Background: Patients (pts) with RRMM often develop resistance to standard treatments, underscoring the need for novel therapies with new mechanisms of action (MOA). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells.

The activity of melflufen plus dex was shown in heavily pretreated RRMM pts refractory to pomalidomide and/or anti-CD38 monoclonal antibody (mAb) therapy in the phase 2 HORIZON study (OP-106; overall response rate [ORR], 29%; median progression-free survival [PFS], 4.2 months; median overall survival, 11.6 months), with acceptable safety (Richardson et al. EHA 2020. Abs. EP945). The approved agents dara and BTZ have nonoverlapping MOA to melflufen, supporting the rationale for combining these agents to overcome therapy resistance. This is an update of efficacy and safety from the phase 1/2 ANCHOR study (OP-104; NCT03481556) of melflufen plus dex and dara or BTZ in RRMM.

Methods: Pts had to have RRMM and be refractory to (or intolerant of) an IMiD and/or PI, with 1-4 prior lines of therapy. Pts assigned to the dara arm could not have received prior anti-CD38 mAb therapy; those assigned to the BTZ arm could not have been PI-refractory. Melflufen (30, 40, or 20 mg intravenously [IV]) was administered on day 1 of each 28-day cycle. Dara arm: dara 16 mg/kg IV once weekly (8 doses), every 2 weeks (8 doses), then every 4 weeks + dex 40 mg (20 mg if aged ≥75 years) weekly. BTZ arm: BTZ 1.3 mg/m2 subcutaneous + 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. Pts are treated until progressive disease (PD) or unacceptable toxicity. The primary objectives were to determine the optimal melflufen dose in combination (phase 1) and to assess ORR (phase 2).

Results: As of data cutoff (06 April 2020), 33 pts were treated with melflufen (30 mg, n=6; 40 mg, n=27) plus dex and dara and 10 pts with melflufen (30 mg, n=3; 40 mg, n=7) plus dex and BTZ.

Dara arm: Median age was 64 years (range, 35-78), and median number of prior lines was 2 (range, 1-4). High-risk cytogenetics were present in 42% of pts; 61% of pts were refractory to last therapy, and 79% received prior frontline autologous stem cell transplantation (ASCT). Median treatment duration was 8.4 months (range, 1.0-23.7), and 45% of the pts received ≥8 cycles; 4 pts (67%) and 5 pts (19%) were still on treatment in the 30-mg and 40-mg cohort, respectively. Pts discontinued treatment primarily due to PD (36%). ORR was 70%, including 1 stringent complete response, 1 complete response, 10 very good partial responses (VGPRs), and 11 PRs. At a median follow-up of 11.9 months, median PFS was 11.5 months (95% CI, 6.7-not reached [NR]). Median duration of response was 12.5 months (95% CI, 8.3-NR). The most common grade 3/4 treatment-related adverse events (TRAEs; ≥5 pts) were neutropenia (58%), thrombocytopenia (55%), and anemia (24%); grade 3/4 nonhematologic TRAEs were uncommon. Twelve pts (36%) experienced serious TEAEs, most commonly influenza (9%), pneumonia, parainfluenza virus infection, and febrile neutropenia (6% each). Two pts experienced fatal AEs (myeloma progression and sepsis [1 pt], general physical health deterioration); sepsis was considered related to study treatment.

BTZ arm: Median age was 71 years (range, 61-82), and median number of prior lines was 2.5 (range, 1-4). High-risk cytogenetics were present in 40% of pts; 70% of pts were refractory to last therapy; 30% received prior frontline ASCT, and 90% received a prior PI. Median treatment duration was 5.6 months (range, 1.4-22.8); 2 pts (67%) and 5 pts (71%) were still on treatment in the 30-mg and 40-mg cohorts, respectively. Two pts discontinued due to PD; 1 due to lack of efficacy. ORR was 60%, including 3 VGPRs and 3 PRs. PFS data are not yet mature. No dose-limiting toxicities were observed. The most common grade 3/4 TRAEs (≥2 pts) were thrombocytopenia (80%), neutropenia (60%), and anemia (40%); grade 3/4 nonhematologic TRAEs were uncommon. Six pts (60%) experienced serious TEAEs, most commonly pneumonia (20%). No deaths were reported.

Conclusion: Melflufen plus dex as a triplet regimen with BTZ or dara has encouraging activity in heavily pretreated RRMM with poor prognostic factors and was well tolerated. Analysis of the dara arm in more pts with longer follow-up suggests consistent responses with continued therapy.

Disclosures

Ocio:Takeda: Honoraria; GSK: Consultancy; Asofarma: Honoraria; MDS: Honoraria; Oncopeptides: Consultancy; Secura-Bio: Consultancy; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria. Efebera:Celgene: Research Funding; Pharmacyclics: Research Funding; Ohio State University: Current Employment; Takeda: Honoraria, Speakers Bureau. Hájek:Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Maisnar:Janssen, Amgen, Takeda, Celgene/Bristol-Myers Squibb, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Eveillard:Amgen, Celgene, Janssen, Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Karlin:Celgene: Other: Personal fees; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Ribrag:argenX: Current equity holder in publicly-traded company, Research Funding; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BAY1000394 studies on MCL: Patents & Royalties; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria; AZD: Honoraria, Other; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Institut Gustave Roussy: Current Employment; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mateos:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Sydvander:Oncopeptides AB: Current Employment; Medivir AB: Ended employment in the past 24 months. Norin:Oncopeptides AB: Current Employment, Current equity holder in publicly-traded company. Mannikko:Oncopeptides AB: Consultancy; Oy 4Pharma Ltd: Current Employment.

OffLabel Disclosure:

This is a phase 1/2 investigational study of melflufen in RRMM

Author notes

*

Asterisk with author names denotes non-ASH members.