In one study, Asian and Pacific Islander cancer patients were 60 to 80 percent less likely to be diagnosed with a blood clot-related event than their Caucasian counterparts (for more information about ethnicity and blood clot complications, please refer to the abstract in Thrombosis Research).

The reason for these differences between ethnicities is still not entirely understood, but is likely a combination of environmental and genetic factors.

Dr. Hongfeng Guo, lead investigator of the study, explained that the increased risk of blood clot complications in Caucasian patients may be at least partially explained by specific genetic mutations in clotting factors. These mutations are very rare in the Chinese population, and, therefore, decrease the risk of blood clot formation.

The study findings do, however, confirm earlier studies conducted in Caucasian populations that suggest Velcade (bortezomib) provides protection against blood clots in multiple myeloma patients (for more information about these earlier studies, please refer to the British Journal of Haematology).

In addition, Dr. Guo further clarified in email correspondence with the Myeloma Beacon that the researchers’ findings may also be applied to other Asian populations and Asian Americans.

Patients with multiple myeloma have an increased risk of developing complications due to the formation of blood clots. Furthermore, the use of some multiple myeloma drugs, such as thalidomide (Thalomid) and Revlimid (lenalidomide), significantly increases the risk of blood clot complications.

The combination of thalidomide and dexamethasone (Decadron) is a common initial, or induction, therapy for myeloma patients. However, this treatment is known to greatly increase a patient’s risk for blood clot-related events.

Previous studies have shown that the rate of blood clot complications was low in myeloma patients who received Velcade in combination with dexamethasone. Although Velcade appears to lower the risk of blood clot complications, the mechanism by which Velcade accomplishes this is not fully understood.

In their study, the researchers sought to determine the effect of the addition of Velcade to thalidomide-dexamethasone induction therapy on the development of complications related to blood clots. 

A total of 32 Chinese patients who received Velcade-thalidomide-dexamethasone (VTD) therapy were included in the study.  Velcade was administered at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day cycle. Dexamethasone, at a dose of 20mg/day, was given on days 1 through 4 and 8 through 11. Thalidomide, at a dose of 100-1200mg/day, was administered daily. 

Anticoagulants, given to prevent the formation of blood clots, were not administered to patients in this study. 

Ninety-one percent of patients responded to the treatment. Nineteen percent of patients achieved a complete response, 13 percent achieved a very good partial response, and 59 percent achieved a partial response.

Complications resulting from blood clots were very low. Only one patient (3 percent) enrolled in the study experienced these complications.

Researchers added that further research is needed to fully understand how Velcade protects against blood clot-related events in multiple myeloma patients.

For more information, please see the study in Leukemia Research (abstract).

The researchers had reported earlier this summer that the addition of thalidomide (Thalomid) to Velcade (bortezomib), melphalan (Alkeran), and prednisone (referred to as VMPT), followed by long-term treatment with Velcade and thalidomide (VT), improved response rates and progression-free survival in elderly multiple myeloma patients compared to the current standard of care (see related Beacon news).

However, the researchers had to lower the Velcade dosage from a twice-weekly infusion to once-weekly because many patients discontinued treatment due to side effects, in particular peripheral neuropathy (nerve damage to the extremities that can cause pain and tingling sensations).

A total of 511 newly diagnosed multiple myeloma patients over the age of 65 were included in the study.  Of these patients, 139 received 1.3 mg/m² of Velcade twice a week before the researchers switched to once weekly dosing. The remaining 372 received 1.3 mg/m² of Velcade once weekly from the time of treatment initiation.

In their retrospective analysis, the researchers evaluated the impact of the reduced dosing schedule on patient outcomes and side effects. They were particularly interested in finding out if the once-weekly dosing schedule had an impact on the rate of peripheral neuropathy and treatment discontinuation.

The researchers found that there were no significant differences in response rates between patients receiving once- or twice-weekly Velcade.  Eighty-five percent of patients receiving once-weekly Velcade achieved a partial response or better, compared to 86 percent of patients receiving a twice-weekly dose.

The median progression-free survival time for patients receiving once-weekly Velcade was 33.1 months, compared to 31.7 months for patients receiving twice-weekly Velcade.

The three-year overall survival was also similar between the two treatment groups. Eighty-eight percent of patients in the once-weekly treatment group were alive three years after diagnosis, compared to 89 percent of patients in the twice-weekly treatment group.

The researchers explained that the reduction in Velcade dosage allowed patients to remain on treatment longer.  The average cumulative Velcade dose was similar between the two groups, resulting in similar efficacy.

Patients in the once-weekly Velcade treatment group received a median cumulative dose of 39.4 mg/m²_, which was similar to the 40.1 mg/m² median cumulative Velcade dose that patients received in the twice weekly treatment group.

Side effects related to reduced blood cell and platelet levels were similar between the treatment groups. The risk of severely low platelet levels was slightly lower in patients receiving Velcade once weekly.

However, the occurrence of side effects not related to blood cell counts was significantly lower in the once-weekly Velcade treatment group (35 percent) than in the twice-weekly Velcade treatment group (51 percent).

Most pronounced were differences in peripheral neuropathy between the two treatment groups. Eight percent of once-weekly treated patients experienced severe nerve damage, as opposed to 28 percent of those treated twice a week.

Of those patients treated with Velcade once a week, only 5 percent could not complete their full treatment schedule due to the severity of their nerve damage, as compared to 15 percent of those treated twice weekly.

Fewer patients in the once-weekly treatment group (17 percent) needed Velcade dose reductions due to nerve damage than patients in the twice-weekly treatment group (41 percent).

The rate of improvement or resolution of the treatment-induced nerve damage after completion of treatment in patients with moderate to severe nerve damage was similar between the two treatment groups (64 percent and 66 percent, respectively).

For more information, see the study in the journal Blood (abstract).

Biotest Pharmaceuticals Initiates Phase 1/2 Trial Of BT-062 For Multiple Myeloma – Biotest Pharmaceuticals has started recruiting patients with relapsed or refractory multiple myeloma for a Phase 1/2 clinical trial of BT-062. This initial trial will focus on determining BT-062’s safety, anti-tumor activity, and dosage limits. BT-062 is a toxic drug bound to an antibody that helps deliver the treatment to cancer cells. For more information, please see the clinical trial description and the Biotest website.

Cylene Initiates Phase 1 Trial of CX-4945 For Multiple Myeloma – Cylene Pharmaceuticals has started recruiting patients with relapsed or refractory multiple myeloma for a Phase 1 clinical trial of CX-4945. The Phase 1 study is designed to test CX-4945’s safety, tolerability, and dosage limits. CX-4945 is an oral CK2 inhibitor, a class of drugs that causes cell death in cancerous cells. A separate Phase 1 trial will also be conducted to determine the use of CX-4945 for the treatment of solid tumors. For more information, please see the Cylene press release and the clinical trial description.

Minnesota Cancer Researchers Receive $26 Million To Study Stem Cell Therapies – Dr. Philip McGlave and Dr. Jeffrey Miller, researchers at the University of Minnesota’s Masonic Cancer Center, will receive $26 million from the National Institutes of Health to continue their study of stem cell therapies used to treat blood and bone cancers, among other disorders. Dr. McGlave’s research will focus on improving stem cell transplants and cell-based treatments, while Dr. Miller will continue research on the immune system to reduce the rate of relapse of leukemia after stem cell transplantation. They will also collaborate with blood and bone marrow experts at cancer centers throughout the country. For more information, please see the University of Minnesota press release.

Signal Genetics And Array BioPharma Partner To Advance Personalized Medicine In Multiple Myeloma – Signal Genetics, a predictive genetic testing company focused on oncology, recently announced the company will work with Array BioPharma to identify patients for treatment using genetic markers. Signal Genetics’ genomic testing instrument, MyPRS, will be used to provide Array BioPharma with genetic information during clinical trials for its multiple myeloma drug candidate, ARRY-520. This collaboration may lead to the development of personalized treatment options for myeloma patients based on genetic markers. For more information, please see the Signal Genetics press release (pdf) and the Array BioPharma website.

Multiple myeloma affects plasma cells, a subset of white blood cells that fight infections by producing antibody. In multiple myeloma patients, cancerous plasma cells produce one kind of abnormal antibody.

In some myeloma patients, this abnormal antibody binds to a protein produced in the kidney.  These antibody-protein complexes then accumulate in the structures of the kidney, causing damage and decreased kidney function.

Kidney damage is a common and potentially serious complication in multiple myeloma. Reversal of this damage can only be achieved by preventing the accumulation of protein-antibody complexes in the kidney.

Previous studies have suggested that Velcade (bortezomib) and Velcade-based regimens are particularly effective in reversing kidney damage in multiple myeloma patients.

Additionally, the active compounds in Velcade are broken down in the body through processes that do not involve the kidneys. As a result, Velcade does not interfere with kidney function and usually does not cause kidney-related side effects.

In this clinical trial, researchers investigated the efficacy of Velcade-doxorubicin (Adriamycin)-dexamethasone (Decadron) (referred to as VDD) in myeloma patients with antibody-associated kidney damage and the treatment’s potential of restoring kidney function in this patient population.

Sixty-eight multiple myeloma patients with antibody-associated kidney damage were treated with VDD. During the study, patients received a median of eight treatment cycles.

A total of 66 percent of patients achieved a partial response or better, and 38 percent of patients achieved a complete response.

Sixty-two percent of patients showed improved kidney function with VDD treatment. Kidney function was restored in 31 percent of patients.

Nine patients enrolled in the study were receiving dialysis due to severe impairment of kidney function. Three of these nine patients became dialysis-independent following treatment.

Researchers noted that kidney improvement correlated with response to treatment. Patients who achieved a complete or very good partial response showed the greatest improvement in kidney function.

Median progression-free survival time was 12 months, and the median overall survival time had not yet been reached.

Low red blood cell count was the most common and severe side effect of the treatment and was experienced by 50 percent of patients in the study.

Infection was the most severe side effect not related to blood cell levels. Serious infections were experienced by 19 percent of patients and resulted in four patient deaths.

For more information, see the article in the Journal of Clinical Oncology (abstract).

Treatment with high-dose chemotherapy followed by stem cell transplantion is a standard therapeutic approach for younger, newly diagnosed multiple myeloma patients.  High-dose chemotherapy prior to stem cell transplantation, often called a conditioning regimen, is administered with the intention of eliminating cancerous cells from the patient’s bone marrow. 

High-dose melphalan (Alkeran), administered as a single dose of 200 mg/m², is currently the most widely accepted conditioning regimen for multiple myeloma.

According to the study authors, little research has focused on improving the efficacy of the conditioning regimen by combining melphalan with other treatments, which may help improve stem cell transplantation outcomes.

