However, patients who received the three-drug combination had comparable overall survival and progression-free survival rates as patients who received melphalan plus prednisone.  Additionally, side effects were more common among patients treated with the three-drug combination.

High-dose chemotherapy followed by autologous stem cell transplantation is the standard of care for transplant-eligible myeloma patients.

Patients who are elderly or who have concurrent illnesses, however, are often ineligible for transplantation and require safer forms of treatment.

One option for these patients is melphalan (Alkeran) plus prednisone, known as MP, a standard initial treatment for myeloma inEurope.

Although not as widely used, the combination of cyclophosphamide, thalidomide (Thalomid), and dexamethasone (Decadron), known as CTD, produces fewer blood-related side effects compared to MP.

A previous study conducted in Polandshowed that CTD is safe and effective both for newly diagnosed myeloma patients prior to stem cell transplantation as well as relapsed and treatment-resistant patients (see related Beacon news).

In the current study, the authors compared the efficacy and safety of a reduced-dose regimen of cyclophosphamide, thalidomide, and dexamethasone, called CTDa, to that of the MP regimen in myeloma patients ineligible for stem cell transplantation.

The study was part of the larger Phase 3 MRC Myeloma IX trial, which compared the efficacy of the bisphosphonates Zometa (zoledronic acid) and Bonefos (clodronic acid) in myeloma patients (see related Beacon news) who were also treated with different myeloma therapies depending on whether they were transplant eligible. Upon completion of the MRC Myeloma IX trial in 2010, the study authors conducted a follow-up analysis comparing CTDa and MP in the subset of patients treated with either of these two regimens.

The analysis included 856 newly diagnosed transplant-ineligible myeloma patients, all of whom were randomized at the start of the trial to receive either Zometa or Bonefos until disease progression. These patients were also randomized to receive either CTDa (419 patients) or MP (418 patients).

The median age of patients in both the CTDa and MP treatment groups was 73 years. In addition, 76 percent of patients in both treatment groups had advanced myeloma. Both treatment groups received a median of six cycles of therapy.

Furthermore, 225 patients in the CTDa group and 215 patients in the MP group were screened for chromosomal abnormalities.

High-risk patients were those who had at least one of the following chromosomal abnormalities: +1q, t(4;14), t(4;14), t(14;2), t(14;16), or del(17p). Standard-risk patients were those who did not have any of these chromosomal abnormalities.

Among those screened for chromosomal abnormalities, the percentage of high-risk patients was similar between the CTDa group and the MP group (43 percent and 42 percent, respectively).

Patients in the CTDa group received 500 mg of cyclophosphamide weekly, escalating doses of thalidomide from 50 mg per day to 200 mg per day, and 20 mg of dexamethasone daily on days 1 to 4 and days 15 to 18 of successive 28-day cycles until maximum response.

Patients in the MP group received 7 mg/m² of melphalan per day plus 40 mg of prednisone per day on days 1 to 4 of successive 28-day cycles until maximum response.

The researchers found that patients in the CTDa group had a significantly higher overall response rate (64 percent) than patients in the MP group (33 percent), with 13 percent of the CTDa group achieving a complete response compared to 2 percent of the MP group. Similarly, 17 percent of patients treated with CTDa achieved a very good partial response rate compared to 2 percent of patients treated with MP.

However, after a median follow-up of 44 months, median progression-free survival (12 months for CTDa versus 13 months for MP) and overall survival (31 months for CTDa and 33 months for MP) were similar for the two treatment groups.

The researchers also found that among patients in the CTDa group, standard-risk patients had a significantly better overall survival than high-risk patients. Based on these findings, they suggested that standard-risk patients were most likely to benefit from the CTDa regimen.

Compared to patients in the MP group, patients in the CTDa group had higher rates of infection (32 percent versus 26 percent), constipation (41 percent versus 18 percent), blood clots (16 percent versus 5 percent), rash (15 percent versus 7 percent), and sensory neuropathy characterized by pain and tingling in the extremities (24 percent versus 6 percent).

Fifty-seven percent of patients in the CTDa group and 62 percent of patients in the MP group died. The most common causes of death were disease progression, infection, treatment, and kidney failure.

