Given the recent new drug application for carfilzomib and the upcoming annual meeting of the American Society of Hematology — which undoubtedly will host discussions of many potential new myeloma treatments — it seems an appropriate time to go back to the experts’ review from earlier this year and highlight some of its key points.

The experts begin their review by noting that, despite significant advances in the treatment of multiple myeloma during the last decade, it continues to be challenging to find effective therapies for patients at high risk for early relapse and for patients resistant to multiple drugs or drug combinations.  This makes the search for new treatments particularly important.

The Next Generation of Novel Agents

Regimens containing the novel agents Velcade (bortezomib), thalidomide (Thalomid), and Revlimid (lenalidomide) have played a key role in improving progression-free and overall survival in multiple myeloma patients.  According to the authors of the review article, new drugs that work similarly as these novel agents, but have improved efficacy or safety, have been showing particular promise in clinical trials over the past several years.

Carfilzomib: The Next Generation Velcade

Velcade works by inhibiting proteasome, which is responsible for the break down of proteins in both healthy and cancerous cells. Treatment with Velcade results in the accumulation of proteins within the cell, and it is believed that this excess protein leads to cell death, suppressing tumor growth.

Carfilzomib, which belongs to the same class of drugs as Velcade, has shown high efficacy in clinical trials and may have fewer side effects than Velcade (see related Beacon news). Particularly notable are its lower rates of peripheral neuropathy (nerve damage in the extremities).

There also are other proteasome inhibitors under development for the treatment of myeloma, including salinosporamide A (NPI-0052), and MLN9708/2238, a chemical cousin of Velcade that can be taken orally.

Pomalidomide: The Next Generation Revlimid

Pomalidomide is closely related to thalidomide and Revlimid.  Although the exact ways in which this class of drugs works remain unclear, all three are immunomodulatory agents (drugs that affect the immune system), and they apparently encourage a patient’s immune system to attack and destroy myeloma cells. Clinical trials have shown that pomalidomide is effective in patients who are resistant to treatment with thalidomide, Velcade, and Revlimid (see related Beacon news).

Dr. Vincent Rajkumar, a professor of medicine at the Mayo Clinic, noted in a recent column for The Myeloma Beacon that, of the many drugs currently in development for multiple myeloma, only pomalidomide and carfilzomib have shown significant single-agent activity in multiple clinical trials (see related Beacon news).

In addition to the improvements being made in the currently available multiple myeloma drug classes, ongoing research is being done to identify new classes of drugs.

The authors of the review article believe that several drugs, while not showing potential as single agents themselves, may prove to be effective if given in combination with other currently approved drugs, such as Velcade (see related Beacon news).   These include the histone deacetylase inhibitors, Zolinza (vorinostat), panobinostat and Istodax (romidepsin), which have shown activity when combined with Velcade.

The anti CS-1 antibody, elotuzumab has also been included in this list. This drug targets proteins that are displayed on the surface of myeloma cells but not on healthy cells.  Clinical trials are currently underway to examine the activity of elotuzumab in patients with refractory or relapsed myeloma. It is anticipated that the drug will work best when combined with Revlimid and dexamethasone (Decadron), rather than as a single agent.

Other potential drugs that may work best in combination with existing therapies include heat shock protein inhibitors (see related Beacon news), phosphoinositide 3-kinase pathway inhibitors (for example perifosine), and mTOR inhibitors, such as Torisel (temsirolimus).  At this time, however, none of the drugs in these classes have been approved by the U.S. Food and Drug Administration (FDA) specifically to treat multiple myeloma.

The authors conclude their review of current research on new myeloma treatments by touching on an alphabet soup of drugs in early-stage clinical trials – drugs such as ACE-011, BHQ880, BI-505, defibrotide, GDC-0449, imetelstat (GRN163L), MLN4924, MLN8237, NVP-BEZ235, and siltuximab (CNT 328).  In addition, the authors describe several potential early stage treatments that may stimulate the body’s immune system to attack myeloma cells.

Improving Clinical Trial Results

According to the authors of the review, a large number of drugs that are being developed for multiple myeloma have shown promise in preclinical trials.  These preclinical trials are not carried out in humans, but instead in other models of the disease, such as cells grown in the laboratory setting or small animals (for example mice).  The review authors point out, however, that despite initial promise, fewer than 10 percent of cancer drugs that begin testing in humans ever receive approval from the FDA for patient use.

