LocoMMotion: a prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma

Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N = 248; ECOG performance status of 0–1, ≥3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1–20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2–36.0). Median progression-free survival (PFS) and median overall survival (OS) were 4.6 (95% CI: 3.9–5.6) and 12.4 months (95% CI: 10.3–NE). Treatment-emergent adverse events (TEAEs) were reported in 83.5% of patients (52.8% grade 3/4). Altogether, 107 deaths occurred, due to progressive disease (n = 74), TEAEs (n = 19), and other reasons (n = 14). The 92 varied regimens utilized demonstrate a lack of clear SOC for heavily pretreated, triple-class exposed patients with RRMM in real-world practice and result in poor outcomes. This supports a need for new treatments with novel mechanisms of action.


INTRODUCTION
Despite advances in medical treatment that have improved survival, multiple myeloma (MM) remains incurable [1]. Most patients with MM eventually progress or become refractory to treatment with standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), anti-CD38 monoclonal antibodies (mAbs), and others [2]. Currently, there is an incomplete understanding of how heavily pretreated triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) MM patients are treated in a real-world setting and their outcomes.
Findings from the MAMMOTH study, a retrospective study of treatment outcomes in patients in the United States with MM, reported an overall response rate (ORR) of 31% with median overall survival (OS) of 9.3 months in refractory patients who were triple-class exposed [3]. These data highlight the poor outcomes in this heavily pretreated group of patients and suggest the need for more effective therapies.
However, to date there have been no multinational prospective studies examining outcomes of the standard of care (SOC) used in everyday clinical practice for heavily pretreated triple-class exposed patients. Here, we present results from the LocoMMotion study (NCT04035226), the first prospective, non-interventional, multinational study to assess the effectiveness of real-life SOC treatments in patients with RRMM who have been previously treated with a PI, an IMiD, and an anti-CD38 mAb.

SUBJECTS AND METHODS Study design and treatment
LocoMMotion is an ongoing, prospective, non-interventional study detailing the use of real-life current SOC in the treatment of RRMM patients who have received ≥3 prior lines of therapy (LOT) or were double refractory to a PI and an IMiD; received a PI, IMiD, and anti-CD38 mAb; and have documented disease progression during or after their last LOT. There were no exclusion criteria for prior therapies received by patients. The study included a 28-day screening phase (including first day of SOC treatment, where baseline patient and disease characteristics were collected), an SOC treatment phase (time from the first day of SOC treatment until progressive disease, unacceptable toxicity, or initiation of subsequent antimyeloma therapy, where efficacy and safety data were collected), and a follow-up phase until study completion (where patients were followed for survival and subsequent therapies). Study completion was defined as 24 months after first dose of the last patient enrolled in the study. Patient-reported outcomes were also collected (not reported in this article). SOC treatments were defined as those used in local clinical practice for the treatment of adult patients with RRMM, experimental drugs were not allowed. A Response Review Committee (RRC) composed of three leading hematologists in the field of MM reassessed responses per IMWG criteria, in a blinded manner, to ensure consistency of the assessments.
This study was conducted in accordance with the declaration of Helsinki. All patients provided written informed consent. An independent ethics committee/institutional review board at each center approved the study protocol.
To account for potential missing assessments in real-world clinical practice that are required for response evaluation, per strict IMWG criteria [6], additional measures were applied, as follows. The study was designed to collect all available data necessary for response evaluation at a minimum of each cycle of treatment (including serum protein electrophoresis, serum immunofixation electrophoresis, serum-free light chains, serum quantitative immunoglobulins, 24-hour urine M-protein quantitation by electrophoresis, urine immunofixation electrophoresis, as well as plasmacytomas, bone lesion, and bone marrow assessments). RRC reassessment of the response for each cycle of treatment was blinded to ensure consistency of assessment. The RRC used the strict IMWG criteria [6] with limited flexibility to mitigate potential missing information and avoid underestimation of the response.

