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Meta-Analysis
. 2025 Aug 20;43(24):2679-2691.
doi: 10.1200/JCO-24-01253. Epub 2025 Feb 18.

Co-Occurrence of Cytogenetic Abnormalities and High-Risk Disease in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma

Martin F Kaiser  1   2 , Pieter Sonneveld  3 , David A Cairns  4 , Marc S Raab  5 , Jesús San-Miguel Izquierdo  6 , Rick Zhang  7 , Jorge Acosta  8 , Alessandra Larocca  9 , Rakesh Popat  10 , Cong Li  11 , Marc-A Baertsch  5 , Sarah R Brown  4 , JuanJose Lahuerta Palacios  12 , Anita K Gandhi  13 , Sandrine Macé  14 , Pellegrino Musto  15 , Kwee Yong  10 , Elias K Mai  5 , Franck Dubin  14 , Joan Blade  16 , Andrea Capra  17 , Gordon Cook  4   18 , Uta Bertsch  5 , María-Victoria Mateos  19 , Mario Boccadoro  20 , Graham H Jackson  21 , Norma C Gutiérrez  22 , Francesca Gay  23 , Niels Weinhold  5
Affiliations
Meta-Analysis

Co-Occurrence of Cytogenetic Abnormalities and High-Risk Disease in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma

Martin F Kaiser et al. J Clin Oncol. .

Abstract

Purpose: Survival for patients with multiple myeloma (MM) has improved but outcomes remain heterogeneous. Consistent diagnostic identification of high-risk disease is desirable to address unmet patient need. The aim was to investigate the consistency of association of co-occurrence of high-risk cytogenetic abnormalities (HRCAs) with prognosis in patients with newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM), and across a range of treatment modalities.

Methods: A systematic review of randomized controlled trials of MM that reported testing for HRCA between January 1, 2000, and December 9, 2021, was performed. Groups were contacted and asked to locally perform a novel, federated analysis of their data for single hit (one HRCA) and double hit (≥two HRCAs), using a centrally provided algorithm. Analysis results were centrally collated and meta-analyzed to assess the hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) for one/≥two HRCAs across patient subgroups using random-effects models.

Results: Twenty-four trials including 13,926 patients were included. The median age of participants was 66.5 years (IQR, 59-72) and 56.5% were male (IQR, 52-60). The HR for PFS was 2.28 (95% CI, 2.05 to 2.54) for patients with ≥two HRCAs and 1.51 (95% CI, 1.38 to 1.65) for patients with one HRCA. The HR for OS was 2.94 (95% CI, 2.49 to 3.47) and 1.69 (95% CI, 1.52 to 1.88) for the two subgroups, respectively. In studies initiated since 2015, the effect abides (≥two HRCA PFS, HR, 2.39 [95% CI, 1.96 to 2.91]; OS, 3.10 [95% CI, 2.10 to 4.60]) both for NDMM and RRMM. Heterogeneity related to transplant eligibility and relapsed/refractory status was as expected.

Conclusion: The association of ≥two HRCAs with the poorest outcome in NDMM and RRMM, and across treatment modalities, as demonstrated here for the first time to our knowledge, allows for more focused development of novel approaches to these patients with high unmet need.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Figures

FIG 1.
FIG 1.
Study selection. aTwo studies (MRC Myeloma IX and NCRI Myeloma XI were platform trials including pathways for transplant-eligible and transplant-ineligible NDMM). IMiD, immunomodulatory drug; MRC, Medical Research Council; NCRI, National Cancer Research Institute; NDMM, newly diagnosed multiple myeloma; PI, proteasome inhibitor.
FIG 2.
FIG 2.
Random-effects meta-analysis of all studies considering PFS, by patient group and overall. EMN, European Myeloma Network; GEM, Grupo Español de Mieloma; GIMEMA, Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto; GMMG, German Multicenter Myeloma Group; HOVON, Dutch-Belgian Hemato-Oncology Cooperative Group; HR, hazard ratio; MRC, Medical Research Council; MM, multiple myeloma; MUK, Myeloma UK; NCRI, National Cancer Research Institute; NDMM, newly diagnosed MM; PFS, progression-free survival; RE, random-effects; RRMM, relapsed/refractory MM; TE, transplant-eligible; TNE, transplant-ineligible.
FIG 3.
FIG 3.
Random-effects meta-analysis of all studies considering OS, by patient group and overall. EMN, European Myeloma Network; GEM, Grupo Español de Mieloma; GIMEMA, Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto; GMMG, German Multicenter Myeloma Group; HOVON, Dutch-Belgian Hemato-Oncology Cooperative Group; HR, hazard ratio; MM, multiple myeloma; MRC, Medical Research Council; MUK, Myeloma UK; NCRI, National Cancer Research Institute; NDMM, newly diagnosed MM; OS, overall survival; RE, random-effects; RRMM, relapsed/refractory MM; TE, transplant-eligible; TNE, transplant-ineligible.
FIG 4.
FIG 4.
Kaplan-Meier estimates of survivor function for PFS separated by co-occurrence of cytogenetic abnormality for representative trials in (A) NDMM TE—HOVON-65/GMMG-HD4, (B) NDMM TNE—NCRI Myeloma XI, and (C) RRMM—OPTIMISMM. GMMG, German Multicenter Myeloma Group; HOVON, Dutch-Belgian Hemato-Oncology Cooperative Group; MM, multiple myeloma; NCRI, National Cancer Research Institute; NDMM, newly diagnosed MM; PFS, progression-free survival; RRMM, relapsed/refractory MM; TE, transplant-eligible; TNE, transplant-ineligible.
FIG 5.
FIG 5.
Kaplan-Meier estimates of survivor function for OS separated by co-occurrence of cytogenetic abnormality for representative trials in (A) TE—HOVON-65/GMMG-HD4, (B) TNE—NCRI Myeloma XI, and (C) RRMM—OPTIMISMM. GMMG, German Multicenter Myeloma Group; HOVON, Dutch-Belgian Hemato-Oncology Cooperative Group; NCRI, National Cancer Research Institute; OS, overall survival; TE, transplant-eligible; TNE, transplant-ineligible; RRMM, relapsed/refractory multiple myeloma.
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