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

Despite the higher rate of side effects, the study authors suggested that the combination of melphalan (Alkeran), prednisone, and thalidomide (Thalidomid) (MPT) should be considered a standard of care for newly diagnosed patients who are over 65 years old or ineligible for a stem cell transplant.

According to the Italian researchers, previous trials that compared the efficacy of MPT versus melphalan-prednisone (MP) have given variable results. All of these studies showed an increase in patient response; however, not all studies showed improvements in overall survival (see related Beacon news).

To shed more light on the issue, the Italian researchers conducted a clinical trial that compared MPT versus MP in 118 newly diagnosed multiple myeloma patients over the age of 65 who were ineligible for stem cell transplantation.

All patients received 0.25 mg/kg of melphalan and 60 mg/m² of prednisone orally for four days, every 28 days, for a maximum of 48 weeks. Thalidomide was given at 100 mg daily for 48 weeks. Patients who did not completely respond to treatment after six cycles had the option to be treated for six additional cycles.

As in previous studies, the researchers observed a better overall response rate in patients receiving MPT (87 percent) than in patients receiving MP (47 percent). In particular, 20 percent of patients receiving MPT achieved a complete response, compared to 7 percent of patients receiving MP.

After a median follow-up of 30 months, the progression-free survival was 33 months for patients receiving MPT, compared to 22 months for patients receiving MP.

Overall survival for patients receiving MPT was 52 months, compared to 32 months for patients receiving MP. However, the study authors pointed out that the difference in overall survival between the two groups was not large enough to be significant.

The researchers observed an increased rate of side effects in patients receiving MPT.  The most common side effect was low white blood cell counts, which was seen in 28 percent of MPT-treated patients and 13 percent of MP patients.  The rate of infection was also higher in MPT patients (9 percent) compared to MP patients (2 percent).  Both side effects led to a delay in treatment for 30 percent of patients.

Other common side effects included deep vein thrombosis (11 percent in MPT patients versus 0 percent in MP patients), nerve damage in the extremities (6 percent in MPT patients versus 0 percent in MP patients), and constipation (17 percent for MPT patients versus 6 percent for MP).

An ongoing, related Phase 3 trial is comparing MPT to the combination of Revlimid (lenalidomide) and low-dose dexamethasone (Decadron), another standard of care for newly diagnosed elderly or transplant ineligible myeloma patients.  This trial is being sponsored by Celgene, the pharmaceutical company that markets Revlimid and thalidomide, and is being conducted at centers throughout the world.  It is currently recruiting participants.

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

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.

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).

Dr. Palumbo and his colleagues compared VMPT followed by VT maintenance, which they hypothesized to be the “best possible treatment approach for elderly patients,” to the current standard of care, VMP.

“The use of the four-drug combination dramatically increased the response rate,” as well as the progression-free survival, said Dr. Palumbo.

In this study, 511 patients at least 65 years of age received either VMPT-VT or VMP without maintenance for nine 6-week cycles. The dosages of VMPT and VMP were identical, and the VT maintenance therapy consisted of 1.3 mg/m² Velcade twice monthly and 50 mg thalidomide daily.

In March 2007, the dosage of Velcade was lowered in the VMP and VMPT therapies from a twice-weekly infusion to once-weekly in order to address a high patient discontinuation rate due to side effects of peripheral neuropathy (nerve damage to the extremities that can cause pain and tingling sensations).

The Velcade reduction decreased the rate of peripheral neuropathy from 13 to 18 percent to 2 to 4 percent, and it reduced discontinuation rates from 16 percent to 4 percent. Although low-dose Velcade dramatically improved issues with peripheral neuropathy, it did not reduce the efficacy of the overall treatment, as patient response rates remained unchanged.

After nine cycles of treatment, patients responded better to VMPT than VMP. There was a particularly significant difference in complete response rates (38 percent vs. 24 percent). Additionally, more patients on VMPT achieved at least a very good partial response (59 percent vs. 50 percent). Likewise, patients on VMPT were more likely to achieve at least a partial response (89 percent vs. 81 percent). Maintenance with VT did not increase the response rates.

The survival rate after three years was similar for the two groups: 86 percent of patients receiving VMPT plus VT maintenance were still alive, and 84 percent of the patients receiving only VMP were alive.

