Melflufen Plus Dexamethasone as a Triple Regimen with Bortezomib, Daratumumab in Heavily Pretreated Relapsed/Refractory Multiple Myeloma Well-Tolerated

Results from a recent study found that melflufen plus dexamethasone as a triple regimen with bortezomib and daratumumab in patients with heavily pretreated relapsed or refractory multiple myeloma (RRMM) with poor prognostic factors was well-tolerated, according to data to be presented at the virtual American Society of Hematology (ASH) conference.

Patients with RRMM often develop resistance to standard treatments, which underscores the need for novel therapies with new mechanisms of action. Melphalan flufenamide, or melflufen, is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly releases alkylating agents into tumor cells.

The activity of melflufen plus dexamethasone was shown in heavily pretreated RRMM patients refractory to pomalidomide and/or anti-CD38 monoclonal antibody therapy in the phase 2 HORIZON study, with acceptable safety.

For this new study, patients with RRMM were intolerant of an IMiD and/or a proteasome inhibitor (PI), with 1 to 4 prior lines of therapy. Patients assigned to the daratumumab arm could not have received prior anti-CD38 mAb therapy. Further, those assigned to the bortezomib arm could not have been PI-refractory.

Melflufen was administered on day 1 of each 28-day cycle in 20, 30, 40 mg intravenously (IV). The daratumumab arm was administered at 16 mg/kg IV once weekly (8 doses), every 2 weeks (8 doses), then every 4 weeks plus dexamethasone 40 mg weekly. For the bortezomib arm, 1.3 mg/m2 subcutaneous plus dexamethasone 20 mg was administered on days 1, 4, 8, and 11 plus dexamethasone 40 mg on days 15 and 22. Patients are treated until progressive disease or unacceptable toxicity, with the primary objectives to help determine the optimal melflufen dose in combination and to assess overall response rate.

As of data cutoff on April 6, 2020, 33 patients were treated with melflufen plus dexamethasone and daratumumab, and 10 patients with melflufen plus dexamethasone and bortezomib. In the DARA arm, the median age was 64 years with a median number of prior lines at 2. High-risk cytogenetics were present in 42% of patients, 61% of patients were refractory to last therapy, and 79% received prior frontline autologous stem cell transplantation. Additionally, median treatment duration was 8.4 months, and 45% of the patients received more than or equal to 8 cycles, with 67% and 19% of patients still on treatment in the 30 mg and 40 mg cohort, respectively.

Treatment discontinuation was primarily due to peritoneal dialysis (PD), with an ORR of 70% including 1 stringent complete response, 1 complete response, 10 very good partial responses, and 11 PRs. At a median follow-up of 11.9 months, median progression-free survival (PFS) was 11.5 months. Further, median duration of response was 12.5 months, with the most common grade 3 or 4 treatment-related adverse events (TEAEs) being neutropenia, thrombocytopenia, and anemia. The most common TEAEs that were experienced by 12 patients included pneumonia, parainfluenza virus infection, and febrile neutropenia; however, two patients, experienced fatal adverse events.

In the bortezomib arm, the median age was 71 years, and a median number of prior lines was 2.5. High-risk cytogenetics were present in 40% of patients, with 70% of patients being refractory to last therapy, 30% receiving prior frontline autologous stem cell therapy, and 90% receiving a prior PI.

Median treatment duration was 5.6 months, and 5 patients were still on treatment in the 30 mg and 40 mg cohorts, respectively. Two patients discontinued treatment due to PD, whereas 1 discontinued due to lack of efficacy. The overall response rate was 60%, with the PFS data were not yet mature. The most common grade 3 or 4 TRAEs were thrombocytopenia, neutropenia, and anemia. Serious TEAEs were experienced in 6 patients, the most common being pneumonia.

REFERENCE

Myeloma/Amyloidosis: therapy, excluding transplantation: relapsed/refractory multiple myeloma. Poster presented at ASH Virtual Conference. December 6, 2020.