Therapy for Elderly Multiple Myeloma Patients

Abstract & Commentary

By Andrew S. Artz, MD, Section of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationship to this field of study.

Synopsis: This large European randomized trial of elderly MM patients helps delineate the role of initial therapy for elderly patients not considered eligible for autologous stem cell transplant. There were 488 eligible patients 65 to 75 years of age randomized to melphalan-prednisone (MP), dexamethasone (DEX) alone, M-DEX, or DEX-interferon-alfa 2b (DEX-IFN). Complete responses were rare. More patients in the M-DEX achieved a PR than in the other arms. PFS survival was superior in the MP and M-DEX arms but OS was similar. MP had the least non-hematologic toxicity. In elderly MM patients not eligible for transplant, MP remains the standard approach as initial therapy. The benefit of novel agents in this population requires testing.

Source: Facon T, et al. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006;107:1292-1298.

High-dose myeloablative chemotherapy followed by autologous stem cell rescue has been the standard therapy for eligible patients with multiple myeloma (MM)1, although the timing of transplant remains controversial. Melphalan-Prednisone (MP) is often considered for those ineligible for transplant and has been standard for over 30 years. High dose pulse dexamethasone (DEX) monotherapy has often been employed as it accounts for the majority of the activity of VAD (vincristine, adriamycin, dexamethasone) but is better tolerated.2

Between 1995 and 1998, the Intergroupe Francophone du Myelome (IFM) group randomized newly diagnosed MM patients aged 65 to 75 years requiring treatment to MP vs 3 other Dexamethasone-based regimens: M-DEX (melphalan-dexamethasone), DEX alone, and DEX-IFN (DEX-interferon alfa-2b). The median age was 70 years for the 488 eligible patients who were equally allocated among the four treatment groups. The data safety and monitoring board stopped accrual based upon on an interim analysis. Compared to MP and M-DEX, DEX showed inferior PFS (P < 0.001) and OS (P = 0.03).

Complete responses were rare. At least a PR was obtained by 70% in the M-DEX arm compared to approximately 40% in the other 3 arms (P < 0.001). The melphalan groups (MP and M-DEX) had significantly longer PFS (22.4 ± 1.2 months) than the DEX and DEX-IFN groups vs (12.6 ± 1.3 months) (RR, 1.55; P < .001). Overall survival did not differ among groups. Severe non-hematologic toxicities were lower in MP (16%) compared to the DEX based regimens (28%) (P = .01).

Commentary

While high-dose chemotherapy followed by autologous stem cell transplantation remains the standard approach for younger patients with MM, the majority of patients are older and may not necessarily be eligible or benefit from such an approach. Trials guiding treatment in this large cohort have been limited.

This large scale randomized trial comparing MP to three other DEX based regimens of DEX alone, Melphalan-DEX, and DEX-interferon alfa-2b offers guidance. Melphalan-based regimens (MP, M-DEX) showed improved PFS. No OS benefit was demonstrated although the study was stopped early by the data safety and monitoring board. The enhanced response rate of M-DEX was counterbalanced by the increased non-hematologic toxicities of the DEX based regimens compared to MP. The authors appropriately conclude the MP is a reasonable standard therapy for elderly patients ineligible for transplant. Those needing a more rapid response may be considered for DEX alone or M-DEX initially. One drawback to initial MP therapy however is the myelotoxicity of melphalan may prevent eventual autologous stem cell collection should the patient later be considered transplant eligible.

The low complete response rates in initial therapy of all the tested combinations suggest a potential role for newer agents with significant activity such as thalidomide, bortezomib, or lenalidomide. Such agents require testing as initial therapy in older MM patient with a watchful eye on both response rates and toxicity.

References

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

2. Alexanian R, et al. Primary dexamethasone treatment of multiple myeloma. Blood. 1992;80:887-890.