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Winter 2004/2005 Volume 6, Issue 3:
New Developments in Multiple Myeloma
By Morie A. Gertz, MD
Dr. Morie Gertz of the Mayo Clinic brings up to date on new developments in treatment and supportive care.
Biologic Factors

Multiple myeloma is characterized by multiple chromosomal abnormalities. Abnormalities of chromosome 14 are seen in nearly half of patients with multiple myeloma. Clinical implications are found when these abnormalities are present. In a presentation on a group of myeloma patients, it was demonstrated that patients that showed rearrangement from a piece of chromosome 4 to chromosome 14, technically called a translocation, were associated with a markedly different prognosis and potentially poorer outcomes than patients who had no evidence of this rearrangement. In this study, it was found that the most important predictors of outcome were the translocation 4;14, the deletion 13, and whether the patient was chemotherapy-responsive or chemotherapy-resistant. It was felt that translocation 4;14, which is performed on the bone marrow plasma cells, provided important prognostic information that complements the beta-2 microglobulin. In fact, when patients had the 4;14 translocation, the presence of deletion 13 added very minimal additional information.

Therapy for Newly Diagnosed Patients

One study presented a program for newly diagnosed myeloma patients who were treated with Velcade®, thalidomide, and dexamethasone. Patients received four months of treatment. Treatment was exceedingly well tolerated, with only one blood clot seen in the group and no significant neuropathy due to the short duration of therapy. Eighty percent of patients responded, and the majority then went on to have stem cells collected for transplantation. In this program, no more than two cycles were required to see a response. The average time to see a response was less than three weeks.

The Eastern Cooperative Oncology Group (ECOG) reported a study on the use of Revlimid® and dexamethasone. In a prior study, the combination of thalidomide and dexamethasone produced exceptionally high response rates in newly diagnosed patients with myeloma. However, the side effect profile was high, with nearly two-thirds of patients having important complications related to treatment, including blood clots in 18%. This program represented an attempt to find a less toxic, but equally effective, initial therapy for myeloma patients. In this protocol, the combination of Revlimid® and dexa-methasone was given with one aspirin per day. Thirty newly diagnosed patients were treated. The response rate was 83%. There were no blood clots. No serious neuropathy was seen. This highly successful protocol has lead to a successor study that was, in part, generated by a conference with IMF support group members, which is comparing Revlimid® plus dexamethasone in standard dose to the same dose of Revlimid® with lower-dose dexa-methasone to see if the high response rates can be maintained with less side effects from dexamethasone.

A study of Velcade® as a single agent was also evaluated. The medicine was given alone for two cycles (six weeks), and, if less than a PR after 2 cycles or less than a CR after 4 cycles was seen, dexamethasone was added. At the end of two cycles, 40% of patients had responded. With the addition of dexamethasone, the overall response rate was improved to 88% with 25% of patients achieving a complete or near complete response. Neuropathy was seen in a third of patients. Half of patients with neuropathy had their symptoms resolve after stopping the medication. Importantly, subsequent stem cell harvest was successful and engraftment was prompt.

Two other phase II trials evaluating Velcade®-based regimens were also presented. One study examined the PAD regimen (Velcade®, Adriamycin, and dexamethasone) as an induction regimen in previously untreated patients who then went on to stem cell transplantation. The trial results demonstrated a 95% response rate, including 29% complete and near-complete responses prior to transplant, and a 57% complete and near-complete response rate following stem cell transplant. Twenty of 21 patients had stem cells mobilized and 18 of 20 patients received a stem cell transplant. Forty-eight percent of patients experienced peripheral neuropathy, however symptoms were improving in all patients after completion of therapy. Another phase II trial also evaluated the use of Velcade® plus dexa-methasone as an induction regimen prior to stem cell transplantation. This trial also demonstrated a high response rate of 80%, including 30% complete or very good partial responses. Stem cell harvest was adequate in all 29 patients. A phase III comparative trial of Velcade® plus dexamethasone vs. VAD is being started by the IFM in France.

An important study in older myeloma patients who were felt not to be candidates for stem cell transplantation was conducted in Europe. Patients over the age of 55, ranging up to age 85, with an average age of 72, were randomized to take oral melphalan and prednisone, or oral melphalan, prednisone, and thalidomide. Two hundred patients have been enrolled in this study. The thalidomide dose was 100mg per day. The melphalan and prednisone was given in standard doses orally for seven days every six weeks. Patients receiving thalidomide required the use of daily injections of low molecular-weight heparin to prevent blood clots. All patients received preventative antibiotics. At the end of the study, the overall response rate in the melphalan, prednisone, and thalidomide group was 77% vs. 47% in the melphalan and prednisone group. There was a significantly longer time period before the patients in the thalidomide arm needed an alternate therapy. The addition of thalidomide to melphalan and prednisone appears to improve initial response rates. Thalidomide was discontinued in 40% of patients by 24 months. The higher response rates reported were similar to response rates in older patients who received a stem cell transplant.

