Paper Details

ABSTRACT

Introduction:

Despite significant therapeutic advances, patients with multiple myeloma (MM) relapse over the course of the disease and develop resistance to most available drugs. This limits treatment options, particularly in heavily pretreated patients and following exposure to or relapse after immunotherapy.

Melphalan flufenamide (Melflufen) is the first peptide-conjugated drug of its kind for MM. Melflufen combined with dexamethasone (melf-dex) has demonstrated antitumor efficacy in advanced relapsed/refractory MM (RRMM) (≥ 3 prior lines of treatment), rescuing triple-refractory patients with no other options in clinical trials, and can be initiated promptly and administered as outpatient therapy in both community and academic hospital settings. Nevertheless, real-world evidence (RWE) remains limited, particularly in patients exposed to novel immunotherapies.

Methods:

This retrospective, observational, multicenter study included 65 patients with RRMM from 33 Spanish centers treated with at least one cycle of melf-dex in the real-world setting between 2023 and 2026. Data were collected from the registry of the Asociación Madrileña de Hematología y Hemoterapia [AMHH]). A local ethics committee approved the study. Summary statistics were used for descriptive analyses. Kaplan-Meier estimates and the median with 95% confidence interval were calculated for survival analysis.

Results:

Every patient received melflufen 40 or 30 mg (dose-adjusted for renal function) by peripheral intravenous infusion on day 1 of each 28-day cycle, and oral dexamethasone 40 mg once weekly (20 mg for patients ≥75 years). A total of 40 patients (from 26 centers) with complete data among the 65 included in the registry were evaluated in this analysis. Median age was 66 years (range 43-95); 14 (35%) were ≥75 years; 13 (32.5%) had ECOG ≥2; and 19 (47.5%) had undergone ≥1 autologous stem cell transplantation. The median (range) number of prior lines of therapy was 4 (1-13). Eighty-five percent (n=34) of patients were triple-refractory, and 57.5% (n=23) were penta-refractory. Twenty-three patients (57.5%) have received prior immunotherapy (anti-BCMA, 11 [27.5%]; anti-GPRC5D, 4 [10%]; anti-BCMA+anti GPRC5D, 7 [17.5]; other, 1 [2.5]). Extramedullary disease was observed in 17 patients (42.5%), and 18 (45%) had at least 1 high-risk cytogenetic abnormality.

Outcomes in the total cohort (n=40) and in the immunotherapy-exposed subgroup (anti-BCMA+/- anti-GPRC5D, 21 evaluable patients) were respectively: overall response rate (ORR), 32.5% (n=13) and 26% (n=6); CR in 2 (5%) and 2 (9.5%) patients; stable disease (SD), 35% (n=14) and 38% (n=8). Median duration of response (mDoR) was 8.3 (95%CI 1.9, 12.8) and 5.8 (95% CI 1.9 –not reached) months, and median progression-free survival (mPFS) was 3.2 months (95%CI: 2.3-7.3) and 3 months (95%CI: 1.6-5.8), respectively. At a median follow-up of 8.9 and 8.5 months, the median overall survival (mOS) was 15.7 (95% CI:10.8-20.0) in the entire population and 23.2 (95% CI: 7.3-not reached) among those previously treated with immunotherapy. Twenty-six patients (65%) progressed after melf-dex. The outcomes in those patients who received treatment post-progression (n=20) were ORR, 40% (n=8) with a mDoR (95%CI) of 8.3 (1.9–13.3) months, a mPFS of 4.8 (CI:1.9-10.8) months, and a mOS of 19.8 (13.8– 24.0) months.

Thirty-two (80%) patients had adverse events. Hematologic toxicities included thrombocytopenia (n=26, 65%), anemia (n=21, 52.5%), and neutropenia (n=20, 50%). Thirteen (37.5%) patients developed ≥1 infection. Twenty-one (52.5%) patients required temporary treatment interruption due to side effects (mostly hematological). Adverse events leading to permanent discontinuation were observed in 2 patients (5%; thrombocytopenia [n=1] and infection [n=1]).

Conclusions:

This spanish RWE registry with melf-dex in patients with advanced RRMM shows comparable outcomes to those reported in clinical trials. This regimen demonstrated clinically meaningful responses with manageable toxicity in a heavily pretreated patient population, including those exposed to anti-BCMA+/- anti-GPRC5D therapies, with no new safety findings observed. Larger cohorts are needed to refine these y results and determine the efficacy of melf-dex in a contemporary set of patients with RRMM.