The authors therefore stress that more preclinical testing is needed and that the models used during this testing should more closely mimic the disease as it is observed in humans. They emphasize, for example, that the environment surrounding the tumor is of equal importance to the tumor itself, and suggest that more models take this so-called “microenvirnoment” into more careful consideration.

They also recommend that patients be carefully selected when clinical trials of a drug begin.  Because some drugs may perform better in specific patient populations, these populations should be established before the start of clinical trials, and patients should be screened to ensure they are in this population before they are enrolled.

Personalized Treatment For Multiple Myeloma

The experts conclude their review by noting that, through work carried out over several decades, cancer biologists have discovered that cancer treatment cannot be a “one-size-fits-all” solution.  At the same time, determining the best method for treating an individual patient for their cancer at the correct time during their disease has proven to be the most challenging aspect of research.  Many researchers believe, however, that this kind of “personalized therapy” offers the most hope for cancer patients.

In this regard, the authors note that the International Staging System, the availability of genetic testing, and the development of risk classification systems by institutions such as the Mayo Clinic and the University of Arkansa have all contributed to greater individualization of multiple myeloma treatment.

The ultimate goal, according to the review authors, will be to identify subsets of patients that will respond most effectively to certain drugs or drug combinations and, thereby, improve the progression-free and overall survival of myeloma patients.  Further investigation is therefore needed into the classification of patients and the development of clinically relevant tests to identify patient classes.

While such studies may not be easy to implement, the authors believe that such issues are likely the next major frontier of myeloma research in the coming years.

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

Phase 2 Trial Of Carfilzomib For Multiple Myeloma Is Recruiting Patients – The Multiple Myeloma Clinical Research Section at the National Cancer Institute is recruiting participants for a Phase 2 trial to test the effectiveness of the investigational drug carfilzomib in combination with Revlimid and dexamethasone (Decadron) in newly-diagnosed multiple myeloma patients. Patients will receive eight 28-day treatment cycles. Those who show at least stable disease after the treatment may continue to receive 12 cycles of low-dose Revlimid maintenance therapy. In addition to current standard, clinical methods for determining responses to the drugs, the researchers will use new molecular methods to assess response and to detect minimal residual disease. To participate in the trial, please contact the research nurse, Mary Ann Yancey, at (301) 435-9227 or .

Chicago Area Workshop For Multiple Myeloma Patients – The Multiple Myeloma Research Foundation will hold a one-day educational workshop for myeloma patients and their family members on August 20 in Oak Brook, IL. The program will be led by Dr. Todd Zimmerman, a myeloma expert from the University of Chicago Medical Center. Throughout the day, myeloma experts will talk about treatments options for newly diagnosed and relapsed/refractory patients, including stem cell transplants, supportive care options, and clinical trials.  The specialists will also be available to answer questions.  Registration will begin at 9 a.m., and the program will last from 10 a.m. until 3:30 p.m. at the Hamburger University at the Hyatt Lodge. For more information or to register, please see the Multiple Myeloma Research Foundation website. 

For a more detailed listing of myeloma-related events, please check the Myeloma Beacon Events Calendar.

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.

The first talk was given by Dr. David Siegel of Hackensack University Medical Center in New Jersey.  Dr. Siegel presented results from a study of single-agent carfilzomib in myeloma patients who had relapsed multiple times and did not respond to their last treatment (abstract).

Among the 257 evaluable participants, 24 percent achieved at least a partial response, 10 percent a minimal response, and 35 percent stable disease.  Importantly, carfilzomib was as effective in patients with unfavorable chromosomal abnormalities (28 percent achieved at least a partial response).

Patients responded to carfilzomib for a median of 8.3 months, and median overall survival was 15.5 months.  Disease progression and survival were both dependent on the patient’s response to treatment.  Better responses corresponded with longer progression-free survival and survival.

Dr. Siegel said that there were “surprisingly few” blood-related side effects, particularly in terms of severe side effects  Twelve percent of patients developed peripheral neuropathy (nerve damage to the extremities that can cause pain and tingling sensations), but less than 1 percent developed severe neuropathy.