Endpoints and assessments
The primary endpoint was ORR, defined as the proportion of patients who achieved partial response (PR) or better according to the IMWG criteria, as assessed by the RRC. Secondary clinical assessments included rates of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), duration of response (DOR), progression-free survival (PFS), and OS. Safety assessments included incidence and severity of treatment-emergent adverse events (TEAEs). Incidence of secondary primary malignancies was also collected.

Statistical analyses
Given the observational nature of the study, no direct hypothesis was tested; sample size was based on clinically acceptable precision of the 95% confidence interval (CI) for the primary objective. When the sample size was 230, using the large sample normal approximation, the width of a twosided 95% CI varied from 0.107 to 0.130 for an expected proportion varying from 0.20 to 0.40. A sample size of 230 patients was assumed sufficient to investigate secondary objectives. Continuous variables were summarized using the number of observations, mean, standard deviation, coefficient of variation, median, and range. Time-to-event data were summarized by 25th, 50th, and 75th percentiles with two-sided 95% CIs. Categorical values were summarized using the number of observations and percentages.

DISCUSSION
Results of this first, prospective study of real-life SOC treatment in triple-class exposed patients with RRMM demonstrate poor outcomes with currently available treatments and confirm rapid disease progression after application of salvage therapy. ORR (29.8%) was low, and median PFS (4.6 months) and median OS (12.4 months) were short for these patients. None of the patients evaluated reached sCR and only 1 patient achieved CR, indicating responses were not deep. Responses were not durable, particularly for patients that did not achieve VGPR, who had a median DOR of 4.5 months (95% CI: 3.5-7.3). At the time of enrollment in the study, the majority of patients (74%) were refractory to three classes of antimyeloma drugs, which appeared to be an important prognostic factor of worse outcomes with current SOC treatments. This was indicated by median PFS with SOC treatment of 3.9 months (95% CI: 3.4-4.6) in patients who were triple-class refractory at baseline and 8.2 months (95% CI: 5.7-12.0) in patients who were not triple-class refractory. These data are consistent with several retrospective studies in heavily pretreated patients with RRMM, including the MAMMOTH study, that have generally shown low OS rates and rapid disease progression [3,7,8]. Poor outcomes in triple-class exposed patients demonstrate an unmet need for improved treatments in this heavily pretreated group.
As evidenced by the 92 combinations of SOC treatments received by patients, there is not a clearly defined SOC for triple-class exposed patients in real-world practice. This lack of SOC therapy not only leaves patients with few options for well-established treatment, but also complicates the design of clinical trials to compare SOC with new treatments. Data from this study may serve as a benchmark for future comparisons with emerging therapies, as has been the case for the MAMMOTH study in patients who were refractory to anti-CD38 mAbs, which has been used as an indirect comparator against clinical trials lacking a direct comparator arm [9,10].
One limitation of the observational nature of the LocoMMotion study is that the incidence of TEAEs was likely underestimated. While TEAEs within routine clinical practice were common, occurring in 83.5% of patients, with about half of patients (52.8%) experiencing grade 3/4 TEAEs, it is likely that this is an underestimation that may  be attributed to the tendency for physicians to more frequently report adverse events that are clinically relevant or require prescription of additional medications. However, the prospective design of the study enabled collection of all available hematology laboratory results, allowing for calculation of toxicity grades based on the National Cancer Institute Common Terminology Criteria for adverse events, providing a more realistic representation of the toxicity observed with SOC treatments. In summary, the findings of the LocoMMotion study clearly demonstrate that there is no well-established real-world SOC treatment for triple-class exposed patients with RRMM. The SOC treatments currently being utilized result in poor outcomes and often fail to prevent disease progression. Although the SOC for myeloma will continue to evolve, especially as accessibility and use of BCMA-targeting therapies increases, this study highlights the urgent need for new treatment approaches with novel therapies to improve outcomes in this group of patients.