Results from preclinical studies suggest that treatment with melphalan in combination with Velcade (bortezomib) may result in increased myeloma cell death. However, it is not clear if Velcade should be administered before or after melphalan to maximize the synergistic effect of the drugs.

In their study, the researchers sought to determine if the sequence in which Velcade and high-dose melphalan were given before stem cell transplantation affected the efficacy and side effects of the regimen.  They also sought to determine the maximum tolerated dose of Velcade that could be administered with high-dose melphalan.

The researchers recruited 39 newly diagnosed multiple myeloma patients who were divided into two treatment groups.

In the first, patients received Velcade treatment 24 hours prior to high-dose melphalan.  In the second, patients received Velcade 24 hours after high-dose melphalan was administered. 

Within these treatment groups, patients received either 1.0 mg/m², 1.3 mg/m², or 1.6 mg/m² Velcade, administered in a single dose.  These doses were used to determine the maximum tolerated dose that could be administered with melphalan.

Researchers found that of the patients who received Velcade after high-dose melphalan, 55 percent achieved a very good partial response or better within 100 days after the transplant compared to 47 percent of those who received Velcade prior to high-dose melphalan.

Patients who received Velcade after high-dose melphalan had a higher rate of complete response (30 percent) than those treated with Velcade prior to high-dose melphalan (11 percent). 

There were no differences in the progression-free survival or the overall survival of patients between treatment groups.  For both groups, the overall survival rate was 36.7 months and progression-free survival was 15.3 months.

After conditioning therapy, researchers compared the number of cancerous cells still present in the bone marrow between treatment groups.  Although they found that a greater reduction of cancerous cells was achieved whenVelcade was administered after melphalan therapy, results between treatment groups were not found to be statistically different.

Side effects of Velcade and high-dose melphalan were not different or more severe than those seen with high-dose melphalan alone.  This was true even for patients who received the highest doses of Velcade. 

The study authors suggested that randomized clinical trials be conducted to investigate the efficacy of this regimen compared to melphalan alone.

For more information, please see the study in Clinical Cancer Research (abstract).

However, both treatment combinations were associated with an inferior response in patients with a deletion in chromosome 17. Additionally, prior resistance to thalidomide, increases in certain enzyme levels, and the presence of tumor cells outside of the bone marrow were also associated with poor outcomes in response to Revlimid-dexamethasone with or without Velcade.

In this recently published study, Greek researchers compared the efficacy of Revlimid (lenalidomide)-Velcade (bortezomib)-dexamethasone (Decadron) (RVD) treatment to Revlimid-dexamethasone (RD) treatment in relapsed or therapy-resistant (refractory) multiple myeloma patients.

A prior Phase 2 clinical trial showed that RVD treatment increased response rates compared to RD treatment alone in relapsed and refractory myeloma patients.

It is unknown, however, whether RVD treatment can overcome the poor outcomes associated with chromosomal abnormalities in this subset of patients.

The Greek researchers therefore included pre-treated relapsed and refractory myeloma patients with a variety of chromosomal mutations in their study.

Since Velcade is known to cause nerve damage, patients with severe nerve damage, a result of prior treatment, were given the RD combination without Velcade. Patients who had milder nerve damage received the RVD treatment. A total of 50 patients received RD, and 49 patients received RVD.

The response rates and the quality of responses were similar between RVD and RD-treated patients, with 63 percent and 61 percent of patients, respectively, achieving at least a partial response.

Response rates were lower in patients with high-risk chromosomal abnormalities in both treatment groups.  However, 55 percent of patients with chromosomal abnormalities responded when treated with RVD compared to 31 percent of patients treated with RD.

Further analysis revealed that a deletion in chromosome 17, prior thalidomide resistance, the presence of plasma cell tumors outside the bone marrow, and increased levels of an enzyme responsible for processing lactate were all associated with a poor response to both RVD and RD treatment.

The time to disease progression in both RVD and RD treatment groups (7 months and 9 months, respectively) were not statistically different. However, patients with high-risk chromosomal abnormalities had a significantly lower time to disease progression of 5.6 months. Patients with a deletion in chromosome 17 had the shortest time to disease progression (2 months).

Researchers did not observe any difference in overall survival among patients treated with RD or RVD. However, patients with chromosomal abnormalities who received RD treatment showed shorter overall survival than patients with chromosomal abnormalities who received RVD treatment.

The most common side effect of treatment was nerve damage to the extremities. This was more common in RVD-treated patients, with 66 percent of patients suffering from nerve damage over the course of treatment.  Of those treated with RD therapy, 30 percent experienced a worsening of their already existent nerve damage.

The researchers suggested that more clinical trials be conducted to determine the optimal treatment sequence of novel agents in patients with chromosomal abnormalities.

For more information, please see the study in Leukemia (abstract).

“Back in 2003, very few doctors knew what amyloidosis was, had ever seen it, or treated it. I dare say that a lot of doctors had never even seen the word or read anything about it,” stated Wilson.

Amyloidosis is a disease that affects organs such as the heart, liver and kidneys. It is caused by the accumulation of proteins in these organs. A form of amyloidosis is associated with multiple myeloma and can have an impact on treatment options (please see the related Beacon news article for more information on multiple myeloma-associated amyloidosis).

Leading up to Wilson being diagnosed with myeloma, she first started experiencing ankle swelling and remembered being surprised about it because she was quite active as a teacher and worked out regularly at the gym.

The symptoms crept up so slowly that at first, she did not associate them with anything out of the ordinary. “You take a mental note of it, but it’s not bad, not bad enough for you to go to the doctor for it,” she said of the symptoms.  “You just kind of ignore it, and it goes away. So, some of the early symptoms might be missed even by the patient. Not until something actually hits you with a two-by-four do you go, ‘Whoa, this is not normal.’”

Further complicating her diagnosis, the onset of Wilson’s symptoms coincided with menopause. As she suffered with swollen ankles and heart palpitations, she assumed she was simply experiencing symptoms of menopause.

Both her physician and a cardiologist recommended she avoid salt and elevate her feet to reduce the swelling in her legs. It was not until she saw her gynecologist and received some routine blood work that her doctors began to suspect something was amiss.

Wilson’s serum protein levels were low and her cholesterol, which had always been normal, was very high, both indications of kidney disease. She was referred to a nephrologist. She was diagnosed with nephrotic syndrome, a kidney disorder that results in too much protein being excreted in the urine, leading to swelling throughout the body (edema).

Her nephrologist did further testing to determine the underlying cause of her nephrotic syndrome. It was then that Wilson was referred to an oncologist.  She agreed to a bone marrow biopsy, which came back positive for M protein. “And then the doctor told me, ‘Well, you have multiple myeloma,’” to which Wilson responded, “Ok, so let’s start treating!”

She was put on melphalan (Alkeran) and prednisone, which was the standard first-line treatment for myeloma in 2003.  Though she responded hematologically to treatment, meaning her M protein and plasma cell levels returned to normal range, Wilson still suffered with edema.

Her doctors were puzzled; she remembered them questioning, “Hematologically, you’re responding to treatment, but why aren’t your kidneys responding?”

Despite her ongoing kidney involvement, her treating oncologist and specialists at the Moffitt Cancer Center, where Wilson went for a second opinion, did not biopsy her kidneys. “Nobody wanted me to have a kidney biopsy because they said the treatment would be the same,” Wilson said.

It was not until after she switched to a new oncologist that she was urged to have a kidney biopsy.

Her kidney biopsy was sent for Congo red staining, the only definitive test to confirm for amyloidosis.  She was diagnosed with amyloidosis, and her new oncologist suggested she talk to Dr. Brian Durie, a myeloma expert at Cedars-Senai Medical Center in Los Angeles.

Meanwhile, Wilson’s edema worsened, and she had to be hospitalized. “I was on thalidomide (Thalomid) and dexamethasone (Decadron), and that wrecked havoc on everything. I was a walking Michelin man, and my legs were so swollen they were actually weeping.”

She talked to Dr. Durie during her hospital stay. He recommended she see a specialist at the Mayo Clinic in Rochester, Minnesota. She contacted the Mayo Clinic right away and received a call from Dr. Angela Dispenzieri within days.

It was then that Wilson learned of the complications thalidomide treatment has for amyloidosis patients. Dr. Dispenzieri informed her that thalidomide is known to cause further organ damage to organs effected by amyloidosis, which in Wilson’s case were her kidneys.

She went to the Mayo Clinic to see Dr. Dispenzieri for the first time in November 2003. They discussed the possibility of stem cell transplant, and although she underwent stem cell harvesting, Wilson ultimately decided against the transplant.

In retrospect, Wilson is glad she decided against the transplant because, at the time, her serum protein levels were low and she had gained weight because of the harvesting procedure. “Those two things, independently are bad risk indicators, so either one of those did not give me good odds to survive stem cell transplant,” said Wilson.

Wilson and her doctor decided to pursue a different protocol. “The last one I did was Velcade (bortezomib), and I ended that April 2009. I was declared in remission,” she said.

As of today, Wilson is no longer being treated for amyloidosis or multiple myeloma.  Because of the damage left to her kidneys as a result of amyloidosis and its treatment, she is still treated for nephrotic syndrome with diuretics and Lipitor (atorvastatin calcium).

Survival instinct was what kept her going in the fight against her diseases. “I don’t want to die, I want to feel good,” is what Wilson kept telling herself. She decided “to educate myself to what is potentially going to give me the best odds, the best outcome, the best quality.”

Wilson has found exercise to be the most important component of her recovery. “The number one health improvement factor is exercise,” she said. After her diagnosis, she took up Tai Chi, a form of relaxation and meditation she found therapeutic during her multiple myeloma and amyloidosis treatment.

Wilson also does yoga and recently completed a 5k run, both remarkable feats for someone who could not even sit Indian style on the floor when her legs and knees were swollen with edema. “I have to move, and the more I move, swim, and walk, the better I feel.”

“I’ve started to be my old self, more and more.  As I age, I feel I have some time to make up, so I can really subtract those years [with myeloma and amyloidosis] from my chronological age!” she said, laughing. “Those don’t count, so we’re going back to 54!”

Wilson had plenty of good advice for other patients: “Number one, get on a support group and ask questions.”

She also encouraged patients to get a second opinion and learn as much as possible about the disease. “You need to make sure you are up-to-date and that you verify everything you read. And that is not just for myeloma and amyloidosis. That is for an herbal remedy or whatever. Cross reference everything,” she advised.

The following article describes amyloidosis as it relates to multiple myeloma and includes some of the current treatment recommendations for patients with this dual diagnosis.

What Is Amyloidosis?

Amyloidosis occurs when proteins accumulate in organs such as the heart, kidney, liver, or intestines. 

