By Lynda Williams, medwireNews Reporter
medwireNews: The presence of two or more high-risk chromosomal aberrations (HRCAs) in patients with multiple myeloma is associated with an especially poor outcome throughout the disease course, shows research published in the Journal of Clinical Oncology.
Martin Kaiser (The Royal Marsden Hospital NHS Foundation Trust, London, UK) and co-workers say their meta-analysis of data from 24 randomised clinical trials demonstrates the adverse relationship in patients with newly diagnosed disease, regardless of eligibility for transplantation, and those with relapsed/refractory MM.
The team used a federate analysis approach to collate information for 55% of 13,926 patients with full genetic information who participated in phase 2 and 3 intervention clinical trials that reported data after 2000. This included nine studies of transplant-eligible newly diagnosed MM (n=4106), seven studies of transplant-ineligible newly diagnosed MM (n=1816) and eight studies of relapsed/refractory MM (n=1802).
The patients were aged a median of 66.5 years, 56.5% were men, and they were evenly split between International Staging System prognostic groups I (34.5%), II (37.0%) and III (24.0%).
HRCAs considered included t(4;14), gain(1q) or amp(1q) and del(17p), as well as t(14;16)/MAF translocation where results were available. There was a similar distribution among the trials of patients with no hit (no HRCAs), single hit (one HRCA) or double hit (more than two HRCAs) MM, with a median 37.4% having single hit and a median 13.8% a double hit, the investigators say.
“Meta-analysis of all studies showed highly consistent separation of risk groups by co-occurrence of HRCAs”, report Kaiser et al after assessing progression-free survival (PFS) and overall survival (OS).
Across all the trials, the hazard ratio (HR) for disease progression or death was a significant 2.28 for patients with double hit MM and 1.51 for those with single hit, versus patients with no HRCAs, and the corresponding HRs for death were a significant 2.94 and 1.69.
Moreover, “double hit MM was consistently associated with the most adverse outcomes” among patients with newly diagnosed MM who were and were not eligible for transplantation and those with relapsed/refractory disease, the researchers observe.
The prognostic impact of HRCAs was strongest for patients with transplant-eligible MM, with significant PFS and OS HRs of 2.53 and 4.17, respectively, and weakest, but still significant, among those with relapsed/refractory MM, with corresponding HRs of 2.05 and 2.21.
“Strikingly, the prognostic impact of ≥two HRCAs was maintained in trials initiated in the past decade with modern combination therapies, highlighting the ongoing unmet need of HRMM [high-risk multiple myeloma]”, say Kaiser and co-authors.
Specifically, when assessing only trials that reported data after 2015, the PFS and OS HRs for double hit versus no HRCAs were 2.39 and 3.10, respectively. And again, these associations were true among trial participants with newly diagnosed MM (HR=2.62 and 4.81) and those with relapsed/refractory MM (HR=2.34 and 2.45).
Moreover, the relationship between the number of HRCAs and prognosis was “consistently observed in studies considering combination of proteasome inhibitors and immunomodulatory agents such as FORTE for [newly diagnosed] MM and OPTIMISMM in [relapsed/refractory] MM, as well as anti-CD38 monoclonal antibody combination therapy such as in ICARIA”, the team emphasizes.
Kaiser and co-authors summarise: “The association of ≥two HRCAs with the poorest outcome in [newly diagnosed] MM and [relapsed/refractory] MM, 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.”
They add that the “results accordingly also form a basis and framework for future detailed and delineated exploration of single hit disease.”
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J Clin Oncol 2025; doi:10.1200/JCO-24-01253