Sequential or Combination Therapy for Multiple Myeloma

Ajay Nooka; Sagar Lonial


Expert Rev Hematol. 2012;5(5):533-545. 

In This Article

Abstract and Introduction


In myeloma management, whether to offer sequential or combination therapies has largely remained elusive, partly for the reason that there are no conclusive studies evaluating this question and partly owing to the paradigm shift in myeloma outcomes over the last decade raising the same question again, but now in a different context with active agents such as immunomodulatory drugs and proteasome inhibitors being available. Historically, in myeloma, combination cytotoxic chemotherapy compared with the standard-of-care melphalan and prednisone regimen resulted in similar response rates, raising the question of efficacy of the cytotoxic combination therapies with high toxicities and the preference for sequential therapies in order to lower the toxicity of the chosen treatment. However, with the use of more active novel agents with favorable toxicity profiles such as bortezomib, thalidomide and lenalidomide, re-evaluation of this question is necessary.


In the practice of oncology, the question of sequential versus combination chemotherapy is often asked and frequently debated. In solid tumors, such as metastatic breast cancer or lung cancer, combinations rarely lead to improvements in overall response rate and are often associated with increased toxicity, ultimately limiting quality of life, and the added benefit of objective improvements in progression free survival (PFS) or overall survival (OS) is absent. In addition, individual agents given in combination may be clinically antagonistic, as is the case with the hormone receptor antagonist, tamoxifen, in conjunction with cytotoxic chemotherapy. Thus, all agents should not be combined with each other without adequate preclinical rationale and testing to demonstrate at least additive or synergistic benefit. This should be the case even if each agent in the combination has single-agent anti-tumor activity. However, there are numerous examples in oncology where combination therapy does offer significant benefit over sequential therapy both in the context of curative or palliative therapy. These include regimens such as R-CHOP for non-Hodgkin lymphoma, ABVD for Hodgkin lymphoma or FCR for chronic lymphocytic leukemia. Combination therapy does have biology- and tolerability-based limitations, which are often a direct result of assessments rather than conceptual concerns over combinations. In myeloma, the issue of combination versus sequential therapy has been historically dominated by the use of largely ineffective combinations of chemotherapy (M2 regimen, VBMCP) when compared with standard melphalan and prednisone (MP) regimen. Given the low overall response rates (ORR) for any of these historical regimens, it is not surprising that the use of sequential therapy was equivalent (or equally ineffective) to the use of combination therapy. However, with the use of newer more active agents such as bortezomib, thalidomide and lenalidomide, reconsideration of sequential therapy is warranted.