AUTHOR=Abdallah Al-Ola , Lesokhin Alexander , Wrobel Tomasz , Jamroziak Krzysztof , Dytfeld Dominik , Touzeau Cyrille , Suvannasankha Attaya , Leleu Xavier , Silbermann Rebecca , Khan Abdullah M. , Kumar Shaji , Gertz Morie , Laubach Jacob P. , Jou Ying-Ming , Bar Merav , Das Prianka , Wang Yu , Demers Korey , Stong Nicholas , Perumal Deepak , La Motte-Mohs Ross , MacLachlan Kylee , Dimopoulos Meletios-Athanasios TITLE=Nivolumab and daratumumab combination regimens for the treatment of relapsed and refractory multiple myeloma: results of a randomized phase I/II clinical trial JOURNAL=Frontiers in Hematology VOLUME=2 YEAR=2023 URL=https://www.frontiersin.org/journals/hematology/articles/10.3389/frhem.2023.1244494 DOI=10.3389/frhem.2023.1244494 ISSN=2813-3935 ABSTRACT=Purpose

The phase I/II trial CheckMate 039 (NCT01592370) evaluated the safety, tolerability, and efficacy of nivolumab-daratumumab (ND) in patients with relapsed/refractory multiple myeloma (RRMM).

Methods

Patients with RRMM were randomized to receive ND with or without pomalidomide-dexamethasone (Pd) in cohort A and ND or D monotherapy in cohort B. The primary endpoint was safety. Secondary endpoints included minimal residual disease (MRD) negativity status, overall response rate (ORR), duration of response, and progression-free survival (PFS).

Results

Cohort A (n = 11) was terminated early due to safety concerns observed with immunomodulatory agents and checkpoint inhibitor combinations in other clinical trials. In the small number of patients treated in cohort A, no new safety concerns were observed but patients who received NDPd had numerically more grade 3/4 adverse events (AEs) and serious AEs compared with ND. Grade 3/4 AEs occurring in ≥ 1 patient in the ND group was anemia (3/6 patients); in the NDPd group, these were neutropenia (3/5 patients), upper respiratory tract infection (2/6 patients), and pneumonia (2/6 patients). In cohort B (n = 63), AE rates were similar between ND and D (any-grade: 87.8% vs 95.5%; grade 3/4: 53.7% vs 45.5%). Grade 3/4 AEs occurring in ≥ 1 patient in the ND group were neutropenia (19.5%), anemia (9.8%), thrombocytopenia (9.8%), and bronchitis (7.3%); in the D group these were anemia and pneumonia (both 9.1%). Immune-mediated AEs for ND were consistent with the known safety profile of nivolumab. In cohort A, all patients (5/5) receiving NDPd and 4/6 receiving ND achieved a response. In cohort B, the ORR with ND was numerically higher than D (22/41 [53.7%] vs 9/22 [40.9%]) and both groups had a median PFS of 6.6 months. ND also showed promising MRD negativity results (next-generation sequencing 10-5, 24.0%; next-generation flow 10-5, 22.2%).

Conclusion

NDPd demonstrated no new safety signals and encouraging efficacy despite its early termination. ND was well tolerated with a manageable toxicity and few AEs leading to discontinuation, and demonstrated a numerically higher ORR but equivalent PFS compared with D. Any clinical benefits to OS require a longer follow-up.

Clinical trial registration

https://clinicaltrials.gov/, identifier NCT01592370.