There are three major types of amyloidosis: primary, secondary, and hereditary.  Each type of amyloidosis is classified by its underlying causes and the type of protein that accumulates in organs. 

Primary amyloidosis is the most common form of amyloidosis and the only form that occurs with multiple myeloma. It is caused by fragments of abnormal antibodies (called light chains). These light chains stick to one another and accumulate in organs throughout the body. Although the exact cause of primary amyloidosis is unknown, the disease starts in the bone marrow.

Secondary amyloidosis is caused by a chronic infection or inflammatory disease such as rheumatoid arthritis. Treatment of the underlying chronic infection or inflammatory disease can slow or stop the progression of this type of amyloidosis.

Hereditary amyloidosis is a rare type of the disease and the only type that is inherited.  Most commonly, a mutation of a protein made in the liver leads to protein accumulation in organs for this type of amyloidosis. 

Occurrence Of Multiple Myeloma-Associated Amyloidosis

Multiple myeloma is a cancer of the plasma cells. These cells are an important part of the immune system responsible for the production of antibodies, which are one of the body’s first defenses against infection. In multiple myeloma, the plasma cells overproduce one type of abnormal antibody. 

The overproduction of abnormal antibodies puts myeloma patients at risk for developing amyloidosis.

Not all multiple myeloma patients will develop amyloidosis.  “Every light chain is a little different,” explained Dr. Rafael Fonseca of the Mayo Clinic.

He added that patients with amyloidosis have light chains with a shape that make them more prone to stick to one another.

It is estimated that 10 to 15 percent of multiple myeloma patients will experience symptoms from the development of amyloidosis during the course of their disease.  However, as many as 38 percent of myeloma patients may develop amyloidosis but experience none of its symptoms.

Symptoms

The symptoms of amyloidosis depend upon which organs are involved and how much protein has accumulated in them. 

One of the hallmark symptoms of amyloidosis is swelling of the tongue.  This is caused by the accumulation of light chains in the intestine and digestive system.  Accumulation in the intestine can also cause a loss of appetite, diarrhea, and chronic nausea.     

The nervous system is also a common site of protein accumulation.  Resulting nerve damage can cause carpal tunnel syndrome (pressure on the median nerve in the wrist), another characteristic symptom of amyloidosis in multiple myeloma patients. 

Other symptoms involving the nervous system include tingling, prickling, and numbness in the upper and lower extremities. 

An additional symptom unique to amyloidosis is bruising around the eyes.  This can occur when proteins accumulate in the tissues that connect, support, or surround other structures and organs of the body.

Other common symptoms include fatigue, weight loss, shortness of breath, swelling of the legs, and enlargement of the liver.

Researchers note, however, that the presence of symptoms alone is not enough to diagnose amyloidosis. 

In order to confirm the diagnosis, a fine needle abdominal fat pad biopsy, rectal mucosa biopsy, or a bone marrow biopsy must be performed, and patients must meet the criteria defined by chemical testing of the biopsy.

Treatment

Treatment for amyloidosis is aimed at reducing or eliminating the plasma cells that are responsible for the production of the abnormal light chain proteins.  Such treatment reduces the accumulation of light chains throughout the body, which can alleviate some of the symptoms associated with amyloidosis.

Treatment for amyloidosis is similar to treatment for multiple myeloma. “Currently, many treatments can be used for both [multiple myeloma and amyloidosis]” said Dr. Fonseca.

Patients typically receive a stem cell transplant along with high-dose chemotherapy.

Patients who are not eligible for stem cell transplantation may receive oral melphalan (Alkeran) and prednisone. They may also be treated with intravenous chemotherapy in the form of medium- or high-dose melphahlan or vincristine (Oncovin)-doxorubicin (Adriamycin)-cyclophosphamide (Cytotoxan).

The use of Velcade (bortezomib) and Revlimid (lenalidomide) for the treatment of amyloidosis is currently being studied.  Initial trial results suggest that these drugs are effective for the treatment of amyloidosis patients.

The treatment of amyloidosis is, however, more challenging than treatment for multiple myeloma due to the associated organ damage.  Particularly unfavorable from a treatment standpoint is damage to the heart and kidneys. 

When considering the dual treatment of multiple myeloma and amyloidosis, complications due to organ involvement must be taken into account. 

To date, research on the simultaneous treatment of amyloidosis and multiple myeloma has been focused mainly on special considerations regarding induction and high-dose melphalan therapies.

Induction Therapy   

A patient’s first treatment regimen of chemotherapy drugs is called induction therapy. The goal of induction therapy is to control the myeloma, reduce tumors, and enhance stem cell collection for transplantation.

According to a study published in Bone Marrow Transplantation, in patients diagnosed with amyloidosis alone, induction therapy has been shown to provide no additional benefit prior to stem cell transplantation than transplantation alone. 

In fact, delaying the transplant by nine weeks for induction therapy prevented 13 percent of patients from continuing to transplant due to progression of their amyloidosis, ultimately resulting in death.

Based on this study, current recommendations suggest physicians treat myeloma-associated amyloidosis patients directly with stem cell transplantation.

If induction therapy is needed to reduce tumors prior to stem cell collection, it is recommended that patients receive a short course of dexamethasone (Decadron).  It is further cautioned not to delay stem cell transplantation to achieve maximal or complete response during induction therapy.

High-Dose Melphalan Treatment

Currently, high-dose melphalan treatment given in combination with stem cell transplantation is the treatment of choice for selected myeloma patients.  Damage to organs in amyloidosis patients, however, puts them at higher risk for treatment complications, which may result in death. 

Some studies report that as many as 45 percent of amyloidosis patients may experience life-threatening complications resulting from high-dose melphalan therapy and stem cell transplantation, as compared to less than 2 percent of multiple myeloma patients.

It is known that patients with amyloidosis alone may require a reduction in melphalan dosage if they have heart involvement or damage to more than two organs.  In these patients, the conventional melphalan dosage of 200 mg/m² may result in life-threatening complications following stem cell transplantation.

Recent studies conducted at both the Boston University Medical Center (abstract) and the Mayo Clinic (abstract) suggest similar findings in patients with both myeloma and amyloidosis. 

The Boston University study demonstrated that patients with both diseases had a higher rate of treatment-related deaths and a lower complete response rate than patients with the individual diseases alone. 

Furthermore, in the Mayo Clinic study, researchers demonstrated that patients with involvement of the heart, kidney, or more than two organs were less likely to proceed to stem cell transplantation. These patients also had a worse outcome compared to patients with no symptomatic organ involvement.

Most often, multiple myeloma patients with amyloidosis are excluded from clinical trials.  As a result, little is known regarding the response of these patients to novel agents. 

In order to get a full understanding of this unique subset of patients, researchers stress that it will be important to include them in clinical trials moving forward.

Amyloidosis Support Groups

Those battling amyloidosis can feel overwhelmed and isolated by the diagnosis of the rare disease. Muriel Finkel, President and founder of Amyloidosis Support Groups, lost a close family relative to amyloidosis. She started organizing support groups for amyloidosis patients, caregivers, and families in 2004 to ensure that people do not “feel all alone the way my husband and I did,” she said.

Today, seven years after its start, Amyloidosis Support Groups provide patients with an array of resources, from over 20 support groups across the United States to a 24/7 toll-free hotline as well as information about the disease, including ongoing and upcoming clinical trials.

Amyloidosis Support Groups have also assembled a medical board of advisors who are available to answer patient’s questions about the disease.  “We are a messenger to help people be more aware,” said Finkel.

And a messenger is something patients look for when they are diagnosed. “We patients, we read everything that comes out,” said Kathy Wilson, a patient who was diagnosed with multiple myeloma and amyloidosis in 2003. “And Muriel, she sends it to us! She doesn’t let us miss anything!”

The Myeloma Beacon will soon be featuring an interview with Kathy, in which she will share her experiences with multiple myeloma and amyloidosis.

Over the past decade, the life expectancy of multiple myeloma patients has improved. Currently, most multiple myeloma patients are projected to live 7 to 10 years with good quality of life. Multiple myeloma remains, however, an incurable disease for most patients.

Allogeneic (donor) stem cell transplantation is currently the only treatment option that has the potential to cure multiple myeloma. In donor stem cell transplantation, patients undergo chemotherapy to kill off the myeloma cells and then receive stem cells from a donor to replenish their blood cells.

Despite its therapeutic potential, the use of donor stem cell transplantation is highly debated in the medical field due to the safety risks and rate of relapse. After a stem cell transplant, patients may experience bleeding, infection, and graft-versus-host disease, a complication when transplanted stem cells attack the patient’s body.

In its recently published report, the International Myeloma Working Group (IMWG) made recommendations based on the review of stem cell transplant registries and studies that used several different transplant protocols.

Full Donor Stem Cell Transplants

The IMWG reviewed three transplant registries that contain data on patients who received myeloablative allogeneic (full donor) stem cell transplants. The goal of this type of transplant is to eradicate all myeloma cells before donor stem cells are transplanted into the patient to re-grow new blood cells.

The IMWG also reviewed several clinical trials that compared full donor transplants to autologous transplants. In an autologous transplant, a patient’s own stem cells are collected before intense therapy to kill the myeloma cells, and then the patient’s stem cells are transplanted back afterward. Because the patient’s own stem cells are used in an autologous transplant, it is associated with fewer complications than a donor transplant.

A review of these registries and studies revealed that full donor stem cell transplants were associated with high treatment-related mortality. The lowest reported percentage of treatment-related mortality among these registries and studies was 30 percent, though most groups reported at least 40 percent. The IMWG wrote that a 30 percent or higher mortality rate is “unacceptably high.”

The experts concluded that although myeloablative therapy proved effective for a small percentage of patients, it is not a good option for patients with multiple myeloma who can be treated with autologous stem cell transplantation.

Since treatment-related mortality is improving for full donor stem cell transplants, the IMWG suggested that these transplants could be further studied in well-designed clinical trials.

Reduced-Intensity Donor Stem Cell Transplants

As compared to full donor transplants, the IMWG found that non-myeloablative (also called mini or reduced-intensity conditioning) donor stem cell transplantation, either alone or preceded by autologous transplantation, was associated with a lower treatment-related mortality, as low as 9 percent in two studies. However, patients undergoing the reduced-intensity regimen were twice as likely to relapse (54 percent versus 27 percent).

The IMWG did not find convincing evidence during its review to suggest that donor stem cell transplantation improved survival compared to autologous stem cell transplantation. The group recommended that reduced-intensity donor transplants only be used in clinical trials.

Donor Transplantation In High-Risk Myeloma Patients

Likewise, the IMWG did not find convincing data to support the use of donor stem cell transplantation for patients with high-risk myeloma. However, many of the studies included small numbers of patients.

