Melflufen and Dexamethasone Plus Bortezomib or Daratumumab in Relapsed/Refractory Multiple Myeloma Refractory to an IMiD or Proteasome Inhibitor: Updated Analysis of the Phase 1 ANCHOR Study (OP-104)

Purpose of the Study: Despite recent therapeutic advances, multiple myeloma (MM) remains incurable. Melflufen is a lipophilic peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells through peptidase activity. In the phase 1/2 O- 12-M1, melflufen + dexamethasone was active in relapsed/refractory MM (RRMM; overall response rate [ORR], 31%; median overall survival, 20.7 months), with acceptable safety (Richardson et al. Blood. 2017; Abstract 3150). The OP-104 ANCHOR study is assessing melflufen + dexamethasone in triplet combination with bortezomib or daratumumab (NCT03481556).

Summarized Description of the Project: Patients must have RRMM and be refractory (or intolerant) to an IMiD and/or proteasome inhibitor (PI) with 1-4 prior lines of therapy. Patients who receive bortezomib or daratumumab cannot be refractory to a PI or have had prior anti-CD38 monoclonal antibody therapy, respectively. Melflufen (30, 40 or 20 mg  intravenously)  is  administered on  day 1 of 28-day cycles in 1 of 2 regimens selected based on prior therapy and investigator choice. Regimen A: bortezomib 1.3 mg/m2 subcutaneously + dexamethasone 20 mg on days 1, 4, 8, and 11 and 40 mg on  days  15  and  22.  Regimen  B:  daratumumab 16 mg/kg intravenously weekly (8 doses), every 2 weeks (8 doses), then every 4 weeks + dexamethasone 40 mg weekly. Patients are treated  until  disease  progression  (PD)/unacceptable  toxicity.  The primary objective is determining the optimal melflufen dose in combination.

Results: As of 6 February 2019, 15 patients were treated: 5 with bortezomib + melflufen (30 mg, n=3; 40 mg, n=2); 10 with daratumumab + melflufen (30 mg, n=4; 40 mg, n=6).

Regimen A (bortezomib combination): Median age was 70 years (63-82). Median prior lines was 2 (2-4); 2 patients were refractory to last therapy. Median time since diagnosis was 5.8 years (1.2-7.4). No dose-limiting toxicities (DLTs) were observed. After 27 cycles, 3 patients (60%) experienced grade 3/4 treatment-related adverse events (TRAEs), most commonly thrombocytopenia (60%) and neutro- penia (40%). One patient experienced treatment-related serious AEs (TRSAEs; grade 3 neutropenia and grade 3 pneumonia). All patients remained on treatment. ORR  was 100% for  the 30-mg (median, 9 cycles) cohort. The 40-mg cohort was recruiting at the time of data cutoff; response had not been assessed (median, 1.5 cycles).

Regimen B (daratumumab combination): Median age was 63 years (35-78). Median prior lines was 2.5 (1-3); 6 patients were refractory to last therapy. Median time since diagnosis was 5.0 years (1.9-8.2). No  DLTs  were  observed  at  any  dose  level.  After  59  cycles,    6 patients experienced grade 3/4 TRAEs, most commonly neutro- penia (40%) and thrombocytopenia (30%). No patients experienced TRSAEs. Nine patients remained on treatment; 1 patient discontinued after 2 cycles due to PD (best response, stable disease). ORR was 100% in the 30-mg (median, 8 cycles) and 50% in the 40-mg (median, 3 cycles) cohort. Nonresponders (n=3) were still early in treatment (median, 2 cycles). Phase 2 was  initiated  with  melflufen 40 mg.

Conclusion: Melflufen + dexamethasone is feasible as a triplet regi- men with bortezomib or daratumumab, with promising tolerability and efficacy in RRMM. The study is actively recruiting in both regimens.