“Probably, we are going to have a median overall survival of 6 years,” Dr. Palumbo predicted. “We were moving just a few years ago from a median survival of 3 years. We are now going to approach 4, 5, and probably within this study, a 6-year median survival.”

Also at the three year mark, the progression-free survival rate was 54 percent in the VMPT plus maintenance group, and 40 percent in the VMP group.

“If you consider the best treatment available today, the progression-free survival is usually around 2 years,” said Dr. Palumbo. “The addition of the fourth drug is moving from an expected remission duration of 2 years to an expected remission duration of 3 years.”

Dr. Palumbo went on to explain why the VMPT-VT regimen is particularly effective. “The four-drug combination was mainly increasing the complete response rate … The maintenance approach is prolonging the remission duration. So, here we combine the high complete response rate coming from the four-drug combination with the maintenance approach prolonging remission duration.”

The safety of the two treatments was similar, but there was a higher rate of serious side effects among the patients who received VMPT-VT. Serious side effects included low white blood cell counts (30 to 35 percent of patients), low platelet counts (20 percent), and low red blood cell counts (10 percent).

Several physicians in attendance were interested in replacing thalidomide with Revlimid, either just in the maintenance arm (e.g. VMPT-VR) or both in the upfront therapy as well as the maintenance (e.g. VMPR-VR). Dr. Palumbo expressed interest in using Revlimid as part of the maintenance therapy, but cautioned that low white blood cells associated with Revlimid might decrease the efficacy if used in the upfront therapy.

Dr. Palumbo concluded by saying, “[VMPT-VT] is a new, better standard of care for elderly patients because the progression-free survival was significantly superior” than VMP alone, which is the current standard of care.

For more information, please refer to abstract 8013 on 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.

The first two presentations dealt with Velcade (bortezomib)-related research.

Dr. Antonio Palumbo of the University of Turin presented the results of the first study.  It compared two regimens for the treatment of newly diagnosed elderly myeloma patients.  The first regimen involved initial treatment with four drugs: Velcade, melphalan (Alkeran), prednisone, and thalidomide (Thalomid) (VMPT) followed by maintenance therapy with Velcade plus thalidomide (VT).  The other regimen consisted of initial treatment with Velcade plus melphalan and prednisone (VMP) without maintenance therapy.  The results favored the VMPT+VT regimen, and Dr. Palumbo argued that this regimen should become the new standard of care for newly diagnosed elderly myeloma patients.

Dr. Palumbo also believes the results of this trial indicate that weekly administration of Velcade is superior to the drug’s standard dosing schedule, because weekly dosing seems to reduce the incidence of peripheral neuropathy (pain and tingling in the extremities).  This statement did not go unchallenged, however, in the discussion of the study by Dr. Ruben Niesvizky of Cornell University.  He said that Velcade should be administered weekly only in certain specific situations.

The second presentation was by Dr. Philippe Moreau of the University Hospital in Nantes, France.  The study compared two Velcade-based regimens as initial therapy prior to stem cell transplant in newly-diagnosed multiple myeloma patients.  One regimen included low-dose Velcade, low-dose thalidomide, and dexamethasone (Decadron) (vTD), and the other regimen included standard-dose Velcade and dexamethasone (VD).  Based on response rates both before and after stem cell transplant, vTD appears to be the superior regimen.  Patients on the vTD regimen also experienced peripheral neuropathy less frequently than those on the VD regimen.

The next two presentations shed light on a particularly interesting and controversial issue: the role of stem cell transplants when treating multiple myeloma.

This issue is addressed head-on in the third presentation,  also given by Dr. Antonio Palumbo.  The presentation reviewed initial results from a clinical trial with 402 newly diagnosed myeloma patients.  All of the  patients received an initial round of treatment with Revlimid and low-dose dexamethasone.  About half of the patients received further treatment with Revlimid, melphalan, and prednisone (MPR), while the other half received high-dose melphalan (MEL200) chemotherapy and an autologous stem cell transplant.  In the final phase of the trial, which is still ongoing, half of the patients will receive maintenance with Revlimid and half will not.

After 12 months, overall survival in the MEL200 and MPR patient groups is high and basically equal (98% and 97%, respectively).  There is also no statistically significant difference in response rates. However, Dr. Palumbo said there is evidence that the MEL200 regimen seems to be better for high-risk patients, but the MEL200 patients did have a noticeably higher rate of serious side effects.

