Sequential or Combination Therapy for Multiple Myeloma

Ajay Nooka; Sagar Lonial


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

In This Article

Rationale for Combination Regimens

'Sequential therapies' refer to treatment with drug regimens administered one after another rather than concurrently. The underlying concept of sequential therapies arises from the idea of preserving therapeutic options for later use in the disease course, and trying to limit the toxicities associated with combination therapies. In this mindset, less-toxic sequential therapies presume that the therapeutic end points of PFS and OS are the same with both approaches. However, equivalent outcomes may not be the case if combinations result in synergistic tumor-cell apoptosis. With available evidence, one can make a compelling case for combined therapies among both relapsed and newly diagnosed myeloma patients. First, the use of combination approaches in treating myeloma, as in many other cancers, are more effective at inducing durable responses than sequential single agents. Second, myeloma cells follow Gompertzian rather than exponential kinetics, which forms the basis for autologous stem cell transplant, suggesting enhanced susceptibility to combination therapies with the goal of minimizing residual tumor burden. Third, combinations allow targeting using the principle of induced-pathway dependence or addiction. Exposure of malignant cells to a single agent often results in preferential over-activation of a survival pathway that can be targeted using the second agent as part of a combination strategy. Finally, combination therapies can lead to synergistic mechanisms of tumor apoptosis, allowing for better overall and depth of response when compared with single-agent therapy. Thus, combination schemes with novel agents based on a preclinical rationale are key for the transformation of myeloma prognosis.[1] Further combination therapies are discussed with respect to proteasome inhibitor and immunomodulatory drug (IMiD)-based combination strategies.