The IMWG wrote that a full donor transplant may be considered for “exceptional cases” in which the patients are “aware of their unfavorable prognosis and accept the risks of myeloablative conditioning.” The group suggested further studies in patients with chromosomal abnormalities t(4;14), t(14;16), and 17p- as well as patients who do not achieve at least a very good partial response after autologous transplantation.

Improving Donor Transplants

The IMWG stressed that future studies of donor stem cell transplantation be aimed at improving the efficacy and safety of the procedure.

They highlighted the need to better understand the graft-versus-myeloma effect to improve efficacy and the need to better manage graft-versus-host-disease to improve safety.

They also suggested that novel agents, such as thalidomide (Thalomid), Revlimid (lenalidomide), and Velcade (bortezomib), might improve the efficacy of donor stem cell transplantation. They cautioned, however, that the optimal timing and dosage of such protocols has not yet been determined.

For more information, please see the study in the Journal of Clinical Oncology (abstract).

 “Low-dose thalidomide was well tolerated, and serious side effects described with high or even intermediate doses were diminished,” said Dr. Anna Dmoszynska, the lead author of the study, in an email to the Beacon.

In recent years, thalidomide (Thalomid) has proven to be an effective therapy for multiple myeloma when given alone or in combination with other drugs. One such combination consists of cyclophosphamide, thalidomide, and dexamethasone (Decadron).

The results of a study published in March showed that this therapy, commonly referred to as CTD, is effective for newly diagnosed multiple myeloma patients (see related Beacon news).

However, treatment with thalidomide is associated with an increased risk of blood clot formation and nerve damage.

The goal of the Polish study was to determine the safety and efficacy of CTD with low-dose thalidomide as a therapy for newly diagnosed multiple myeloma patients prior to stem cell transplantation as well as salvage therapy in relapsed and treatment-resistant (refractory) myeloma patients.

Low-dose thalidomide (100 mg) was used in an attempt to decrease side effects observed at higher doses (300 mg to 800 mg).

A total of 132 patients were included in the study, 64 of whom were newly diagnosed and 68 of whom had received prior treatment.

Patients received cyclophosphamide (625 mg/m² orally on day 1), thalidomide (100 mg orally on days 1 to 28), and dexamethasone (20 mg orally on days 1 to 4 and 8 to 11) in 28-day treatment cycles. The median number of cycles administered was 6, ranging from 3 to 9 cycles.

Of the newly diagnosed myeloma patients receiving CTD, 74 percent achieved a partial response or better.  Forty nine percent of treatment resistant patients and 65 percent of relapsed myeloma patients also achieved a partial response or better during treatment.  

Complete remission was achieved in 9.4 percent of newly diagnosed patients and 3.9 and 5.9 percent of resistant and relapsed patients, respectively.

The median time to disease progression was significantly longer in newly diagnosed patients (21 months) compared to resistant and relapsed patients (15 months and 10 months, respectively).

At 20 months after start of treatment, 73 percent of both newly diagnosed and resistant myeloma patients were alive, compared to 51 percent of relapsed patients. 

CTD with low-dose thalidomide was well tolerated in most patients.  The most common side effect was nerve damage to the extremities, which was observed in 26 percent of patients. Nerve damage was severe enough to stop treatment in 3 percent of patients.

The researchers pointed out that more comparative research is necessary in order to optimize the dosages and administration of the CTD regimen.

However, Dr. Dmoszynska believes the therapy may become important in situations where cost is an issue. “It is not expensive in comparison to other protocols, but it is very effective. The three drugs are also administered orally, so it is ideal for outpatient treatment.”

For more information, please see the study in Leukemia Research (abstract).

The benefits associated with complete response were similar regardless of whether complete response was achieved early or late in the treatment course.

Based on these findings, the researchers concluded that the achievement of a complete response should be considered an important treatment goal. They recommended that VMP be continued in patients tolerating therapy, thereby improving response and clinical benefit.

These findings resulted from further analysis of a Phase 3 clinical trial known as VISTA, which compared the efficacy of Velcade (bortezomib), melphalan (Alkeran), and prednisone (VMP) to melphalan and prednisone (MP) alone in newly diagnosed multiple myeloma patients ineligible for stem cell transplantation.  

Results of the VISTA trial had demonstrated that patients on VMP had better response rates and longer overall survival than patients on MP. In particular, 30 percent of patients treated with VMP achieved a complete response compared to 4 percent of patients treated with MP.

In their follow-up analysis, the researchers analyzed the trial data further to see if the achievement of a complete response was associated with improved outcome.

The researchers found that the time to disease progression, time to next therapy, and the treatment-free interval were all longer in patients who achieved a complete response compared to patients who achieved a partial response, regardless of treatment with VMP or MP. 

The overall survival, however, was not statistically different between patients who achieved a complete response and patients who achieved a partial response.   

In particular, for patients on VMP treatment, the median time to progression has not yet been reached for patients who achieved a complete response, whereas it was 21.7 months in patients who achieved a partial response.  

With a complete response on VMP, the median time to next therapy was 37.8 months and the median treatment-free-interval was 29.9 months, compared to a median time to next therapy of 25.2 months and a median treatment-free interval of 13.9 months in patients who achieved a partial response.

Further analysis was completed on patients who received VMP to evaluate if the timing of the response affected outcome in these patients. 

Researchers found that the quality of response improved with prolonged VMP treatment.

Although most patients achieved best responses within the first four cycles of therapy, 28 percent of complete responses were achieved after four cycles. 

For more information, please see the study in the scientific journal Blood (abstract).

The current standard of care for multiple myeloma patients under the age of 65 is treatment with high dose chemotherapy followed by stem cell transplant.  High dose chemotherapy prior to stem cell transplant, often called a conditioning regimen, is administered with the intention of eliminating cancerous cells from the patient’s bone marrow.

Melphalan (Alkeran), administered as a single dose of 200 mg/m² (MEL200), is currently the most widely accepted conditioning regimen for multiple myeloma.

However, little research has focused on improving the efficacy of the conditioning regimen, which may result in better responses following stem cell transplant.

“I think this study will stimulate the investigation of more efficient conditioning regimens for multiple myeloma, since very little has been done in this field in the past,” said Dr. Juan Jose Lahuerta, principal investigator of the study, in an email to The Myeloma Beacon.

The goal of this study was to compare a conditioning regimen that included busulfan (Myleran) to the standard MEL200 regimen.

Of the 767 newly diagnosed multiple myeloma patients under the age of 70 enrolled in the study, 225 received oral busulfan (12 mg/kg) followed by a single dose of melphalan 140 mg/m² (BUMEL). The remaining 542 patients received a MEL200 conditioning regimen.

At the time of the transplant, no statistical differences were seen between the BUMEL and MEL200 conditioned groups.  The average time to stem cell collection and platelet engraftment, meaning that the stem cells began producing platelets again, was similar.  Furthermore, the hospitalization time averaged 20 days for both groups.

Responses to treatment were similar between both groups.  Partial response or better after the stem cell transplant was seen in 90 percent of BUMEL-conditioned patients compared to 92 percent of MEL200 patients.

Time to disease progression was significantly improved in the BUMEL conditioned group. Five years after the transplant, 39 percent of patients in the BUMEL-conditioned group remained progression free compared to 21 percent of MEL200 conditioned patients.

At the time of follow up, the median progression-free survival for BUMEL-conditioned patients was 41 months, compared to 31 months for those who received MEL200.

Despite the improved progression-free survival of BUMEL-treated patients, the overall survival between the two groups was similar.

The median time of survival was 79 months for BUMEL-conditioned patients and 71 months for those who received MEL200. The five-year overall survival rates for BUMEL and MEL200 patients were 55 percent and 57 percent, respectively.

Patients who received the BUMEL conditioning regimen were at a significantly increased risk of developing veno-occlusive disease compared to those who received MEL200.

Veno-occlusive disease is a complication of high-dose chemotherapy in which some of the small veins of the liver are blocked. Patients with veno-occlusive disease often experience weight gain due to fluid retention and increased liver size.  The condition is also associated with kidney failure.

Of those patients who received BUMEL conditioning, 8 percent were diagnosed with veno-occlusive disease, compared to less than 1 percent of patients who received MEL200.  In 3 percent of BUMEL patients, death was directly attributed to veno-occlusive disease, compared to less than 1 percent of patients in the MEL200 group.

Furthermore, a higher percentage of patients in the BUMEL group died within 100 days of transplant from causes other than multiple myeloma, including stroke and infection in the blood stream.  Of those treated with BUMEL, 5 percent died from such complications, compared to 3 percent treated with MEL200.

The researchers concluded, “Our analysis suggests that BUMEL may have greater anti-myeloma activity than MEL200; however, this should be balanced against its higher toxicity profile and treatment related mortality.”

They suggested that the study be extended using the intravenous formulation of busulfan, which other studies have demonstrated to reduce or eliminate the risk of veno-occlusive disease.

For more information, please see the full article in Haematologica.

Stem cell mobilization is the process of increasing the number hematopoietic (blood forming) stem cells in the circulating blood to ensure that enough are available to be collected for the transplant. Hematopoietic stem cells are primarily found in the bone marrow and circulate in very low concentrations in the blood. During mobilization, the administration of growth factors, such as granulocyte colony-stimulating factor (G-CSF), causes hematopoietic cells in the bone marrow to be released into the circulating blood stream.

Although G-CSF is the most commonly used mobilization agent, one recent study reported that only 34 percent of patients treated with G-CSF alone mobilized a sufficient number of stem cells for transplant over a two day collection period.

Other studies have shown that initial treatment with Revlimid (lenalidomide) has a negative impact on stem cell mobilization when G-CSF was used as a single mobilization agent.

Supplementing G-CSF with chemotherapy such as cyclophosphamide can increase the number of stem cells harvested during collection and reduce collection failure rates compared to the administration of G-CSF alone.

While cyclophosphamide is effective in improving stem cell yields, it increases the risk of low blood cell counts and high fevers associated with low white blood cell counts. In order to avoid these side effects, researchers in this study investigated the efficacy of an etoposide (VP-16) and G-CSF combination as a stem cell mobilization regimen in multiple myeloma patients.

Etoposide is a form of chemotherapy used for the treatment of lung cancer, testicular cancer, and lymphoma.  Previous studies have shown that etoposide is highly effective in mobilizing stem cells.

The 152 multiple myeloma patients enrolled in the study received 375 mg/m² of etoposide once daily on days 1 and 2 of the stem cell mobilization process. G-CSF was administered twice daily starting on day 3 until the last day of stem cell collection. Stem cells were collected from all patients between day 7 and day 13 of treatment.