The fourth presentation, by Dr. Paul Richardson of Harvard University, reviewed the results of a study of the Revlimid+Velcade+dexamethasone (RVD) combination therapy for newly diagnosed myeloma patients.  All 66 patients in the trial received 24 weeks of the RVD regimen.  After the initial therapy, patients who responded to treatment could receive an autologous stem cell transplant or maintenance therapy.

The overall response rate to the initial 24 weeks of RVD therapy was 100 percent.  The 18-month estimated overall survival rate was 97 percent across all patients in the study.  Just as importantly, there does not appear to be any statistical difference in either overall survival or progression-free survival between patients who received a stem cell transplant and those who did not.

Thus, in these new studies, the data do not indicate whether stem cell therapy is superior to therapy with a novel myeloma agent such as Revlimid, thalidomide, or Velcade.

The next two presentations,  however, provided important evidence that maintenance therapy with a novel agent improves outcomes for myeloma patients who have received a stem cell transplant.

Both of the presentations reviewed results from trials where Revlimid was the maintenance therapy tested.  The first presentation, by Dr. Philip L. McCarthy of Roswell Park Cancer Institute in Buffalo, looked at results from a United States trial with more than 400 patients.  All patients in the trial received a stem cell transplant.  Half then received Revlimid as maintenance therapy, while the other half received only a sugar pill (placebo) as their “maintenance therapy.”

The patients who received Revlimid maintenance experienced more side effects than the patients on placebo.  However, there was an estimated 58% lower chance of disease progression in the maintenance patients compared to the placebo patients.  The overall survival rate is also higher among the Revlimid patients, but the difference is not statistically significant.

One telling statistic: Results were so favorable in the Revlimid maintenance therapy arm of the trial that, when given a choice in 2009, a large majority of placebo arm patients chose to switch to Revlimid maintenance therapy.

The other presentation about Revlimid as maintenance therapy was by Dr. Michel Attal of the University Hospital in Toulouse, France.  The study he discussed involved over 600 myeloma patients, all of whom received autologous stem cell transplants followed by consolidation therapy with Revlimid.  The design of the French study was roughly similar to the U.S. trial discussed by Dr. McCarthy.  The French study, however, started before the U.S. study, so it has longer-term data.

As in the U.S. study, maintenance therapy with Revlimid noticeably reduced the rate of disease progression.  Three-year survival was 88 percent among the Revlimid maintenance patients and 80 percent in the placebo patients.  Once again, though, this survival difference is not statistically significant.

After Drs. McCarthy and Attal gave their presentations, Dr. Sergio Giralt of the MD Anderson Cancer Center in Houston commented on the talks by sharing his thoughts on how to use maintenance therapy in day-to-day practice.  His first recommendation was to use Revlimid maintenance therapy for high-risk patients or those who do not respond well to their stem cell transplant.  As for patients who respond well (have a complete response) following their transplant, Dr. Giralt feels the decision is more difficult, because there is not firm evidence that Revlimid maintenance extends patients’ lives.  He did say that Revlimid appears to work equally well for patients who have had either thalidomide or Revlimid in their transplant induction therapy.  At the same time, in response to questions from meeting attendees, Dr. Giralt said he would not switch patients to Revlimid who are currently on thalidomide maintenance therapy and doing well.

The seventh presentation of the morning was by Dr. Bart Barlogie of the University of Arkansas for Medical Sciences (UAMS).  During his talk, Dr. Barlogie described how he and his UAMS colleagues are using genetic testing – specifically “gene expression profiling” — to better identify specific types of high-risk myeloma patients.  This is important, he said, because the new myeloma therapies introduced in the last 5-10 years have primarily benefited low-risk myeloma patients.  By better classifying the different kinds of high-risk patients, the UAMS researchers hope to find better ways to treat those patients.

Dr. Barlogie’s presentation was followed by a presentation by Dr. Sagar Lonial of Emory University.  Dr. Lonial discussed the results of a Phase 1/2 clinical trial investigating elotuzumab as a potential myeloma therapy.  The trial involved 29 patients who had relapsed or refractory myeloma.  They received elotuzumab as well as Revlimid and dexamethasone.  The overall resopnse rate to the treatment was 82 percent in all patients, and 95 percent in patients who had never been treated with Revlimid.  Median time to progression has not yet been reached after 8 months.

