Melphalan, Prednisone and Thalidomide: The Standard Approach for Myeloma in Elderly Patients?

Abstract & Commentary

By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: In a multi-institutional randomized clinical trial, the combination of melphalan, prednisone and thalidomide (MPT) proved superior to melphalan and prednisone alone (MP) for the treatment of newly diagnosed multiple myeloma in elderly patients when measured in terms of response rate and event-free survival. Longer, and possibly larger, studies will be needed to see if overall survival is similarly affected.

Source: Palumbo A, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomized controlled trial. Lancet. 2006;367:825-831.

Two thirds of cases of multiple myeloma are diagnosed after the age of 65 years.1 Whereas for younger patients, high-dose chemotherapy with hematopoietic reconstitution has been shown to increase the rate of complete response and extend event-free and overall survival,2,3 for the bulk of patients with this disease, such an aggressive approach has not become standard. In fact, for older myeloma patients, no other drug regimen has exceeded outcomes achieved by melphalan/prednisone.4,5

Thus, improvements are sorely needed for the management of this disease in the elderly.

Thalidomide, by virtue of its cytokine inhibition, inhibition of angiogenesis, stimulation of cellular immunity or altered expression of cellular adhesion molecules has been demonstrated to have anti-tumor activity, including, notably, patients with multiple myeloma.

In the current study which was conducted by the Italian Multiple Myeloma Network, oral melphalan and prednisone (MP) was compared to MP with added daily thalidomide (MPT). Fifty-four centers throughout Italy participated in the study and 331 patients were randomized. The eligibility criteria were quite inclusive. Patients 65 years and older who were considered not to be transplant candidates and without pre-existing neuropathy were considered eligible. Patients who presented with abnormal cardiac, renal or hepatic function or chronic respiratory disease were not excluded. Experimental therapy (MPT) consisted of oral administration of melphalan at 4 mg/m2 on days 1-7 and oral prednisone at a dose of 40 mg/m2 on days 1-7. Each cycle was repeated every 4 weeks for a total of 6 cycles. Thalidomide was administered at 100 mg per day continuously during the 6 cycles of MPT. The control arm (MP) received melphalan and prednisone on the same schedule for 6 cycles.

Response to treatment was monitored by measurement of protein in serum and urine every 4 weeks and the response rate was determined by criteria established by the European Group for Blood and Marrow Transplantation/International Bone Marrow Transplant Registry.6

Patients treated with MPT had higher response rates and longer event-free survival than those treated with standard MP. Combined complete or partial response rates were 76% for MPT and 47.6% for MP for an absolute difference in response rate of 28.3% (95% CI, 16.5%-39.1%). Two-year event-free survival rates were 54% for MPT and 27% for MP (HR for MPT, 0.51; 95% CI, 0.35-0.75; P = 0.0006). Three-year-survival rates were 80% for MPT and 64% for MP (HR for MPT, 0.68; 95% CI, 0.38-1.22; P = 0.19). Rates for grade 3 or 4 adverse events were 48% in MPT patients and 25% in MP patients (P = 0.0002). However, midway through enrollment because of an apparent association of increased thromboembolism in MPT-treated patients, enoxaparin was prescribed to those on this arm. Thereafter the rate of thromboembolic events fell from 20% to 3% (P = 0.005). Grade 3-4 neuropathy occurred in 10 MPT treated patients.

Commentary

Myeloma occurs most frequently in older patients and this clinical trial is to be credited for its inclusive design, the entry criteria disallowing only 29 of 382 assessed patients. Although the findings regarding the response rate's added advantage with thalidomide are totally consistent with expectations (based upon prior reports) it was encouraging to note the manageable toxicity that some might have expected would be higher in this population. In this regard the trial highlights the importance of DVT prophylaxis when using thalidomide in myeloma patients, a problem that also might be expected to be of higher prevalence in elderly patients.

At the American Society of Clinical Oncology (ASCO) 42nd Annual Meeting to be held in Atlanta, June 2-6, 2006 the plenary session will feature a similar research presentation from the a French consortium of myeloma investigators.7 In their trial of myeloma patients 65 years and older (n = 436), 3 regimens were examined. These were MP, MPT and an aggressive regimen of VAD x 2, cyclophosphamide 3 gm/m2 and 2 courses of MEL-100 (including stem cell rescue). In this trial, thalidomide was escalated to a maximum of 400 mg/day (as tolerated). The data to be presented will demonstrate superiority of MPT and the suggestion will be forwarded that this approach should be the reference treatment for older myeloma patients who are considered to be ineligible for high-dose treatment. The data from both Italy and France would support this conclusion.

References

1. Ferlay J, et al. IARC Cancer Base No 5, version 2.0. Lyon (France): IARCPress, 2004.

2. Child JA, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-1883.

3. Attal M, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91-97.

4. Boccadoro M, et al. Multiple myeloma: VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients. J Clin Oncol. 1991;9:444-448.

5. Kyle RA, Rajkuumar SV. Multiple myeloma. N Engl J Med. 2004;351:1860-1873; Erratum in: N Engl J Med. 2005;352:1163.

6. Blade J, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998;102:1115-1123.

7. Facon T, et al. Proc ASCO. 2006;24(18S):1.