Sixteen percent of patients completed all 12 cycles of treatment.  The majority of patients who discontinued therapy did so because of disease progression.  Nine percent of patients died on study, also mostly due to disease progression.

Dr. Siegel concluded by saying he thought carfilzomib is “an amazing new drug.”

Next, Dr. Paul Richardson from the Dana-Farber Cancer Center in Boston presented a Phase 2 study of elotuzumab, a humanized monoclonal antibody (abstract).  Elotuzumab was given in combination with Revlimid (lenalidomide) and low-dose dexamethasone (Decadron) to relapsed/refractory multiple myeloma patients who had not received prior Revlimid therapy.

A total of 63 patients received treatment.  Half of the patients received 10 mg/kg elotuzumab, and the other half received 20 mg/kg.

In the low-dose elotuzumab group, 90 percent of participants achieved at least a partial response.  In the high-dose group, 72 percent achieved the same response, indicating more favorable results with the lower dose.  Median time to response was 2 months.

The median progression-free survival was not yet reached during the 4.9 months of follow-up.  However, progression-free survival was more than 1 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 effect was fever.  Preventative treatment helped to reduce, but not eliminate, the occurrence of injection site reactions.  No treatment-related deaths occurred.

The researchers will be going forward with the lower dose of elotuzumab in a Phase 3 trial that will start in early 2011.

Next, Dr. Suzanne Lentzsh presented results of a Phase 1 study of Treanda (bendamustine) in combination with Revlimid and dexamethasone in patients with relapsed or refractory multiple myeloma (abstract).  Treanda is an alkylating agent approved to treat two types of leukemias.  The goal of this study was to determine the maximum tolerated doses of Treanda and Revlimid in this combination.

Treanda was tested at 75 and 100 mg/m² on days 1 and 2 of a 28 day cycle, and Revlimid was tested at 5 and 10 mg on days 1 to 21.  The doses tested for Revlimid are much lower than what is commonly used for induction treatment in myeloma, causing several questions from the audience about the dosing choices used in the study.

The maximum tolerated dose was 75 mg/m² Treanda and 10 mg Revlimid plus dexamethasone.

Low blood cell counts were common with this regimen.  Almost half of the participants experienced severe low white blood cell counts.  Fatigue was the most common side effect that was not blood-related.

Among the 26 study participants, 9 percent achieved a very good partial response, 57 percent a partial response, and 9 percent a minimal response.  Half of the patients achieved their best response within 1.8 months.

Median time to progression was 4.3 months, and median overall survival was 10.9 months.

Dr. Lentzsh said that this combination may be particularly well suited for older patients or those with peripheral neuropathy.

The final myeloma-related presentation of the conference was given by Dr. Irene Ghobrial, who presented results from a Phase 1/2 study of Torisel (temsirolimus) in combination with weekly Velcade (bortezomib) (abstract).

Torisel is approved for the treatment of advanced kidney cancer. A previous study showed that the overall response rate with Torisel alone is 43 percent in myeloma patients.

This study included heavily pre-treated patients, most of whom had relapsed or were resistant to Velcade treatment. Phase 1 of the study included 20 patients, and Phase 2 included 43 patients.

The purpose of Phase 1 was to test the safety of the combination to determine the maximum tolerated doses of both drugs.  Velcade was tested at 1.3 and 1.6 mg/m², and Torisel was tested at 15 and 25 mg. The maximum tolerated doses were 1.6 mg/m² Velcade 4 out of 5 weeks and 25 mg Torisel weekly.

Almost all patients experienced side effects, especially low platelet counts, which are associated with both Velcade and Torisel. Other types of low blood cell counts were common as well. One patient died due to septic shock.

In the Phase 2 study, 47 percent of patients responded to treatment with 5 percent complete responses, 9 percent very good partial responses, 19 percent partial responses, and 14 percent minimal responses. For patients previously treated with Velcade, responses were predominantly stable disease, with 20 percent achieving a minimal response or better.

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

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

Earlier this week, The Myeloma Beacon published “as it happens” updates from the fourth day of ASH in this thread in the Beacon’s myeloma forums.

Myeloma cells produce M proteins. Higher levels of M proteins are directly related to increased disease progression and severity.