The final presentation of the morning compared the impact on myeloma patients of two different bisphosphonate drugs: Bonefos (clodronate) and Zometa (zoledronic acid).  Bisphosphonates are often prescribed to myeloma patients to help reduce the risk of bone fractures and bone decay associated with multiple myeloma.

In his presentation, Dr. Gareth Morgan of the Royal Marsden Hospital in London (United Kingdom) reviewed the results of a study involving almost 2000 myeloma patients.  The patients were given either Bonefos or Zometa in addition to their anti-myeloma therapy.  Zometa proved to be more effective than Bonefos in preventing fractures and other “skeletal-related events,” and the patients taking Zometa also had longer overall survival than those who took Bonefos (50 months vs. 44.5 months).  The incidence of osteonecrosis of the jaw (ONJ) was higher, however, in patients who took Zometa than in patients taking Bonefos (3.5% vs. 0.3%).  (Bonefos is not approved for sale in the United States, but it is generally available in Canada, Europe, and Australia.)

Looking ahead to Day Four of the ASCO meeting, there is an educational session devoted exclusively to complications associated with myeloma and myeloma therapies. There also will be a poster session focusing on ongoing multiple myeloma related clinical studies.  Look for the Beacon’s summary of the day’s events in another ASCO update sometime tomorrow.

Almost 40 myeloma-related posters were up for meeting attendees to view during the daytime poster session on “lymphoma and plasma cell disorders.”  Among those 40-or-so posters, six concerned research done by the myeloma team at the University of Arkansas for Medical Sciences (UAMS), and two of those six stood out in particular.  Both of those studies concern the Total Therapy program that is being continually updated and investigated at UAMS.

In the first of the two UAMS posters, researchers followed 231 patients who had undergone tandem stem cell transplants. The key result: 45 patients are still alive after 17 years. Those results significantly exceed current national averages in the 10 percent range for 10-year survival.

The second key UAMS poster examined the second and third iterations of the Total Therapy regimen (TT2 and TT3), comparing those who continued on the recommended post-transplant maintenance protocol of Velcade (bortezomib), thalidomide (Thalomid), and dexamethasone (Decadron) to those who ended maintenance therapy early. The study results indicate that patients who dropped therapy earlier had a shorter time to their next required treatment.  Or, to put it another way, patients who stayed on maintenance therapy longer delayed the return of their myeloma.

Among the rest of the posters at the session, one from the European Cancer Network deserves mention.  The study analyzed results from six previously conducted clinical trials.  It confirmed that adding thalidomide to melphalan (Alkeran) and prednisone for previously untreated elderly myeloma patients significantly improves time to progression and overall survival.

The Mayo Clinic also had an interesting poster.  It compared three drug regimens for newly diagnosed multiple myeloma patients: Revlimid (lenalidomide)+dexamethasone (RD); cyclophosphamide (Cytoxan)+Revlimid+dexamethasone (CRD); and cyclophosphamide+Velcade (bortezomib)+dexamethasone (CyBorD).  The results rather clearly indicate that the CRD combination is inferior to the other two regimens.  As to which of the other two regimens looks best, the authors come down in favor of CyBorD.  Yet the data the authors present in their poster seem a bit less clear on this point: median progression free survival, for example, was longer for the RD patients than for CyBorD patients (3.2 years vs. 2.6 years).

In addition to the poster session, there also was an important evening symposium whose theme was ”Novel Therapies for Myeloma.” During the symposium, the results of four recent clinical studies were presented and then discussed.

The first study presented was the Phase 2 carfilzomib single agent study in relapsed/refractory patients. Carfilzomib is a proteasome inhibitor like Velcade, but studies thus far have indicated that it may have fewer side effects than Velcade.  There is therefore a lot of interest and “buzz” about carfilzomib at this year’s meeting.

Response to carfilzomib in the Phase 2 study was much higher in Velcade-naïve patients (45-55 percent versus 21 percent), which is perhaps not surprising given the similar way that carfilzomib and Velcade work. Duration of response was significant even in patients achieving only minimal response. Side effects were described as clinically manageable. Due to a lack of significant adverse events, Dr. Ravi Vij of Washington University (St. Louis) said that the results suggest carfilzomib is favorable for use in combination with other treatments. Additionally, due to the lack of side effects, there is interest in studying carfilzomib at much higher doses.

