KEY TAKEAWAYS
- The phase 1/2a ANCHOR study evaluated melflufen in combination with bortezomib + dex (Vd) or daratumumab + dex (Dd) in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM).
- The primary objectives of the ANCHOR study were to determine the optimal dose of melflufen in each combination and evaluate the overall response rate.
- Melflufen plus Vd or Dd demonstrated promising activity in RRMM patients with 2 previous lines of therapy.
Melflufen is a first-of-its-kind peptide-drug conjugate (PDC) that utilizes aminopeptidases and esterases to release alkylating agents into tumor cells swiftly. Melflufen + dexamethasone (dex) is approved for use in Europe in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) who have progressed >3 years after a prior autologous stem cell transplant if one was received.
Patients must have RRMM resistant or intolerant to a prior IMiD, proteasome inhibitor (PI), and 1 to 4 initial LOTs. Initial PI therapy was permitted, but patients could not have been refractory to PIs in the most recent LoT. Prior anti-CD38 monoclonal antibody therapy was not allowed in the Dd arm. Patients received 30 or 40 mg of intravenous (IV) melflufen on day 1 of each 28-day cycle. Vd arm: subcutaneous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 plus oral dex (20 mg on days 4, 8, and 11 and 40 mg on days 15 and 22; dose reduced for patients 75 years of age). Dd arm: daratumumab 16 mg/kg intravenously once weekly (2 cycles), every 2 weeks (4 cycles), then every 4 weeks + oral dex (40 mb on days 1, 8, 15, and 22).
The primary objectives were to ascertain the optimal dose of melflufen in each combination (phase 1) and to evaluate the overall response rate (phase 2). 23 patients received melflufen (30 mg, n=15; 40 mg, n=8) +Vd, and 33 patients received melflufen (30 mg, n=6; 40 mg, n=27) +Dd as of February 9, 2022 (data cutoff date). The median prior LoTs were higher in the Vd arm, whereas more patients in the Dd arm had been exposed to high-dose alkylators. The partial clinical hold issued by the Food and Drug Administration of the United States led to the premature termination of the study on February 23, 2022. Vd arm: Median (range) treatment duration was 8.3 months (2.8-40.0 months) for the 30-mg cohort and 12.0 months (2.1-34.7 months) for the 40-mg cohort. The ORR across all cohorts was 78% (2 complete responses or better [CR], 5 very excellent partial responses [VGPR], and 11 partial responses [PR]. At a median follow-up of 21 months, progression-free survival (PFS) was 14.7 months (95% confidence interval [CI], 8.5-33.5 months); overall survival (OS) was undetermined, with 17 patients (74%) alive at the data cutoff. Cytopenias were the most prevalent treatment-emergent adverse events (TEAEs) of grade 3; thrombocytopenia led to treatment discontinuation in 3 patients; grade 3 nonhematologic TEAEs were uncommon.
There were no dose-limiting toxicities (DLTs) and three catastrophic adverse events (1 chronic cardiac failure and 2 COVID-19 pneumonia).Dd arm: In the 30-mg cohort, the median (range) treatment duration was 24.1 months (0.9-44.6), while in the 40-mg cohort, it was 6.2 months (0.9-41.2). The overall response rate was 73% (3 CR, 8 VGPR, and 13 PR). At a median follow-up of 30.0 and 32.8 months, respectively, PFS (95% CI) was 12.9 months (7.7-15.4), and OS was 26.1 months (16.4-not estimable). Thrombocytopenia and neutropenia were the most prevalent grade 3 TEAEs and TEAEs leading to treatment discontinuation; nonhematologic grade 3 TEAEs were uncommon. There were no DLTs and four fatal adverse events (2 sepsis, 1 chronic cardiac failure, and 1 general physical health deterioration).
Melflufen plus Vd or Dd demonstrated promising activity in RRMM patients with 2 previous LoTs. Safety and efficacy analyses concluded that 30 mg of melflufen should be the recommended dose for triplet regimens.
Clinical Trial: https://www.clinicaltrials.gov/ct2/show/NCT03481556
Enrique Maria Ocio San Miguel, Yvonne A. Efebera, Roman Hájek, Jan Straub, Vladimir Maisnar, Jean-Richard Eveillard, Lionel Karlin, Maria-Victoria Mateos, Albert Oriol, Vincent Ribrag, Paul Richardson, Stefan Norin, Jakob Obermüller, Nicolaas A. Bakker, Ludek Pour/ANCHOR (OP-104): MELFLUFEN PLUS DEXAMETHASONE AND DARATUMUMAB OR BORTEZOMIB IN RELAPSED/REFRACTORY MULTIPLE MYELOMA—FINAL EFFICACY AND SAFETY RESULTS/Inc, M. G. (n.d.). ANCHOR (OP-104): MELFLUFEN PLUS DEXAMETHASONE AND DARATUMUMAB OR… by Enrique Maria Ocio San Miguel. Library.ehaweb.org. Retrieved July 18, 2023, from https://library.ehaweb.org/eha/2023/eha2023-congress/386705/enrique.maria.ocio.san.miguel.anchor.28op-10429.melflufen.plus.dexamethasone.and.html?f=menu%3D16%2Abrowseby%3D8%2Asortby%3D2%2Ace_id%3D2489%2Aot_id%3D27922%2Atrend%3D4016%2Amarker%3D4178
