The ANCHOR study is a phase 1/2 trial of melphalan flufenamide (melflufen) + dexamethasone (DEX) and daratumumab (DARA) or bortezomib (BTZ) in patients with relapsed/refractory multiple myeloma (RRMM). The results of an analysis of updated efficacy and safety data are presented here.
Patients included in this study had RRMM and were refractory to, or intolerant of, an immunomodulatory drug and/or a proteasome inhibitor (PI), with 1 to 4 prior lines of therapy. Patients in the DARA arm were excluded if they had received prior anti-CD38 monoclonal antibody therapy. Patients in the BTZ arm were excluded if they were PI-refractory. Intravenous (IV) melflufen (30, 40, or 20 mg) was administered on day 1 of each 28-day cycle. In the DARA arm, IV DARA was administered 16 mg/kg once weekly (8 doses), every 2 weeks (8 doses), and then every 4 weeks + DEX 40 mg (20 mg if aged ≥75 years) weekly. In the BTZ arm, BTZ was administered 1.3 mg/m2 subcutaneously + DEX 20 mg (12 mg if aged ≥75 years) on days 1, 4, 8, and 11, + DEX 40 mg (20 mg if aged ≥75 years) on days 15 and 22. Patients were treated until progressive disease (PD) or unacceptable toxicity. The primary objective in phase 1 was to determine the optimal melflufen dose in combination and to assess overall response rate (ORR) in phase 2.
At data cutoff on April 6, 2020, a total of 33 patients had been treated with melflufen (30 mg, n = 6; 40 mg, n = 27) + DEX and DARA, and 10 patients had been treated with melflufen (30 mg, n = 3; 40 mg, n = 7) + DEX and BTZ. Among patients in the DARA arm, the median age was 63 years (range, 35-78 years), and the median number of previous lines of therapy was 2 (range, 1-4). High-risk cytogenetics were identified in 42% of patients. Sixty-one percent of patients were refractory to their last treatment, and 79% previously received frontline autologous stem-cell transplantation (ASCT). Median treatment duration was 8.4 months (range, 1.0-23.7 months), and 45% of patients received ≥8 cycles. A total of 9 patients remained on treatment (4 [67%] in the 30-mg cohort and 5 [19%] in the 40-mg cohort). Treatment discontinuation was primarily a result of PD (36%). The ORR was 70% (1 stringent complete response, 1 complete response, 10 very good partial responses [VGPRs], and 12 partial responses [PRs]). At a median follow-up of 18.9 months, median progression-free survival (PFS) was 12.9 months (95% confidence interval [CI], 7.7-15.4). The median duration of response was 12.6 months (95% CI, 7.6-24.2). The most common grade 3/4 treatment-related adverse events (TRAEs) occurring in ≥5 patients were neutropenia (67%), thrombocytopenia (73%), and anemia (24%). Grade 3/4 nonhematologic TRAEs were uncommon. A total of 12 (36%) patients experienced a serious TRAE. The most common TRAEs were influenza (9%), pneumonia (12%), parainfluenza virus infection (6%), and febrile neutropenia (6%). Four patients experienced fatal adverse events (myeloma progression and sepsis [2, 1 of which was considered possibly related to study treatment], 1 general physical health deterioration, and 1 chronic cardiac failure).
Among patients in the BTZ arm, the median age was 71 years (range, 61-82 years), and the median number of previous lines of therapy was 2.5 (range, 1-4). High-risk cytogenetics were identified in 40% of patients. Seventy percent of patients were refractory to their last treatment, 30% received prior frontline ASCT, and 90% received a prior PI. Median treatment duration was 5.6 months (range, 1.4-22.8 months). A total of 7 patients remained on treatment (2 patients [67%] in the 30-mg cohort and 5 patients [71%] in the 40-mg cohort). A total of 3 patients were discontinued from the study: 2 resulting from PD and 1 because of lack of efficacy. The ORR was 60% (3 VGPRs and 3 PRs). Data on PFS are premature. No dose-limiting toxicities were observed in this arm. The most common grade 3/4 TRAEs occurring in ≥2 patients were thrombocytopenia (80%), neutropenia (60%), and anemia (40%). Grade 3/4 nonhematologic TRAEs were uncommon. A total of 6 (60%) patients experienced a serious TRAE. The most common TRAE was pneumonia (20%). No deaths were reported in this arm. The BTZ arm is still recruiting.
Among patients with RRMM and poor prognostic factors, triple therapy with melflufen + DEX with BTZ or DEX with DARA demonstrated encouraging activity and was well tolerated.
Abstract 417. ASH 2020. December 6, 2020. Melflufen plus Dexamethasone (dex) and Daratumumab (dara) or Bortezomib (BTZ) in Relapsed/Refractory Multiple Myeloma (RRMM) Refractory to an IMiD and/or a Proteasome Inhibitor (PI) - Updated Efficacy and Safety.