Stem cells were successfully collected from all patients after one mobilization regimen.

Stem cells were harvested from 94 percent of these patients in one day of collection.  The majority of patients (61 percent) were able to undergo stem cell collection 11 days after the start of their etoposide and G-CSF regimen.

Furthermore, twice the number of stem cells were collected with G-CSF and etoposide than with G-CSF alone. These numbers were comparable to those obtained with a cyclophosphamide and G-CSF regimen.

Side effects experienced by patients in the study were manageable and were mostly the result of complications caused by low blood cell counts, which required 20 percent of patients to receive blood transfusions.  Severe fevers that required hospitalization or the administration of intravenous antibiotics occurred in 17 percent of patients.

The researchers suggested further studies be conducted to determine which compound yields the best results in combination with G-CSF in patients who are predicted to be poor stem cell mobilizers and which patients may not need a second agent for successful stem cell mobilization.

For more information, please see the study in Biology of Blood and Marrow Transplantation (abstract).

The International Myeloma Working Group identified the following risk factors for patients with smoldering, or asymptomatic, myeloma: the amount of monoclonal protein, the number of bone marrow plasma cells, and the free light chain ratio.

A smoldering myeloma diagnosis is made when monoclonal (M) protein levels are 30 g/l or greater and the proportion of plasma cells in the bone marrow is 10 percent or greater, but there is no associated organ damage.

The International Myeloma Working Group (IMWG) emphasizes that smoldering myeloma must be distinguished from monoclonal gammopathy of undetermined significance (MGUS) because there is a higher risk of progression to multiple myeloma or a related disorder for smoldering myeloma patients.

The frequency of progression to multiple myeloma or a related disease is 10 percent per year in patients diagnosed with smoldering myeloma as compared to 1 percent per year in MGUS patients.

In a previous study, researchers found that five years following a smoldering myeloma diagnosis, 51 percent of patients were predicted to progress to active myeloma or a related disease.  This number increased to 73 percent by 15 years post-diagnosis.

Smoldering Myeloma Risk Factors

In smoldering myeloma, the IMWG identified the amount of the M-protein and the number of plasma cells in the bone marrow as the most important risk factors of disease progression.

In smoldering and multiple myeloma, the M-protein is overproduced by plasma cells and cannot effectively fight infections.

Patients with both 10 percent or greater bone marrow plasma cells and 30 g/l or greater of M-protein were found to be at the greatest risk of disease progression.

Patients with 10 percent or greater bone marrow plasma cells and 30 g/l or greater of M-protein had a risk of disease progression of 87 percent at 15 years, while those with 10 percent or greater bone marrow plasma cells and less than 30 g/l of M-protein had a risk of disease progression of 70 percent at 15 years. Patients with less than 10 percent bone marrow plasma cells and 30 g/l or greater of M-protein had the lowest risk of disease progression (39 percent) at 15 years.

The free light chain ratio was identified as an additional independent factor for disease progression. An abnormal free light chain ratio was associated with higher rates of progression. In healthy individuals and the majority of myeloma patients, an immunoglobulin is composed of two light chains bound to two heavy chains. In some patients, the light chains are separated, creating abnormal “free” light chains in their blood stream.

Abnormal MRI scans of the spine have also been demonstrated to be an increased risk factor for progression.

Smoldering Myeloma Monitoring and Management Guidelines

The IMWG recommends patients have blood and urine analyses done both at the time of diagnosis with smoldering myeloma and two to three months thereafter.  At the time of diagnosis, the IMWG also considers a bone marrow biopsy and a bone scan mandatory procedures.

If the results of initial tests are stable, patients should be monitored every four to six months for a year.  At the end of the year, if results are still stable, evaluation can be extended to once every 6 to 12 months.

Conclusion

Dr. C. Ola Landgren, researcher at the National Institutes of Health and investigator in this study, believes there remains a need to find specific tests to determine which patients will progress to multiple myeloma.

He stated, however, that the guidelines published in the IMWG report “serve as a clinical tool to focus routine labs and clinical work-up on the precursor patients, who, based on crude clinical markers, are more likely to progress. There is no doubt this is a step in the right direction!”

He added, “I truly think there will be a change in the myeloma field during the coming years.  Instead of waiting for the precursor disease to get active and to spread to full-blown multiple myeloma before the doctor will start therapy, I think we will see new targeted treatment concepts, based on molecular profiling/imaging and biologic biomarkers. These strategies will better guide the doctor to start earlier therapy, and they will have abilities to monitor chronic disease management/cure.”

In order to determine specific differences between progressors and non-progressors, Dr. Landgren is conducting a series of studies at the National Institutes of Health on patients with MGUS or smoldering myeloma. He is welcoming patients from around the country to contact Mary-Ann Yancey at  if they are interested in participating in the studies.

For more information, please see the IMWG report (abstract).

The International Myeloma Working Group identified the following risk factors for patients with monoclonal gammopathy of undetermined significance: the amount of monoclonal protein, the type of monoclonal protein, the number of bone marrow plasma cells, and the free light chain ratio.

According to Dr. C. Ola Landgren, researcher at the National Institutes of Health and investigator in this study, approximately three million Americans have a myeloma precursor disease, such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma, but only about 5 percent will develop multiple myeloma or a related disease.

“At the same time, among those who will develop multiple myeloma, I think there is strong evidence to suggest that they all went through a precursor stage. So, the solution is to identify progressors from non-progressors at an early stage and to deliver intervention (i.e. treatment) that will delay/prevent progression to full-blown disease,” added Dr. Landgren.

With their report, the International Myeloma Working Group (IMWG) aims to help doctors identify which patients may be at a higher risk for disease progression and provide guidelines to help monitor and manage their conditions.

MGUS Rates And Risk Factors

A previous study investigated a group of 21,463 people 50 years and older. The researchers identified 3.2 percent of the people as having MGUS.

The researchers found that the rate of MGUS increased with age.  The condition was more common in men than women, and it was approximately twice as common in African-Americans and Africans compared to Caucasians.  Furthermore, the occurrence of MGUS in first degree relatives with MGUS was higher, suggesting a genetic factor (see related Beacon news).

Of those diagnosed with MGUS, approximately 1.5 percent of patients progressed to multiple myeloma or a related disease each year.

The IMWG identified a number of risk factors to help doctors predict which MGUS patients may progress.

The most important risk factor of progression was the amount of the monoclonal (M) protein at the time of MGUS identification. In MGUS and multiple myeloma, the M-protein is overproduced by plasma cells and cannot effectively fight infections.

In one study, the risk of progression to multiple myeloma or a related disorder 20 years after the recognition of MGUS was 49 percent in patients with an M-protein value of 25 g/l compared to 14 percent for patients with an M-protein value of 5 g/l or less.  MGUS patients with an increase in the amount of the M-protein during the first year after diagnosis were at high risk of disease progression.

The type of monoclonal protein overproduced in MGUS patients was also identified as a risk factor. There are several different types of M-protein.  Each MGUS and myeloma patient overproduces just one type.  Those patients with the IgM or IgA type of M-protein were found to be at increased risk of progression compared to those patients with too much IgG.

Additionally, the IMWG cited a report in which patients with greater than 5 percent bone marrow plasma cells were found to be at increased risk of progression.

Lastly, patients with abnormal free light chain ratios were found to be at significantly higher risk for progression than those with a normal ratio. In healthy individuals and the majority of myeloma patients, an immunoglobulin is composed of two light chains bound to two heavy chains. In some patients, the light chains are separated, creating abnormal “free” light chains in their blood stream.

Among MGUS patients with all of the high-risk factors (M-protein levels greater than 15 g/l, overproduction of IgM or IgA, and abnormal free light chain ratios) 58 percent progressed within 20 years of their MGUS diagnosis. For those with none of these factors present, 5 percent progressed.

MGUS Monitoring and Management Guidelines

The IMWG recommends that when a patient is diagnosed with MGUS, doctors should complete a full physical examination of the patient with emphasis on symptoms that may suggest multiple myeloma.

If blood work shows that the serum M-protein is low and of the IgG type and that the free light chain ratio is normal, patients should be categorized as low risk.  In this scenario, patients should be monitored again in six months and, if stable, followed every two to three years until symptoms of multiple myeloma or a related disease appear.

If a patient with MGUS has a high M-protein level of IgA or IgM type and an abnormal free light chain ratio, the IMWG recommends a bone marrow biopsy be conducted to rule out multiple myeloma or a related disease.  If results do not indicate an underlying plasma cell disorder, patients are considered intermediate or high risk.  These patients should be monitored again in six months and then annually until symptoms of multiple myeloma or a related disease appear.

For more information, please see the IMWG report (abstract).

The study authors suggested that patients be given a clinical and neurological assessment prior to treatment with Velcade.  If the patients’ resulting score is high enough to suggest the development of a severe form of Velcade-induced nerve damage, patients should continue to be monitored during Velcade therapy.

Velcade (bortezomib) is a neurotoxic therapy, meaning it causes damage to the body’s nervous system. As a result, multiple myeloma patients treated with Velcade commonly experience tingling and pain located in their hands and feet from nerve damage in their extremities. This nerve damage is a side effect of the treatment and is referred to as Velcade-induced peripheral neuropathy.

One third of patients may experience Velcade-induced peripheral neuropathy during treatment.  This peripheral neuropathy can be painful, and although it usually diminishes when treatment stops, it has been reported that up to 22 percent of Velcade treated patients may develop nerve damage that compromises their quality of life.

Factors that determine whether a patient will develop nerve damage during treatment with Velcade remain controversial.  However, it has been shown that Velcade dose reductions can minimize nerve damage, prompting researchers to suggest that patients should be monitored for the appearance or worsening of peripheral neuropathy during treatment.

The goal of the current study was to determine the effectiveness of continuous neurological assessment in multiple myeloma patients treated with Velcade.  Researchers also sought to identify factors that increase a patient’s risk of developing Velcade-induced peripheral neuropathy.

The study included 58 patients with relapsed or treatment resistant (refractory) multiple myeloma who received at least one cycle of Velcade treatment.  Patients received Velcade at an initial dose of 1.3 mg/m² on days 1, 4, 8, and 11 for as many as eight 21-day cycles.

Continuous nervous system monitoring during Velcade treatment was performed in 24 of the 58 patients.  These patients were assessed by a neurologist prior to Velcade treatment and again every two cycles up to completion of treatment. Velcade-induced peripheral neuropathy in these patients was compared to that in the 34 patients who were not monitored.

Patients receiving neurological monitoring were given a clinical examination, which included patient reporting of numbness, tingling or pain, or weakness in extremities. It also included a physical exam to evaluate reflexes, strength, and sensation in the extremities.

