Triple-class exposed patients with relapsed/refractory multiple myeloma have poor outcomes and no clear standard of care: The LocoMMotion study

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Background

Despite recent treatment advances, multiple myeloma (MM) remains incurable, and most patients eventually relapse or become refractory to treatment. Commonly used treatment regimens for patients with relapsed/refractory MM (RRMM) include combinations of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs).1,2 Patients who have been treated with these three drug classes are referred to as “triple-class exposed”. While one retrospective study in the US showed that triple-class exposed, refractory patients with MM respond poorly to subsequent real-world therapies (overall response rate of 31%),3 there remains a need to better understand real-world standard of care (SOC) treatments and outcomes for this group. We designed the LocoMMotion study, the first prospective, non-interventional, multinational study to address this unmet need.

LocoMMotion Study Design and Results

LocoMMotion (NCT04035226), is being conducted in 76 sites in Europe and the US. It has enrolled 248 adult patients who were triple-class exposed and were either refractory to both a PI and an IMiD or had received ≥3 prior lines of therapy. The study began with a 28-day screening phase to assess baseline patient and disease characteristics. This was followed by an SOC treatment phase, which evaluated the treatments that patients received after being triple-class exposed. The study continued with a follow-up phase that documented subsequent antimyeloma therapies. We defined SOC treatments as those used in local clinical practice for the treatment of RRMM. We assessed response rates (using International Myeloma Working Group criteria), duration of response (DOR), progression-free survival (PFS) and overall survival (OS), along with incidence and severity of treatment-emergent adverse events (TEAEs). 

The enrolled patients had a median age of 68 years and had been diagnosed with MM a median of 6 years prior to the study. Prior to the SOC treatment phase, most patients had been heavily pre-treated (median of 4 prior lines of therapy), with nearly half of the patients having received ≥5 prior lines of therapy. In addition, most patients had become refractory to their last line of therapy. At a median follow-up of 11 months, about half of the patients remained in the study, 43% had completed the study due to death, and 8% had discontinued. During the SOC treatment phase, we found that patients had been treated with 92 unique SOC regimens, including various combinations of corticosteroids, PIs, IMiDs, alkylating agents, and anti-CD38 mAbs. During this time, patients received a median of 4 cycles of therapy and spent a median of about 4 months on treatment. During the follow-up phase, about half of the patients received subsequent antimyeloma therapies, including 99 unique treatment regimens. The large number of treatment regimens utilized in both the SOC phase and the follow-up phase reflect the lack of clear SOC for these patients. 

About 30% of patients had a response (ORR) to real-life SOC therapy and the median DOR was about 7 months. Responses were not deep, with no patients achieving stringent complete response and 12% achieving very good response or better, while 19% of patients had progressive disease as their best response. Median PFS was about 5 months, and median OS was about 12 months. Outcomes were worse for patients who failed to achieve VGPR during the study versus those who reached VGPR, and for patients who were triple-class refractory versus those who were not.

TEAEs were reported in 84% of patients, and about half of the patients in the study had grade 3/4 TEAEs. The most TEAEs common of these were hematologic, and no severe non-hematologic TEAEs were observed in more than 10% of patients. We believe that these rates are underestimated due to the observational nature of the study. By the time of data cut-off, 107 (43%) patients had died, with disease progression being the leading cause of death (30%). Nineteen (8%) patients died due to TEAEs, most commonly infection.

Conclusions and Relevance

LocoMMotion is the first prospective study to explore outcomes of real-life SOC treatment in triple-class exposed patients with RRMM, providing a clearer picture of how these patients are faring with existing treatment options. We demonstrated that there is no well-established SOC treatment for these patients, and that current real-world treatments lead to poor outcomes, often failing to prevent disease progression. Data from this study will be useful as a benchmark for comparisons with emerging therapies, including as an indirect comparator against clinical trials lacking a direct competitor arm. Our results indicate that there is an unmet need for new therapeutic options that can provide better and more durable responses to triple-class exposed patients with RRMM.

Disclosures

This study was funded by Janssen Research & Development, LLC and Legend Biotech, Inc. Medical writing support was provided by Julie Nowicki, PhD, of Eloquent Scientific Solutions, and funded by Janssen Global Services.

References

1. Ravi P, Kumar SK, Cerhan JR, Maurer MJ, Dingli D, Ansell SM, et al. Defining cure in multiple myeloma: a comparative study of outcomes of young individuals with myeloma and curable hematologic malignancies. Blood Cancer J. 2018;8:26. 

2. Franssen LE, Mutis T, Lokhorst HM, van de Donk N. Immunotherapy in myeloma: how far have we come? Ther Adv Hematol. 2019;10:2040620718822660. 

3. Gandhi UH, Cornell RF, Lakshman A, Gahvari ZJ, McGehee E, Jagosky MH, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33:2266-75. 

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