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. 2025 Nov 25;9(22):5828-5836.
doi: 10.1182/bloodadvances.2025017394.

Frail subgroups determine heterogeneous outcomes in older patients with NDMM: long-term follow-up of the HOVON 143 trial

Febe Smits  1   2   3 , Kaz Groen  1   2 , Mark-David Levin  4 , Claudia A M Stege  5 , Roel van Kampen  6 , Ellen van der Spek  7 , Inger Nijhof  8 , Yavuz M Bilgin  9 , Noortje Thielen  10 , Inge Ludwig  11 , Esther G M de Waal  12 , Yorick Sandberg  13 , Alain Kentos  14 , Gert-Jan Timmers  15 , Josien C Regelink  16 , Matthijs Westerman  17 , Koen de Heer  18 , Marie-Christiane Vekemans  19 , Nazik Durdu-Rayman  20 , Nicole C H P de Graauw  21 , Maarten R Seefat  1   2 , Niels W C J van de Donk  1   2 , Paula F Ypma  3 , Kazem Nasserinejad  5 , Sonja Zweegman  1   2
Affiliations

Frail subgroups determine heterogeneous outcomes in older patients with NDMM: long-term follow-up of the HOVON 143 trial

Febe Smits et al. Blood Adv. .

Abstract

Frailty, rather than age alone, is a key determinant of outcomes in older patients with multiple myeloma (MM), yet frailty assessments are often lacking in clinical trials. Consequently, data on the efficacy and tolerability of novel treatments in frail patients remain scarce. Moreover, there is substantial heterogeneity among frail patients, with some classified as frail solely due to age (>80 years) and others due to geriatric impairments and/or comorbidities. To our knowledge, the HOVON 143 trial was the first trial that was specifically designed for frail patients with newly diagnosed MM (NDMM) using the International Myeloma Working Group Frailty Index (IMWG-FI). After a median follow-up of >5 years, we report the long-term progression-free survival (PFS) and overall survival (OS) outcomes, with detailed analyses of frail subgroups. Patients who were classified as frail according to the IMWG-FI were treated with 9 induction cycles of ixazomib, daratumumab, and low-dose dexamethasone, followed by maintenance therapy until progression for a maximum of 2 years. Median PFS was 13.8 months, and median OS was 34.0 months. However, frail subgroup analyses based on geriatric impairments and comorbidities besides age revealed pronounced heterogeneity in outcomes. Both early relapse-related and nonrelapse-related mortality rates were higher in ultrafrail patients and patients who were frail due to impairments than in patients who were frail based on age alone. These findings highlight the need for a more precise frailty definition to identify patients at the highest risk of early mortality. This trial was registered at www.clinicaltrialsregister.eu as EudraCT #2016-002600-90.

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Conflict of interest statement

Conflict-of-interest disclosure: K.G. has received payment/honoraria for presentations from Bristol Myers Squibb and BeiGene (no personal funding). C.A.M.S. has received payment/honoraria for presentations from Amgen, Celgene, Janssen Pharmaceuticals, Novartis, Regeneron, Sanofi, and Takeda; and provided consultancy for J&J and Regeneron. E.v.d.S. received honoraria for educational events from Janssen. A.K. provided consultancy for Amgen, Sanofi, and Janssen-Cilag. G.-J.T. received honoraria for consultancy and travel expenses from Novartis and Janssen. M.W. received honoraria for educational events from Janssen. M.-C.V. provided consultancy for Amgen, Janssen, Celgene, Sanofi, Pfizer, GlaxoSmithKline, and Menarini; and received honoraria for educational events from Amgen, Celgene, Janssen, and Takeda. P.F.Y. received honoraria for educational events from Janssen. N.W.C.J.v.d.D. has received research support from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, and Bristol Myers Squibb; and serves on advisory boards for Janssen Pharmaceuticals, Amgen, Celgene, Bristol Myers Squibb, Takeda, Roche, Novartis, Bayer, Pfizer, Merck, Kite Pharma, AbbVie, Adaptive, and Servier, which are all paid to the institution. S.Z. received research funding from Takeda, Celgene, and Janssen. S.Z. serves on advisory boards for Takeda, Celgene, Janssen, Sanofi, Oncopeptides, and Amgen, all paid to the institution. The remaining authors declare no competing financial interests.

A complete list of investigators in the HOVON 143 Study Group appears in the supplemental Appendix.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Consort diagram of frail patients included in the HOVON 143 depicting timing and reason for treatment discontinuation. ∗One ultrafrail patient died due to sepsis before initiation of the first induction cycle.
Figure 2.
Figure 2.
Survival outcomes for all frail patients and across frail subgroups. (A) PFS, (B) PFS2, and (C) OS.
See this image and copyright information in PMC

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