Nerve conduction studies were also performed at each visit.  These studies are commonly used to evaluate the function of the nervous system and to evaluate numbness, tingling, burning, and weakness in extremities.

Patients were then given a score based on the combination of clinical and nerve conduction evaluations. Patients found to have emerging or worsening peripheral neuropathy during their monitoring received a reduction in their Velcade dosage.

The study authors found that 56 percent of patients who did not receive neurological monitoring during Velcade treatment experienced Velcade-induced peripheral neuropathy compared to 29 percent of patients who were monitored.  Furthermore, severe peripheral neuropathy was experienced by nearly 18 percent of patients who were not monitored compared to 8 percent of patients who were.

Similar to other studies, the majority of patients (62 percent) in this study reported neuropathy symptoms within two treatment cycles. All cases of severe neuropathy were detected within the first four cycles of therapy.

In their analysis, the study authors also found that previous vincristine (Oncovin)-based regimens and poor evaluation prior to Velcade treatment were associated with an increased risk of developing Velcade-induced peripheral neuropathy.

For more information, please see the full study in the Journal of the Peripheral Nervous System.

These findings were presented at the European Hematology Association (EHA) meeting in Barcelona, Spain, last month.

Multiple myeloma is a disease characterized by abnormal plasma cells. Plasma cells are typically located in the bone marrow, but they can be found in the blood as well. The number of abnormal plasma cells in the blood has been shown to go down with myeloma treatment.  However, the existence of abnormal plasma cells in the blood before treatment is associated with poorer outcome.

The study authors were interested in the prognostic significance of normal and abnormal plasma cells in the blood before treatment and after one cycle of treatment in relapsed or refractory myeloma patients.

Their study included 31 multiple myeloma patients who had relapsed or were resistant to at least one prior therapy. Patients were scheduled to receive a Velcade (bortezomib)-containing regimen or a combination treatment of vincristine (Oncovin), doxorubicin (Adriamycin), and dexamethasone (Decadron). 

Researchers measured normal and abnormal plasma cells in the blood immediately before therapy and then again after one cycle of treatment.

They found that patients with detectable abnormal plasma cells in the blood prior to treatment had a shorter time to progression (258 days) than patients with undetectable abnormal plasma cells in the blood (456 days). 

Following one cycle of therapy, patients with increased abnormal plasma cells in the blood had a shorter time to progression (57 days) than patients with decreasing (259 days) or undetectable abnormal plasma cells in the blood (not yet reached after the median observation period of more than 500 days). 

The overall survival time was also decreased for patients with increased abnormal plasma cells following one cycle of therapy (139 days) compared to patients with decreasing or undetectable abnormal plasma cells (not yet reached after the median observation period of more than 500 days).

Although the detection of normal plasma cells in the blood prior to therapy gave no indication of aggressive myeloma, patients with absent or decreasing normal plasma cells following one cycle of therapy had significantly shorter time to progression (217 days) than patients with increasing normal plasma cells (388 days).

Researchers believe that the detection of abnormal plasma cells in the blood prior to treatment may be a new way to identify patients with a more aggressive form of the disease.

Furthermore, it could also serve as a tool to identify treatment-resistant patients as early as the first cycle of therapy.

“If our findings are confirmed in larger studies,” stated the researchers, “these patients may be candidates for immediate switch to alternative therapy.”

For more information, see abstract 0954 on the EHA meeting website.

The findings were presented at the European Hematology Association (EHA) meeting in Barcelona, Spain.

The study aimed to shed light on the controversial issue regarding appropriate initial therapy regimens, also known as induction therapy, for multiple myeloma patients with high-risk chromosomal abnormalities.

“It is of paramount importance [to identify a patient’s chromosomal abnormalities prior to starting induction therapy]. The goal is to tailor therapy according to the [genetic] profile of the single patient,” wrote Dr. Michele Cavo, the study’s lead investigator, in an email to The Myeloma Beacon.

Multiple myeloma patients with high-risk chromosomal abnormalities have a poorer prognosis.  They often do not respond as well to treatment, and survival is poorer as compared to patients without these abnormalities.  However, previous studies have shown that patients with and without chromosomal abnormalities generally respond similarly to Velcade (bortezomib) treatment.

To further investigate this issue, researchers analyzed the complete response and progression-free survival rates of 587 newly diagnosed patients who received Velcade as part of their upfront therapy. Progression-free survival refers to the percentage of patients who are alive and have not experienced disease progression a given length of time after the start of treatment.

Patients received one of three regimens: Velcade-thalidomide (Thalomid)-dexamethasone (Decadron), Velcade-melphalan (Alkeran)-prednisone, or Velcade-melphalan-prednisone-thalidomide.  Patients were also evaluated for chromosomal abnormalities and considered to be high-risk if certain abnormalities were identified.

Researchers found that there was no statistically significant difference in the complete response rates between patients with or without high-risk chromosomal abnormalities (38 percent and 33 percent, respectively).  Furthermore, the predicted progression-free survival rates at 30 months post-treatment were nearly identical for both groups, 62 percent for high-risk patients compared to 66 percent for patients without chromosomal abnormalities.

High-Risk Subgroups

Differences in Velcade activity were observed, however, when researchers further divided the high-risk patients into two distinct subgroups: those with del(13q) and those with t(4; 14), and/or del(17p).

del(13q)

Thirty percent of the study participants carried a deletion occurring in chromosome 13. This portion of the chromosome is known to produce proteins that suppress myeloma cell production, and its deletion causes the continuous growth of cancerous cells.  Patients with this abnormality have poorer prognoses and sometimes become resistant to treatment.

This study revealed that after induction therapy containing Velcade, patients with del(13q) alone had a significantly higher complete response rate (47 percent) than patients with no chromosomal abnormalities (33 percent).  The predicted progression-free survival rate at 30 months post-treatment, however, was similar in both groups, 64 percent for patients in the del(13q) subgroup compared to 66 percent for patients without chromosomal abnormalities.

t(4;14) and del(17p)

Twenty-four percent of the participants were identified with translocations between chromosomes 4 and 14 and/or a deletion within chromosome 17.  Both of these defects lead to enhanced cell proliferation and survival, which contribute to cancerous cell growth.

In this subgroup, researchers directly compared the response in patients with only the t(4;14) mutation to patients with only the del(17p) mutation.  Patients with the del(17p) mutation had a lower chance of achieving a complete response (28 percent) than their t(4;14) carrying counterparts (48 percent).  In contrast, the predicted progression-free survival rate at 30 months post-treatment was similar for both groups, 66 percent for del(17p) and 69 percent for t(4;14).

The results show that in terms of complete response rates, patients with del(17p) may not respond to Velcade as well as other patients.  However, progression-free survival among all groups was similar.

Although the researchers acknowledged that the results of their study are consistent with previous reports that high-risk patients respond similarly to Velcade as patients without chromosomal abnormalities, at least in terms of progression-free survival, they urged that their results be cautiously interpreted.

They recommended that further studies comparing patients receiving the same Velcade-based treatment regimen be conducted in order to “draw firm conclusions about the ability of Velcade-based regimens to overcome the adverse prognosis related to the presence of t(4;14) and/or del(17p).”

In fact, Dr. Cavo stated that with additional studies, “I would be able to collect data from several European Cooperative groups in order to verify the impact of the same treatment regimen on the outcome of patients stratified according to different [chromosomal] abnormalities.”

For more information, see abstract 1906 on the EHA meeting website.

Despite its frequent use in the treatment of multiple myeloma, stem cell transplantation remains a risky procedure with many possible complications.

Patients can either receive their own stem cells during this procedure (autologous stem cell transplant) or receive the stem cells from a healthy donor (allogeneic stem cell transplant). An allogeneic transplant has the potential to cure a myeloma patient. However, donors must have a tissue type that matches the recipient in order to minimize rejection, which happens when the transplanted cells recognize the patient’s cells as foreign and trigger an immune response.

Due to potential rejection, transplants with donor cells are riskier than transplants using the patient’s stem cells. Therefore, the role of allogeneic transplants in the treatment of myeloma is disputed by clinicians and researchers.

This study was designed to evaluate the value of allogeneic stem cell transplantation as part of first line therapy for newly diagnosed myeloma patients.

All patients included in the study were previously enrolled in a Phase 3 trial in which they received thalidomide (Thalomid) induction therapy followed by high-dose melphalan (Alkeran) therapy and autologous stem cell transplantation.

Of those participants, 100 patients had an eligible sibling donor and received total body irradiation and an allogeneic transplant between two and six months after high-dose melphalan therapy. Another 122 patients did not have a donor and, instead, started thalidomide maintenance therapy.

Ninety-six percent of patients who received an allogeneic transplant responded to treatment, with 35 percent achieving a complete response, 35 percent achieving a very good partial response, and 26 percent achieving a partial response.

By comparison, 95 percent of patients who underwent thalidomide maintenance also responded to treatment, with 20 percent achieving a complete response, 55 percent achieving a very good partial response, and 20 percent achieving a partial response.

Researchers found that the average time patients experienced no progression in their disease was 29 months for both the donor transplant group and the thalidomide maintenance group.

At five years post-high dose melphalan therapy, the average overall survival rate had not yet been reached; however, 60 percent of donor transplant patients were alive versus 55 percent of patients receiving thalidomide maintenance therapy.

Based on the similar responses and survival rates, the researchers concluded that there was no improvement of patient outcome by including allogeneic transplantation instead of thalidomide maintenance as part of first line therapy in newly diagnosed multiple myeloma patients.

For more information, see abstract 1098 on the EHA meeting website.

The research presented at the meeting covered all areas of hematology, which is the study of blood, blood-forming organs, and blood-related diseases. Due to the broad number of interests and studies, the meeting was divided into different sessions over the course of the four days, with most of the multiple myeloma sessions being held on the first three days.

On Thursday, researchers attended scientific working groups to discuss specific challenges and advances in their respective fields. The multiple myeloma scientific working group included discussions on the state of ongoing clinical trials and the use of genetic analysis for myeloma patients.

On Friday, education sessions were held primarily to allow practicing physicians an opportunity to maintain and develop professional knowledge and skills in their fields. During the multiple myeloma education session, doctors were presented with information regarding disease outcome, specialized treatment, disease complications, and unusual forms of myeloma.

Research posters were displayed in sessions on both Friday and Saturday. A total of 64 myeloma posters were presented, 28 covering the basic biology of the disease and 36 covering completed or ongoing clinical trials.

On Saturday, presentation sessions featured various hematology topics. A total of 16 myeloma presentations were given, 11 of which presented findings from ongoing and completed clinical trials. Select studies focused on thalidomide (Thalomid) as maintenance therapy and Revlimid (lenalidomide)-melphalan (Alkeran)-prednisone as a treatment for older patients with newly diagnosed disease.

