Baseline CD57 + and CD16 + NK-Cells Predict Treatment Outcome in Non-Transplant Eligible Newly Diagnosed Multiple Myeloma Patients Treated with Daratumumab-Ixazomib-Dexamethasone

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.1940-1940
• Main Authors: Bruins, Wassilis S.C, Duetz, Carolien, Groen, Kaz, Korst, Charlotte L.B.M., de Jonge, A.Vera, Rentenaar, Rosa, Cosovic, Meliha, Eken, Merve, Twickler, Inoka, Homan-Weert, Paola, Verkleij, Christie P.M., Frerichs, Kristine A., van de Donk, Niels WCJ, Zweegman, Sonja, Mutis, Tuna
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-189527

Background Non-fit multiple myeloma (MM) patients have inferior survival, increased toxicity, and higher rates of treatment discontinuation compared with their fit peers. Effective and less toxic treatment strategies are therefore urgently needed for this vulnerable population. The HOVON-143 trial (EudraCT: 2016-002600-90) was specifically designed to assess the efficacy and safety of daratumumab-ixazomib-dexamethasone in non-transplant eligible (NTE), intermediate fit and frail newly diagnosed (ND)MM patients. Patients were treated with nine 28-day induction cycles comprising daratumumab 16 mg/kg intravenously (cycles 1-2: days 1, 8, 15, and 22; cycles 3-6: days 1 and 15; cycles 7-9: day 1), ixazomib 4 mg orally (days 1, 8, and 15) and dexamethasone orally (only on days that daratumumab was given; cycle 1-2: 20 mg; cycle 3-9: 10 mg), followed by 8-week maintenance cycles consisting of daratumumab (day 1) and ixazomib (days 1, 8, 15, 29, 36, 43) for two years or until disease progression. Aims Since daratumumab has well-known NK-cell-mediated effector mechanisms and T-cell-stimulating immunomodulatory effects, we monitored these cell subsets in bone marrow (BM) and peripheral blood (PB) samples obtained before and during treatment. We specifically aimed to better understand these cell subsets related to frailty status, their predictive value for treatment outcome, and their dynamics during treatment. Methods 126 NDMM patients, among which 64 intermediate fit and 62 frail, were monitored. BM was collected at study-entry (baseline) and at disease progression; PB was collected at baseline, before cycle 4, before maintenance, and at disease progression. Absolute numbers of total T-cells and NK-cells (in PB) or percentages of T-cell and NK-cell subsets (in PB and BM) were profiled by flow cytometry. Data were analyzed using FlowSOM and UMAP. Total cells and cell subsets at baseline were compared between intermediate fit and frail patients, between responders (≥ partial response) and non-responders (< partial response), and associated with progression-free survival (PFS) and overall survival (OS). Results At baseline, we found no difference in absolute numbers of total T-cells and NK-cells between intermediate fit and frail patients. Besides, NK-cell phenotype was similar between both groups. However, within the T-cell compartment frail patients had a decreased CD4 +:CD8 + T-cell ratio, reduced naïve CD4 + and CD8 + T cells, and increased PD1 + CD4 + T-cells com