Sequential or Combination Therapy for Multiple Myeloma

Ajay Nooka; Sagar Lonial


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

In This Article

Other Combination Strategies

Bortezomib has been found to sensitize highly chemoresistant MM cell lines to alkylating agents such as melphalan. Bendamustine is an alkylating agent, and in combination with prednisone it has been shown to be efficacious and have a durable response. Berenson et al. evaluated the efficacy of the combination in R/R MM. At the Phase II dose of bendamustine 90 mg/m2 and bortezomib 1.0 mg/m2, ORR was 49% and the combination was well tolerated with promising efficacy.[82] In another Phase I/II study, lenalidomide was added to the combination of bendamustine and dexamethasone. The MTD was 75 mg/m2 for bendamustine and 10 mg for lenalidomide. ORR was 52% and PFS was 4.4 months in patients who were previously refractory to lenalidomide. The high responses achieved in this group of patients suggest that bendamustine and dexamethasone is an active regimen with good tolerability and overcomes resistance to lenalidomide.[83] A bortezomib–bendamustine–dexamethasone regimen in R/R MM patients yielded an ORR of 52% and a PFS of 9.6 months.[84] These results also suggest that combination strategies improve the response rates and prolong PFS and OS.

Combinations of antimyeloma agents with a strong rationale are advancing forward, both in the preclinical and clinical setting. Taking from the example of thalidomide maintenance studies, it clearly demonstrates that patients who showed CR after ASCT in at least two studies did not benefit from thalidomide maintenance, suggesting that thalidomide might act as consolidation therapy by increasing the depth of the response post-ASCT rather than controlling the residual clone. This supports the idea of combination strategies to obtain higher levels of responses, as discussed.[85] The major objective of the combination regimens, as demonstrated in multiple completed and ongoing studies, include higher response rates with a goal of attaining better depth of response, which is being achieved in most cases. A majority of combination regimens are in part derived from preclinical experiences and rationally designed studies (Table 1 & Table 2). This approach may be effective in the relapsed setting, but is clearly more effective in the induction therapy setting where one has the opportunity to induce the maximum depth of response among patients without the acquisition of drug resistance. Caution must betaken as even though newer combinations of drugs have promising results, the long-term benefit for the majority of myeloma patients can only be confirmed by a randomized study, ideally with OS as an end point.