Of note, one presentation regarding multiple myeloma was given at the Presidential Symposium, a session highlighting abstracts considered to be among the strongest submitted to the meeting. Dr. Gareth Morgan from The Institute of Cancer Research in London presented findings showing that Zometa (zoledronic acid), compared to Bonefos (clodronate), prolonged both survival and time to the first bone complication in newly diagnosed myeloma patients. These findings were also presented at the recent American Society of Clinical Oncology (ASCO) 2010 meeting in Chicago (related Beacon news).

Although some of the research from leading United States and European researchers was presented at the recent ASCO meeting, many new findings were also introduced at the EHA meeting. Over the next several days, topics of particular interest from the meeting will be featured in articles on The Myeloma Beacon.

More information on the meeting, including the program itinerary, can be found on the EHA Meeting website.

The study compared CyBorD with Revlimid (lenalidomide)-dexamethasone treatment (abbreviated RD) and cyclophosphamide-Revlimid-dexamethasone treatment (abbreviated CRD). The results of the Phase 2 trials indicate that RD and CyBorD treatment were similar in efficacy and safety. CRD, however, was not as effective and had more severe side effects than RD and CyBorD.

All drugs included in the trials have been approved for use in multiple myeloma by the United States Food and Drug Administration. RD as well as Velcade-dexamethasone are commonly used to treat newly diagnosed myeloma patients. This study shows that the addition of cyclophosphamide may increase the efficacy of the Velcade regimen, but not the Revlimid regimen.

A total of 150 patients were enrolled in the trials, including 40 who were considered high risk due to chromosomal abnormalities.

The average number of cycles completed during the trial varied by regimen, with RD patients staying on therapy the longest (patients completed a median of four cycles CyBorD, eight cycles RD, or five cycles CRD). Following completion of treatment, patients in the CyBorD and RD groups responded much better than those in the CRD group, with near complete response rates of 41 percent, 35 percent, and 11 percent, respectively.

Survival was similar among the treatment groups, with overall median progression-free survival of 2.6 years and 2-year overall survival of 87 percent to 95 percent. However, 3-year survival was significantly longer in patients who subsequently received a stem cell transplant (95 percent survival) as compared to those who did not (75 percent).

Regardless of treatment regimen, high-risk patients experienced earlier relapse than standard-risk patients. Fifty percent of high-risk patients experienced two years without disease progression as opposed to 70 percent of standard-risk patients.

Fewer patients receiving CyBorD (8 percent) and RD (9 percent) experienced severe complications as compared to patients receiving CRD (25 percent). However, 58 percent of CyBorD patients experienced peripheral neuropathy (tingling and pain in the extremities often associated with Velcade therapy), a rate much higher than in the RD (20 percent) and RCD (13 percent) groups.

The researchers concluded that CyBorD treatment resulted in superior response rates and similar or fewer side effects than treatment with RD and CRD. However, they noted, “At this time, improved early depth of response does not translate into different survival outcomes.” They are encouraged, though, by the fact that 82 percent of patients enrolled in the trial have survived four years since treatment.

For more information, see abstract 8131 on the ASCO meeting website.

“There are novel therapies that have improved the outcome, literally doubled the survival, of patients with myeloma. Despite these incredible advances, inevitably most patients relapse, and so we need [new] novel therapies,” said Dr. Kenneth Anderson of the Dana-Farber Cancer Institute.

For this reason, panobinostat is being developed by Novartis for the treatment of relapsed and refractory myeloma patients. Panobinostat works by preventing the breakdown of proteins in tumor cells. It is the resulting accumulation of these proteins that causes the cancerous cell to die.

Initial studies to determine the efficacy of panobinostat as a single drug therapy showed only two patients out of 38 responded. “This degree of activity did not warrant going forward as a single agent,” said Dr. Anderson.

The goal of each Phase 1b combination trial was to determine the maximum tolerated dose of panobinostat. Efficacies of the therapy regimens were also monitored.

Panobinostat In Combination With Velcade

The Phase 1b clinical trial investigating panobinostat in combination with Velcade was presented at ASCO by Dr. Anderson.

Forty-seven patients were enrolled in the panobinostat-Velcade combination trial. All patients had received prior treatment for multiple myeloma, including some patients who had been previously treated with Velcade.

To determine the maximum tolerated doses of panobinostat and Velcade in combination together, patients were divided into five groups. Each group of patients received a different combination of doses.

Researchers found that there were responses even at the lowest doses, and complete and very good partial responses were observed at the highest tolerated dose of panobinostat. The overall response rate was 70 percent, with 10 percent complete response.

“Importantly, and I think this is key, if you look at the patients who are Velcade refractory, we actually have 60 percent responses,” said Dr. Anderson.

Dr. Anderson commented, “I think this is among the most active, if not the most active, combination in Velcade-refractory disease.”

Dose-limiting side effects occurred in patients receiving more rigorous regimens. As a result of these side effects, Dr. Anderson concluded, “Panobinostat can safely be combined with Velcade with a recommended dose of 20 mg of panobinostat three times per week and Velcade at 1.3 mg/m² given twice a week for two weeks.”

Though significantly low platelet counts (81 percent of patients), white blood cell counts (57 percent), and red blood cell counts (21 percent) were side effects of treatment, these levels could be managed with dose modification and platelet transfusion. Other common side effects included diarrhea, nausea, fever, fatigue, and weakness.

An international Phase 3 trial of panobinostat-Velcade compared to Velcade alone in relapsed myeloma is ongoing. Additionally, a Phase 2 trial of panobinostat-Velcade treatment for refractory multiple myeloma is underway in the United States, “hopefully to achieve accelerated approval for this unmet medical need,” said Dr. Anderson.

Panobinostat In Combination With Revlimid And Dexamethasone

Results of the ongoing Phase 1b clinical trial of panobinostat-Revlimid-dexamethasone were presented at ASCO during a poster session. The trial enrolled 46 multiple myeloma patients, 25 of whom had refractory disease.

Patients received 5, 10, 20, or 25 mg panobinostat plus 25 mg Revlimid and 40 mg dexamethasone.

Among the participants who have been evaluated, 57 percent responded to the combination therapy. Additionally, 26 percent of all participants remain on the study.

Dose-limiting side effects occurred in 25 percent of evaluated patients, with nearly half of the patients in the 25 mg panobinostat group experiencing such side effects. The most common serious side effects were low platelet levels (44 percent of patients) and low white blood cell levels (37 percent). Two deaths occurred during the study and were suspected to be treatment related.

Researchers concluded that “no new safety concerns were identified and preliminary efficacy [of panobinostat-Revlimid-dexamethasone therapy] was very encouraging.”

However, during a discussion about the results, Dr. Robert Z. Orlowski of the MD Anderson Cancer Center expressed concern about the side effects, which he said were most likely due to high-dose dexamethasone.

Further studies are ongoing to determine the maximum tolerated dose of panobinostat as well as effects of lower dexamethasone and non-continuous panobinostat dosing.

Although panobinostat alone had minimal benefit as a therapy for myeloma, Phase 1b trials suggest that panobinostat may be highly effective against advanced multiple myeloma when given in combination with other currently used therapies.

For more information, please see abstract 8001 (combination with Velcade) and abstract 8030^ (combination with Revlimid and dexamethasone) on the ASCO Meeting website.

Two studies that are investigating whether novel agents are as effective, or possibly more effective, than an autologous stem cell transplant (ASCT) were presented June 6 at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

The two studies suggest that treatment with novel agents may be as effective as ASCT (in which a patient’s own stem cells are transplanted after chemotherapy), but results of the trials are still preliminary.

Dr. Jean-Luc Harousseau of the Rene Gauducheau Cancer Center in France led a discussion session at ASCO on this topic. He cautioned that it is still too early to abandon the use of ASCT, but he suggested that larger studies with longer follow up would likely provide further support for the replacement of ASCT with novel agents.

“I think the most important point is that upfront autologous transplantation might be useful only in certain subgroups of patients,” said Dr. Harousseau. He advised that studies should be designed to determine which patients would respond to novel agent therapy alone and which would need ASCT.

Results of the first study were discussed in Part 1. Results of the second study are discussed in this article.

Revlimid-Velcade-Dexamethasone Treatment Is Highly Effective In Newly Diagnosed Multiple Myeloma Patients, Even Without ASCT

Dr. Paul Richardson of the Dana-Farber Cancer Center presented interim results of ongoing Phase 1/2 trials for the treatment of newly diagnosed multiple myeloma patients with Revlimid-Velcade-dexamethasone (Decadron), a combination therapy known as RVD. The studies have shown that the combination is highly effective in newly diagnosed multiple myeloma patients and that the regimen is favorably tolerated. The study has also established that RVD may be equally effective given with or without ASCT.

The goal of the Phase 1 trial was to determine the maximum tolerated doses of the drugs in combination. The trial was then expanded in a Phase 2 study to determine the efficacy and safety of the RVD regimen. The researchers also determined the impact of the regimen on stem cell collection and transplant.

A total of 66 newly diagnosed multiple myeloma patients were treated with the RVD regimen. Thirty-five of these patients were enrolled in the Phase 2 study.

Phase 1 established the maximum tolerated dose to be 1.3 mg/m² Velcade, 25 mg Revlimid, and 20 mg dexamethasone.

All patients enrolled in the Phase 2 trial received the established maximum tolerated dose of RVD. Patients received eight three-week cycles of RVD therapy and medication to prevent blood clots and viral infection.

If a patient achieved partial response or better, they could proceed to ASCT or receive maintenance therapy. Forty-seven percent of patients elected to undergo ASCT following RVD treatment.

All patients enrolled in the studies achieved a partial response or better. Overall, 39 percent of Phase 1/2 participants achieved a complete response or a near complete response. Of the 35 patients enrolled in the Phase 2 portion of the study, 57 percent achieved a complete response or a near complete response.

“RVD is highly effective,” said Dr. Richardson. “It is the first regimen to achieve 100 percent response rate or better with remarkably high rates of complete response, near complete response, and also very good partial response.”

Researchers also found patient responses improved with continued therapy. Seventy-five percent of patients achieved improved response between cycles four and eight, and 53 percent improved with treatment beyond eight cycles. The average time to best overall response was 2.1 months.

Furthermore, researchers determined that RVD treatment had no effect on stem cell collection or transplantation.

The 18-month progression-free survival rate was 68 percent for patients who received ASCT following RVD treatment as well as patients who received only RVD.

During the Phase 1 trial, two patients had dose-limiting toxicities. These toxicities were caused by high doses of dexamethasone. Dr. Richardson noted that “high dose dexamethasone with [Revlimid] is problematic.” Patients receiving high-dose dexamethasone during the Phase 1 trial were, therefore, given reduced doses for cycles five through eight.

