Researchers Seek to Understand Clinical Significance of Chromosome 1q Abnormalities in Multiple Myeloma

Amplification of the long arm of chromosome 1 (1q) in patients with multiple myeloma (MM) is associated with poorer progression free survival (PFS), reduced treatment response, and higher likelihood of disease progression or relapse, according to new research. The study, published in the Blood Cancer Journal, investigated the association between disease progression and amplified 1q (Amp1q) compared with gain of the long arm of chromosome 1 (Gain1q), revealing an increased severity of disease for patients with MM and Amp1q abnormalities.

The treatment landscape for MM is continually evolving, and these initial findings provide critical insights into the molecular mechanisms driving disease progression and treatment resistance in patients with Amp1q and Gain1q abnormalities. Image Credit: © OHMAl2T - stock.adobe.com

Amp1q is the most common chromosomal abnormality found in 30% to 40% of patients with transplant eligible newly diagnosed MM (NDMM) and 50% to 80% of patients with relapsed/refractory (R/R) MM. It is characterized by the presence of 4 or more copies of the 1q region in malignant cells, resulting in an overexpression of genes that contributes to increased progression and aggression of disease. The increased clonal size of 1q is associated with poor prognosis, suggesting a “dose effect,” wherein additional genes on chromosome 1q, such as CKS1B, PSMD4, ADAR1, and MCL-1, disrupt normal cellular functions.¹

In comparison, Gain1q, another prevalent chromosomal abnormality, shows a less severe impact than Amp1q but still leads to worse outcomes compared to patients without this abnormality. Specific gene expression profiles further influence the risks associated with Gain1q, as illustrated by studies at the University of Arkansas for Medical Sciences Myeloma Center, which revealed poorer responses to daratumumab therapy in high-risk patients with baseline Gain1q presence. Therefore, investigating the differential effects of Amp1q and Gain1q is essential for gaining deeper insights into their roles in disease progression and treatment response.^2,3

Utilizing data from the FORTE trial, a randomized clinical trial investigating therapeutic combinations including carfilzomib (Kyprolis; Amgen), lenalidomide (Revlimid; Bristol-Myers Squibb), and dexamethasone (Ozurdex; AbbVie) with or without autologous stem cell transplantation (ASCT), the study evaluated 1q abnormalities' impact on treatment response and underlying molecular mechanisms. Participants, enrolled between February 2015 and April 2017, included 477 transplant-eligible patients with NDMM aged ≤65 years. Among 400 patients evaluable for 1q abnormalities, 52 had Amp1q, 129 had Gain1q, and 219 had normal 1q cytogenetics.

Results demonstrated that patients with Amp1q had a median PFS of 21.2 months, which was significantly shorter than those with Gain1q at 54.9 months (HR 1.99, 95% CI 1.33–2.96, P = .0008) and those with normal 1q, for whom PFS was unreached (HR 3.34, 95% CI 2.24–4.98, P < .0001). Amp1q was also associated with shorter overall survival (OS) compared with normal 1q (HR 4.40, 95% CI 2.59–7.49, P < .0001) and to Gain1q (HR 3.22, 95% CI 1.89–5.49, P < .0001). The significant differences in PFS and OS underscore the pronounced adverse impact of Amp1q, highlighting the need for more targeted therapies to overcome high-risk chromosomal abnormalities.¹

The study identified several molecular pathways and genetic changes that influence Amp1q and Gain1q using RNA sequencing (RNAseq) to detect differentially expressed genes. They observed significant deregulation in apoptosis signaling, indicating potential mechanisms by which cancer cells evade programmed cell death, as well as alterations in p38K MAPK signaling pathways, which may promote cell survival in patients with Amp1q mutations. Notably, a gene network centered around Myc, a regulator of cell growth and division, was implicated in the aggressive behavior associated with Amp1q.¹

Further insights included multiple specific genetic alterations in Amp1q cases that can impact treatment response. The study authors observed an upregulation of CD55, which has been implicated in immune evasion and could reduce the effectiveness of anti-CD38 monoclonal antibodies. Additionally, there was increased expression of GPRC5D, which is under investigation as a target for bispecific antibodies and CAR T cell therapies. However, further investigation is needed to more clearly identify the role of 1q abnormalities due to limitations in bulk RNAseq results compared with investigations at the single-cell level.¹

The treatment landscape for MM is continually evolving, and these initial findings provide critical insights into the molecular mechanisms driving disease progression and treatment resistance in patients with Amp1q and Gain1q abnormalities. This underscores Amp1q as a pivotal prognostic marker in NDMM patients with chromosomal abnormalities, emphasizing the imperative to advance targeted therapeutic strategies for this patient population.

References

1. D’Agostino M, Rota-Scalabrini D, Belotti A, et al. Additional copies of 1q negatively impact the outcome of multiple myeloma patients and induce transcriptomic deregulation in malignant plasma cells. Blood Cancer J. June 7, 2024. https://doi.org/10.1038/s41408-024-01075-x

2. Neupane K, Fortuna G.G., Dahal R, et al. Alterations in chromosome 1q in multiple myeloma randomized clinical trials: a systematic review. Blood Cancer J. January 25, 2024. https://doi.org/10.1038/s41408-024-00985-0

3. Mohan M, Weinhold N, Schinke C, et al. Daratumumab in high-risk relapsed/refractory multiple myeloma patients: adverse effect of chromosome 1q21 gain/amplification and GEP70 status on outcome. Br J Haematol. December 9, 2019. DOI:10.1111/bjh.16292