Outcomes of primary refractory multiple myeloma and the impact of novel therapies

Abstract

Over the past decade, use of novel agents, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) has resulted in high response rates and improvement in overall survival (OS) for patients with multiple myeloma (MM); however, the prognostic significance of refractoriness to these agents when used as initial therapy has not been extensively studied. We reviewed the outcomes of 816 consecutive patients treated for MM at our institution since 2006 to evaluate the survival difference between those achieving at least a partial response (PR) to induction therapy and those who were primary refractory. The median OS from start of therapy was significantly shorter for the primary refractory group at 3.6 vs. 7.6 years for the responding patients (P < 0.001). The difference in median OS persisted when only patients receiving a novel agent as part of induction therapy were considered (3.6 vs. 7.9 years, P < 0.001) and in a 4-month landmark analysis (4.2 vs. 7.6 years, P < 0.001). The median OS for patients achieving a complete response (CR), very good partial response (VGPR), PR, or less than PR was not reached (NR), 6.1, 6.4, and 4.2 years from the 4-month landmark, respectively (P < 0.001). The comparatively poor outcomes of patients refractory to induction therapy in the current era of novel agents suggests that this high-risk subpopulation must be further studied for predictors of resistance and, when identified, should be targeted for clinical trials.

Figure 1. Overall survival from start of therapy

(A) Kaplan-Meier curves demonstrating differences in overall survival between responders and non-responders to induction therapy in the entire cohort. (B) Overall survival excluding those who did not receive a novel agent with induction.

Figure 2. Overall survival in landmark investigation

(A) Kaplan-Meier curves demonstrating differences in overall survival between responders and non-responders to induction therapy, including only those who were alive at four months after start of treatment. (B) Overall survival in landmark investigation, with groups separated according to depth of response.