The most common side effect was nerve damage in the extremities. Although 80 percent of patients had nerve damage, Dr. Richardson stressed that this side effect was serious in only 2 percent. He stated, “We recognize that this is an important challenge going forward. Nonetheless, it was reversible in almost all patients and manageable with appropriate symptomatic measures, dose reductions, and schedule changes.”

Other severe side effects included low white blood cell counts (23 percent of patients) and low platelet levels (6 percent). There were no treatment-related deaths.

RVD treatment achieved a 100 percent response rate, favorable tolerability, and was as effective without ASCT follow up. Based on these qualities, Dr. Richardson predicted that “RVD may represent the basis of a future standard of care in this disease.”

Ongoing clinical trials are underway to determine ways to improve the quality of response. A larger trial will begin in July to compare the use of the RVD regimen with or without ASCT.

For more information, please see abstract 8016 at the ASCO meeting website.

Results from the two studies suggest that ASCT (in which a patient’s own stem cells are transplanted after chemotherapy) may not be necessary if replaced with novel agents. However, Dr. Jean-Luc Harousseau of the Rene Gauducheau Cancer Center in France cautioned that further studies are still required.

“Is it really time to abandon autologous transplantation upfront?” Dr. Harousseau asked in a discussion session that followed the two presentations. “My answer is maybe, but not yet.”

Results of the first study are discussed in this article. Results of the second study will be discussed in Part 2.

Conventional Chemotherapy Plus Revlimid May Be As Effective As ASCT In Newly Diagnosed Myeloma Patients

Dr. Antonio Palumbo of Torino University, Italy presented interim results of an ongoing Phase 3 trial. Newly diagnosed patients received initial treatment (induction) with Revlimid (lenalidomide) and low-dose dexamethasone (Decadron), abbreviated Rd. Half of the patients then received conventional chemotherapy plus Revlimid – melphalan (Alkeran), prednisone, plus Revlimid (MPR). The other half received high-dose melphalan and ASCT (MEL200).

In a phase of the trial that is still ongoing, half of the patients who received MPR and half of the patients who received MEL200 will also receive long-term, low-dose Revlimid treatment (known as maintenance therapy), while the other half will not receive maintenance.

To date, the study has found that both MPR and MEL200 similarly improved the response to Rd induction. Progression-free survival and overall survival are similar for both groups. Treatment with MPR, however, resulted in far fewer side effects than MEL200 therapy.

Efficacy And Safety Of Rd Induction

A total of 402 newly diagnosed patients were enrolled in the Phase 3 trial. All patients received 25 mg Revlimid on days 1 to 21 of a 28-day cycle and 40 mg dexamethasone on days 1, 8, 15, and 22. To increase the number of stem cells for transplantation, patients also received cyclophosphamide (Cytoxan) and granulocyte colony-stimulating factor during this time.

After four 28-day cycles of Rd induction, complete response was achieved in 6 percent of patients, very good partial response in 31 percent, and partial response in 49 percent.

Furthermore, 91 percent of patients were able to collect the minimum number of stem cells required for transplantation. This confirmed that Rd induction does not interfere with adequate stem cell collection for transplant.

The Rd induction regimen was very well tolerated, with severe side effects experienced in less than 10 percent of participants.

“This is a very good safety profile,” said Dr. Palumbo of the Rd induction regimen. “The complete remission rate is not so high, but the safety profile is certainly one of the best you can find in combination, including novel agents.”

Efficacy And Safety Of MPR Versus MEL200 Therapy

After Rd induction, about half of the enrolled patients were treated with MPR while the remaining patients received MEL200 therapy. At least three cycles of MPR or one course of MEL200 improved the initial complete response rates in these groups to 13 percent and 16 percent, respectively.

Progression-free survival 12 months following MPR or MEL200 treatment was the same for both groups (91 percent). Likewise, overall survival was similar for both groups (97 percent vs. 98 percent).

“Despite the short follow up, certainly the combination including a new agent is reducing the difference between standard treatment and ASCT,” said Dr. Palumbo in reference to the survival data.

“The interesting thing is that the early results are remarkably similar,” said Dr. Brian Durie of Cedars Sinai in Los Angeles and the International Myeloma Foundation.

MPR therapy was much better tolerated by patients than MEL200. In young patients, the rate of significantly low white blood cell counts was much lower for MPR patients than MEL200 patients (15 percent vs. 86 percent). Similarly, significantly low platelet levels were a side effect for most MEL200 patients (87 percent), while only 8 percent of MPR-treated patients had the same side effect.

Dr. Antonio Palumbo stated, “The comparison is easy in terms of safety profile. No question there is a major advantage for conventional treatment [MPR].”

For more information, please see abstract 8015 at the ASCO meeting website.

“We found the pomalidomide-dexamethasone regimen has significant activity in Revlimid- and Velcade-refractory myeloma,” said Dr. Lacy.

Pomalidomide is a new therapy being developed by Celgene and studied for the treatment of patients with relapsed or refractory myeloma. Similar to thalidomide (Thalomid) and Revlimid, pomalidomide works by stimulating the patient’s immune system to attack and destroy myeloma cells. In addition to its effects on the immune system, pomalidomide also inhibits the growth of new blood vessels, which stunts tumor growth by preventing nutrients and oxygen from reaching cancerous cells.

In previous clinical trials, combination therapy of pomalidomide and dexamethasone, abbreviated pom/dex, has resulted in overall response rates of 63 percent in patients with relapsed multiple myeloma and 32 percent in Revlimid-refractory patients.

The goal of this Phase 2 study was to determine the response rate and duration of remission in response to pom/dex treatment in patients refractory to both Revlimid and Velcade. Researchers also wanted to test the safety of the pom/dex regimen in this population of patients.

A total of 35 patients were enrolled in the trial, 81 percent of whom had received at least five prior treatment regimens. Forty three percent of the patients were considered high risk patients due to chromosomal abnormalities.

The participants were given pomalidomide every day during a 28-day cycle and received dexamethasone once a week (days 1, 8, 15, and 22 of the cycle). All patients also received aspirin daily to prevent the risk of blood clot formation. If patients experienced no response to therapy or experienced disease progression after two cycles of the pom/dex regimen, the daily dose of pomalidomide was doubled.

After treatment with pom/dex, the overall response rate was 26 percent, and an additional 28 percent of patients achieved a minor response. Typically, high-risk patients do not respond as well as low-risk patients. However, there was no significant difference in the response rates for the overall study group and the high-risk patients.

Of the nine patients that increased the dosage of pomalidomide after two cycles, all but one, who experienced a minor response, remained in a stable disease state following the pom/dex treatment.

“We found that this regimen acted rapidly,” said Dr. Lacy. The average time until patients responded to the pom/dex treatment was one month.

Dr. Bart Barlogie of the University of Arkansas responded, “The median time [to response] of one month is very rapid. If it’s so rapid, this would be the best treatment to be given upfront.”

At the time of analysis, 51 percent of the patients remained on trial, with the major reason for going off the study being disease progression. Follow-up showed that 86 percent of patients were alive and 58 percent of patients remained progression free six months after pom/dex treatment.

“Toxicity was manageable and consisted primarily of [low white blood cell counts],” said Dr. Lacy.

The most common serious side effects were low levels of white blood cells (34 percent of patients), platelets (9 percent), and red blood cells (9 percent) as well as nerve damage to extremities (14 percent). Other serious side effects were uncommon.

Based on the results of this Phase 2 study, Dr. Lacy and her colleagues concluded that pom/dex was well-tolerated in heavily pre-treated Revlimid- and Velcade-refractory multiple myeloma patients. They also noted that pom/dex treatment resulted in a rapid response and good rates of remission, confirming the therapeutic benefit for pom/dex in this patient population.

“Very impressive data,” said Dr. Sagar Lonial of Emory Winship Cancer Institute in a discussion session following Dr. Lacy’s presentation. “These were probably some of the most heavily pre-treated patients that we have ever seen in clinical trials.”

Ongoing studies will determine if beginning treatment with the higher dose of pomalidomide will improve the overall response rate.

For more information, please see abstract 8002 on the ASCO meeting website.

Carfilzomib is a new therapy being developed by Onyx Pharmaceuticals and studied for the treatment of patients with relapsed or refractory myeloma. It works similarly to Velcade (bortezomib) by preventing the breakdown of protein in cancer cells, triggering their death. In clinical trials currently underway with the drug, treatment with carfilzomib results in less damage to the peripheral nervous system and fewer cases of low white blood cells than other currently approved multiple myeloma therapies.

The goal of this Phase 1b study was to determine the safety and maximum recommended dose of carfilzomib administered with Revlimid and low-dose dexamethasone, a regimen abbreviated CRd, in patients with relapsed or refractory myeloma. The researchers also studied the efficacy of CRd in these patients.

Results published in the ASCO abstract report on safety and efficacy results for 40 patients. The results presented today at the meeting include an additional 44 patients enrolled in the expansion phase of the trial, further testing full-dose CRd.

All patients enrolled in this clinical trial were previously treated, most with Velcade, Revlimid, or thalidomide (Thalomid). Among the initial 40 participants, 47 percent were refractory to their last therapy, and 84 percent had a history of nerve damage to the limbs related to previous treatments. Patients were given different doses of the CRd combination therapy in a 28-day cycle.

Researchers found that at the full dose of CRd, 6 percent of patients showed a complete response, 27 percent showed a very good partial response, and 42 percent showed a partial response for an overall response rate of 75 percent. They also found that this response improved with long-term therapy (up to 18 cycles of treatment).

More than a third of the patients have received CRd for more than a year and are still participating in the study. All of these patients, however, received reduced doses of carfilzomib and Revlimid.

Researchers did not observe any dose-limiting side effects over an extended period of treatment (14 to 23 months). None of the patients showed signs of severe nerve damage, blood clotting, or fatigue. Although some patients experienced seriously low levels of white blood cells (23 percent of patients), platelets (18 percent), and red blood cells (12 percent), researchers found that levels returned to normal after treatment.

Based on the results of this Phase 1b study, researchers concluded that full-dose CRd was well-tolerated in relapsed/refractory myeloma patients, including patients heavily pretreated with Velcade, Revlimid, or thalidomide as well as patients with a history of treatment-related nerve damage. Additionally, CRd was well-tolerated throughout long-term treatment.

The researchers added that CRd is effective in patients previously treated with Velcade, Revlimid, or thalidomide.

A phase 3 trial comparing full-dose CRd with Rd will begin recruiting patients later this year.

For more information, please see abstract 829 on the ASCO meeting website.