Torisel, a drug already approved for use in advanced renal cell carcinoma, appears to reduce the amount of M protein in the blood and urine by targeting the myeloma cells that produce them.

While studies have shown that treatment with Torisel alone produces little effect in multiple myeloma patients (see related Beacon article), it seems to have potential in combination with other drugs. In this study, Torisel was combined with Velcade, a drug already approved for the treatment of multiple myeloma.

The study was spearheaded by Dr. Irene M. Ghobrial, M.D., at the Dana-Farber Cancer Institute in Boston. Dr. Ghobrial recruited 27 patients for treatment.

Every 35 days, the patients received four weekly IV infusions of 1.6 mg/m² Velcade and five of 25 mg Torisel.

Nineteen of the 27 patients were evaluated to determine how many achieved at least minor response, which is defined as a greater than 25 percent reduction in M protein levels. The study also examined the side effects of the drug combination.

Fifteen of the 19 patients evaluated (79 percent) achieved at least minor response; one (5 percent) achieved complete remission, three (16 percent) achieved very good partial remission, five (26 percent) achieved partial remission, and five (26 percent) achieved minor remission. For more information regarding the criteria set for each level of remission, please see this related Beacon article.

Two patients (10 percent) remained stable, while two (10 percent) experienced disease progression. One patient died from abnormal heart contractions that were determined to be unrelated to the treatment.

For seven patients (37 percent), doctors reduced the dosage given because of adverse side effects. These included: diarrhea, nausea, anorexia, pneumonia, hyperglycemia (high blood sugar levels), sepsis, gastrointestinal bleeding, and reduction in all blood cell types, especially platelet cells.

Despite the side effects, the study authors expressed excitement over the high response rate to the treatment.

For more details regarding the study, please see abstract 748 at the ASH Meeting Web site.

Despite recent advancement in treatment options, many myeloma patients relapse and experience disease progression. Therefore, the search continues for new alternatives to treat the disease, especially for patients where previous therapy has proved unsuccessful.

Torisel, a drug already approved for use in advanced renal cell carcinoma, shows potential for reducing the number of abnormal myeloma cells in the body by inhibiting the protein mTOR. mTOR is responsible for activating the proteins necessary for cell growth and division.

In multiple myeloma, mTOR’s activity enables myeloma cells to grow, increase in number, and resist normal cell death. By inhibiting mTOR, Torisel would prevent these cells from growing and make them more susceptible to chemotherapy. Myeloma cells produce “M” proteins, so by killing myeloma cells, Torisel would also reduce the amount of “M” protein in the blood and urine.

The study was spearheaded by Dr. Sherif Farag, Director of the Bone Marrow & Stem Cell Transplantation Program and Associate Director for Clinical Research at Indiana University Melvin and Bren Simon Cancer Center.

Sixteen multiple myeloma patients who had all relapsed after at least one treatment were recruited for the study. They received 25 milligrams of Torisel weekly by IV infusion until their disease progressed. Their blood and urine “M” protein levels were monitored every four weeks.

One of the 16 patients (6 percent) achieved partial response, which is defined by the International Myeloma Working Group as a greater than 50 percent reduction in “M” protein levels. Additionally, five patients achieved minor response, a greater than 25 percent reduction.  However, four patients experienced an increase in their “M” protein levels.

“The clinical trial did show some activity, but I think the activity is not as strong as the other modern agents like Revlimid (lenalidomide) and Velcade (bortezomib),” said Dr. Farag. “However, it did provide some understanding of how much activity [Torisel] has in its dosage, side effects, and toxicity and its potential for being used in combination with other drugs.”

Because fewer than 1o percent of the study participants achieved partial or complete response, the trial was not expanded. Eventually, all patients stopped the treatment for various reasons, including disease progression and adverse side effects.

During the trial, doctors reduced the dosage of Torisel given to 11 patients (69 percent) because of adverse side effects. These included fatigue, diarrhea, lung inflammation, and reduced white blood cell and platelet counts.

Doctors concluded that the dosage and treatment regimen of Torisel used in the study proved ineffective in treating multiple myeloma.

They recommend further studies that vary how much and how often Torisel is given. They also recommend combining Torisel with drugs that target myeloma cells through pathways other than mTOR for more effective results.

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