The second study presented was a Phase 1b study of panobinostat in combination with Velcade and dexamethasone in relapsed/refractory patients. The overall response rate was 70 percent overall, and 60 percent in patients who have failed treatment with Velcade. The researchers have only collected about three months of data, so no time to progression data have been gathered yet. A significant percent of patients experienced low blood cell counts, but Dr. Kenneth Anderson of Harvard University said these side effect cases were manageable. Dr. Anderson also said that this is the most responsive combination yet observed among patients who have failed Velcade treatment.  A Phase 3 trial of panobinostat and Velcade vs. Velcade alone is ongoing.

The third study presented was a Phase 2 study of pomalidomide in combination with dexamethasone in heavily pre-treated myeloma patients. Pomalidomide is a drug that is chemically related to both thalidomide and Revlimid. The presentation was made by Dr. Martha Lacy of the Mayo Clinic. The overall response rate to pomalidomide was 26 percent, and 54 percent achieved at least a minimal response. Time to response was only 1 month, which is considered very rapid. Dr. Bart Barlogie of the University of Arkansas suggested that pomalidomide plus dexamethasone might be used as front-line therapy for myeloma since the response is so rapid. Overall survival was 86 percent at 6 months. Responses were similar in low and high risk patients, which is atypical.

Dr. Sagar Lonial of Emory University commented favorably on the pomalidomide results, saying “These patients were some of the most previously and heavily medicated of any patients ever included in such a study.” He continued: “These are truly impressive results.”  Future pomalidomide studies are likely to examine the safety and efficacy of a higher dose of the drug.

The fourth study presented was a Phase 1 trial of elotuzomab plus Velcade in relapsed/refractory patients. The overall response rate was 48 percent, and 64 percent achieved at least a minimal response. Time to progression was 9.5 months overall and also in Velcade-refractory patients. The most common side effects were fatigue, anemia, and diarrhea. The most common serious side effect was lymphopenia (lymphocytopenia, or low levels of lymphocyte white blood cells). The elotuzumab plus Velcade combination appeared to be well tolerated with no dose limiting toxicities. The researchers believe that elotuzumab and Velcade may have a synergistic effect.

Overall, there was a lot of excitement about the results presented at the evening symposium.  Many of the symposium attendees came away with a sense that it may not be very long until there are several new treatment options for multiple myeloma patients.

Studies examining the effect of adding thalidomide to MP treatment have previously been conducted in several European countries.  All studies found that the addition of thalidomide increased anti-myeloma effects. However, the results varied significantly for progression-free and overall survival. 

In their study, researchers investigated the effects of adding thalidomide to MP treatment in 357 newly diagnosed myeloma patients from Norway, Sweden, and Denmark who were not candidates for stem cell transplantation.  The median age of patients was 74 years.  Patients were randomly assigned to either receive MPT or MP treatment.  Anti-myeloma effect was determined by the degree of response to treatment. 

Within the first twelve months of treatment, 57 percent of patients receiving MPT therapy achieved at least a partial response compared to 40 percent of patients receiving MP therapy. Thirteen percent of patients on MPT achieved a complete response compared to 4 percent of patients on MP.

Median overall survival for patients treated with MPT combination was 29 months compared to 32 months for patients treated with MP. There was no difference in progression-free survival (15 vs. 14 months) and median time to progression (13 months vs. 12 months) between the two treatment groups.

Patients treated with MPT experienced more side effects than those treated with MP. The most common side effects were constipation, tingling or numbness in fingers and toes, involuntary shaking, difficulty with coordination, confusion, stroke, dizziness and skin rashes.

Thirty-two percent of patients on MPT discontinued treatment within the first three months, compared to 11 percent of patients on MP.

Researchers concluded that MPT showed significant anti-myeloma effects in elderly patients but that did not have an impact on progression-free and overall survival. They added that the differences in results for progression-free and overall survival between the European studies may be due to patient selection and the dose and schedule at which thalidomide was given.

They recommended keeping thalidomide dosages as low as possible in elderly patients to avoid drug-related side effects or treatment discontinuation.

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