Natural History of Patients with Multiple Myeloma Refractory to CD38-Targeted Monoclonal Antibody-Based Treatment

Introduction

Proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) have significantly improved survival in patients with multiple myeloma (MM). Refractoriness to PIs and IMiDs results in poor outcomes with a median survival of about 13 months.Daratumumab and isatuximab are CD38-targeting monoclonal antibodies (MoABs) with remarkable activity in relapsed and refractory MM. The outcome of MM patients in US clinical practice who becomes refractory to CD38 MoABs is unknown. The aim of this multicenter, retrospective study is to investigate the natural history of patients with MM who become refractory to CD38 MoABs (Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure: MAMMOTH study).

Methods

We identified patients from 14 academic institutions in the US with diagnosis of active MM and refractory to daratumumab or isatuximab, administered alone or in combination. Patients were considered refractory to CD38 MoAB if treated with at least 4 weeks of therapy and had evidence of progressive disease (PD) while on therapy or within 60 days after last dose. The time when patients met the above criteria of progression was defined as time zero (T₀). Data including patient-disease characteristics and all therapies administered before and after T₀ were collected with an electronic platform and submitted to peer-based quality check for completeness and internal consistency. For survival outcome analysis, patients were classified into three groups: "Penta-refractory" (refractory to 1 CD38 MoAB + 2 PIs + 2 IMiDs), "Triple-refractory and quad-refractory" (refractory to 1 CD38 MoAB + 1 PI + 1/2 IMiDs, or 1 CD38 MoAB + 1/2 PIs + 1 IMiD), and "Not triple-refractory" (refractory to 1 CD38 MoAB, and not both of a PI and an IMiD). Responses were evaluated using the IMWG criteria.

Results

Two hundred and seventy-five patients were included in this study; median age at T₀ was 65 years (range 27-90). Fifty five percent of patients were males, 52% had IgG isotype, 29% had ISS stage III disease, and 29% had high-risk cytogenetics at diagnosis. Median interval from diagnosis of MM to T₀ was 50.1 months (mo) (range 2.5-230.1). Patients received a median of 4 lines of treatment (1-16) prior to the CD38 MoAB-containing regimen; 72% underwent prior autologous transplant. Daratumumab-refractory patients formed a majority (256, 93.1%) of this cohort. Most of the patients were refractory to lenalidomide (77%), pomalidomide (65%), bortezomib (68%), and carfilzomib (47%). Seventy patients (25.5%) were "penta-refractory" and 148 (53.8%) were "triple-refractory and quad-refractory". Median follow-up from T₀ for survivors was 10.6 mo (range 1.9-42.3 mo). The median overall survival (OS) from T₀ for the entire cohort was 8.6 mo (95% C.I. 7.2-9.9); OS for the groups based on refractoriness to prior treatments are shown (Figure). Two hundred and forty-nine patients (90.5%) received at least one line of treatment after T₀, (median 2, range 1-10). The response rates and depth of responses to each line of treatment post T₀ are shown (Table). Among patients who received ≥ 1 subsequent treatment, the median PFS and OS from T₀ were 3.4 (95% C.I. 2.8-4.0) mo and 9.3 (95% C.I. 8.1-10.6) mo, respectively; the median OS for the 26 patients who received no further treatment was only 1.3 (95% C.I. 0.6-1.9) mo. By multivariate analysis, penta-refractoriness (HR 2.4, p <0.001), high-risk cytogenetics (HR 1.5, p=0.01), elevated LDH (HR 2, p<0.001) and creatinine > 2 (HR 2.4, p=0.01) at the onset of CD38-based therapy predicted inferior OS.

Conclusions

Patients with MM who become refractory to CD38 MoAB are increasingly less responsive to subsequent therapies. While survival is particularly dismal for penta-refractory patients, the outcomes are poor even for patients who are not refractory to other mainstream MM agents. The MAMMOTH study defines a MM population in urgent need for new therapies, and provides benchmark OS, PFS and response data for subsequent investigational therapies in this setting.

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