Longer Duration of Treatment and Maintenance of Best Response with Lenalidomide and Dexamethasone Prolongs Overall Survival in Patients with Relapsed or Refractory Multiple Myeloma
Authors: Miguel Jesús F San , Dimopoulos Meletios A , Stadtmauer Edward A. , Rajkumar S. Vincent , Siegel David , Bravo Marie-Laure , Olesnyckyj Marta , Knight Robert D. , Zeldis Jerome B. , Harousseau Jean-Luc , Weber Donna M. 
Published: October 2019

Abstract
Introduction: Multiple myeloma (MM) accounts for about 20% of deaths from hematological cancers and remains incurable despite conventional and high-dose chemotherapy. Two phase III trials in patients with relapsed or refractory MM (MM-009 and MM-010) showed that lenalidomide combined with dexamethasone resulted in significantly improved response rates and significantly prolonged median time to progression (TTP) and overall survival (OS) compared with dexamethasone alone. This current sub-analysis of lenalidomide plus dexamethasone therapy assessed
whether there was a survival benefit in maintaining patients on therapy after achieving their best response and what the impact of early discontinuation on TTP and OS was.
Methods: Of the 353 patients from MM-009 and MM-010 treated with lenalidomide plus dexamethasone, 32 did not respond. Of the remaining 321 responding patients, 214 had a partial response (PR) or better and 107 patients had stable disease (SD). In this post-hoc sub-analysis, we first assessed the outcome of continuing treatment for ≤10 months vs. >10 months in all 321 patients who achieved SD or better, after they achieved their best response. In this landmark analysis, OS was measured from the time of achieving best response to death from any cause or to last contact. In a second analysis, we assessed the impact of early discontinuation due to adverse events or withdrawn consent on OS and TTP in all patients who achieved SD or better. Therefore, we excluded patients who discontinued treatment due to disease progression, death, or lack of efficacy. Patients who achieved SD or better and who continued on therapy were compared with those who discontinued. OS and TTP were assessed from time of randomization.
Results: In the landmark analysis, of the 321 responding patients (≥PR, n=214; SD, n=107), 223 patients received treatment for ≤10 months after achieving their best response and 98 patients for >10 months after achieving their best response. Patients who continued therapy for >10 months after achieving their first best response had significantly longer OS vs. those who received therapy for ≤10 months (not reached vs. 23.4 months; p<0.0001). At 24 months after achieving their best response, significantly more patients were alive if they continued therapy >10 months vs. ≤10 months (93.8% vs. 48.4%, p<0.0001). In the second analysis, in order to evaluate the impact of discontinuation in patients achieving SD or better, we excluded 134 patients due to disease progression, death, or lack of efficacy. Of the remaining 187 responding patients, 72 discontinued treatment for AE (n=42) or withdrew consent (n=30), while the remaining 115 patients continued treatment. Median OS and TTP were significantly longer for patients who continued vs. those who discontinued treatment (median OS: not reached vs. 29.5 months, p<0.0001; median TTP: not reached vs. 13.6 months, p<0.0001).
Conclusions: In patients achieving SD or better, prolonged duration of treatment was associated with significantly longer OS and TTP. In contrast, early discontinuation of treatment led to reduced OS and TTP. Therefore, efforts should be made to manage adverse events while maintaining patients on therapy. Furthermore, maintaining treatment with lenalidomide and dexamethasone after achieving the optimal response ensures a significant improvement in OS for patients with relapsed or refractory MM.