A European three-arm study compared oral melphalan and prednisone to melphalan, prednisone, and thalidomide to tandem stem cell transplant using a reduced dose of chemotherapy (melphalan 100mg, instead of the usual 200mg) in newly diagnosed myeloma patients, 41% of whom were over 70 years of age. The melphalan and prednisone group received the oral drugs every six weeks for 12 cycles (15 months of therapy). The melphalan, prednisone, and thalidomide group received 200-400mg thalidomide per day (also for 15 months of therapy). Patients randomized to the transplant arm received two cycles of VAD chemotherapy, mobilization with cyclophosphamide, and then two transplants with melphalan 100. There were 153 patients treated with melphalan and prednisone, 95 with melphalan, prednisone, and thalidomide, and 92 that were scheduled to receive two transplants, although only 60 of them actually received a second transplant. The response rate to melphalan and prednisone was 34%. The response rate to melphalan, prednisone, and thalidomide was 84%. And the response rate to the two transplants was 71%. This suggests that conventional treatment with highly active agents may be as good as a stem cell transplant in selected populations.

Another group of patients over age 75 years were treated with melphalan, dexamethasone, and thalidomide. The melphalan was given in standard doses but the dexamethasone was given in approximately half the usual dose (at about 20mg) four days every 14 days, with thalidomide being given 300mg a day for four days every 14 days instead of the usual continuous thalidomide schedule. Patients received cycles every five weeks for a total of 12 cycles. After three months, dexamethasone and thalidomide were only given for the first four days of each five-week cycle. Overall, the response rate was 72% with 10% complete responses. The average time to response was two months, 10% of patients had blood clots, 10% of patients had peripheral neuropathy.

Early results from a smaller phase II trial evaluating melphan, prednisone, and Velcade® were also reported indicating a 91% response rate. A large, international, randomized trial comparing this regimen vs. melphalan predisone was intiated during December.

Treatments for Relapsed Multiple Myeloma

A study from Cleveland Clinic looked at the use of Doxil®, vincristine, dexamethasone, and Revlimid®. The standard regimen called DVd has been a widely used therapy for the treatment of patients with relapsed multiple myeloma. In this protocol, Revlimid® was added and the dose that was tolerable was 10mg for 21 days out of 28. Patients received monthly antibiotics and a baby aspirin every day. In this study, the near-complete response rate was 36.5% and partial response rate was 33%, for an overall response rate of nearly 70%, with good tolerance and a good outcome.

A study on the use of oral melphalan with Velcade® was reported. Patients received cycles every four weeks with a plan for a total of eight cycles. Melphalan was given in standard dose. Velcade® was reduced to 1mg/m2 from the usual 1.3mg/m2 every 28 days. Patients were all previously treated and the response rate was 68%.

A study combining thalidomide with Velcade® was reported. This was a group of myeloma patients that had aggressive disease, 79% had chromosomal abnormalities, and 81% had a previous stem cell transplant. Velcade® was given in the standard dose. Thalidomide was tolerated up to 150mg/day. The outcome showed that 60% of patients in this study had a greater than 25% reduction in their myeloma protein. Patients who had received thalidomide before going on this program did somewhat worse, suggesting that the combination was less effective due to prior thalidomide exposure.

A study from Europe reported on the use of Actimidtm for relapsed myeloma. Twenty previously treated patients were treated with Actimidtm (5mg every other day) and 45% of patients achieved meaningful responses. Dexamethasone was added in six additional patients, and three of them responded, bringing the overall response rate to 60%. The side effects were a reduction in the white blood cell count.

An important study from the National Cancer Institute of Canada (NCIC) looked at maintenance therapy following stem cell transplant. In this protocol, patients received prednisone 50mg every other day with 200-400mg thalidomide every day in an attempt to help maintain responses seen after transplant but, unfortunately, patients did not tolerate the higher-dose thalidomide for prolonged periods of time and thalidomide had to be discontinued due to side effects. It was felt that the higher doses of thalidomide were not sustainable and, therefore, protocols should be using lower doses of thalidomide in a post-stem cell transplant maintenance setting. Currently, the NCIC is conducting a study of post-stem cell transplant maintenance therapy using prednisone (50mg every other day) with thalidomide (200mg a day) and this is being compared to placebo. The use of a placebo is justified since maintenance therapy has not been proven to have survival benefit following stem cell transplant in myeloma.

Supportive care

One important report on supportive care was presented by Dr. Brian Durie and sponsored by the IMF. A web-based, self-reporting survey was taken, with 904 myeloma patients electing to participate in the study. Osteonecrosis, a painful jaw condition, was seen in 7% of patients. Ninety-two percent of the patients had received either Zometa® or Aredia®. Five percent had had radiation therapy. The risk of developing jaw necrosis is a complication of long-term exposure to these bisphosphonates and appears to increase with prior dental problems. Although the survey is not purely scientific due to possible reporting bias, it appears that there might have been a higher risk in patients receiving Zometa® over Aredia®. Caution needs to be exercised before drawing firm conclusions but physicians need to be aware of this complication, rare as it is, in long-term recipients of bisphosphonate therapy.

A protocol was presented on the impact of aspirin in preventing thalidomide thrombosis. This study involved 105 patients treated with liposomal doxorubicin, vincristine, thalidomide, and dexamethasone. Thirty-five received no preventative therapy; 70 received a baby aspirin a day. Twenty-six patients had a blood clot at an average of 109 days after the start of thalidomide. Eleven of 19 blood clots occurred off of aspirin; 15 of 84 blood clots occurred after aspirin was started for an overall blood clot rate of 18% on aspirin, 58% off aspirin. There was no bleeding due to aspirin use. Aspirin is one potential option for the prevention of blood clots in those patients taking thalidomide therapy. Whether it is superior to other methods remains unknown.

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