Decrypting the code of chromosome 1q abnormalities in multiple myeloma

One of the most common cytogenetic abnormalities in myeloma is one of the most widely debated and poorly understood. We have summarized the literature of this mysterious genomic aberration and call for standardization as a key to understanding the significance of +1q and improving patient outcomes.

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It started with a Tweet. On September 10, 2020, Dr. Saad Usmani told “The chromosome 1q story” in a “tweetorial” using ten successive posts to share his knowledge of chromosome 1q copy number gains (+1q) in multiple myeloma (MM). +1q is one of the most common cytogenetic abnormalities in MM, yet remains confusing to many oncologists. The thread sparked substantial interest from the MM social media community, generating discussions about how to define +1q, the impact of copy number, and whether patients with this abnormality should be treated differently. Many prominent myeloma researchers, community oncologists, patient advocates, and aspiring experts debated these topics, and it was clear that there was substantial interest in this area and a need for clarity. Having been the lead author on a retrospective analysis of patients with +1q myeloma1, I found this discussion both fascinating and pertinent to my research during fellowship, and I was able to comment on several points based on my experience with these clinical questions. Subsequently, just ten days into my new career as a myeloma specialist at the University of Wisconsin, I had connected with Dr. Usmani to collaborate with a goal of clarifying the impact of 1q abnormalities in multiple myeloma. This review2 constitutes the first part of that collaboration. Dr. Rafael Fonseca, who led many of the initial studies characterizing recurrent cytogenetic abnormalities in multiple myeloma including +1q, also helped us tell this story.

In our manuscript, we attempted to compile a vast amount of heterogeneous data to try and provide some clarity on +1q in multiple myeloma. Overall, there are three key points. First – and most importantly – we call for uniform reporting and testing of 1q abnormalities in patients with plasma cell disorders. Evaluation and reporting of 1q abnormalities in multiple myeloma has been highly variable and irregular, which makes any kind of data compilation or cross-study comparison very difficult, if not impossible. Because of this, we propose that uniform definitions be employed for 1q abnormalities in the future. We suggest that “+1q” be defined as any plasma cell clone containing extra copies of 1q, and that copy number should be specified whenever possible. Gain(1q) should be considered to mean that a plasma cell clone that has only 1 additional copy of chromosome 1q (3 copies total), whereas amp(1q), signifying “amplification”, should only be used when more than 1 extra copy (greater than 3 copies) of 1q is present. This distinction is important because copy number of 1q has a very clear impact on prognosis. Data from clinical trials and retrospective studies regarding the prognosis of +1q are extensively reviewed in the paper. In summary, while most studies suggest that gain(1q) has a negative impact on patient outcomes, amp(1q) is universally associated with rapid progression and inferior survival among patients with MM, even when compared to patients with gain(1q). In the original studies of gene expression profiling in MM, a majority of the “high risk” genes mapped to chromosome 1q3. Whether this indicates that 1q copy number is a “dose-dependent” factor with amplification leading to increased expression of high-risk genes, or whether there is a biologically different mechanism leading to secondary amplification of 1q is unclear. What is clear, however, is that without uniformity in reporting 1q abnormalities, it will be very difficult to determine for sure whether +1q is itself a poor prognostic factor or predictive of response to new drugs or combination therapies.

Secondly, a plethora of potential hazardous genes exist on chromosome 1, particularly at the 1q21 locus, opening up the possibility for targeted therapy. Of particular interest are the genes encoding CKS1B, MCL-1, IL-6R, and ADAR1, although many other genes have been identified as well. Interestingly, many of these are integrally or peripherally involved in JAK/STAT signaling, particularly through STAT3, making this pathway particularly enticing to explore therapeutic vulnerabilities among patients with +1q MM. It will be particularly interesting to see if +1q is a predictive marker for sensitivity to the bispecific antibody cevostamab, which engages T-cells through binding to CD3 to target FcHR5, a surface protein on plasma cells that is coded at 1q21. As reporting of 1q abnormalities becomes more uniform, these patterns of sensitivity to both novel treatment strategies and existing combination therapies will become more apparent.

Finally, we attempt to put all of this together into an evidence-based management recommendation.  Due to the issues with data interpretation mentioned above, this was quite a challenge, and it must be emphasized that at the time of writing this article, there is no approach that is clearly superior for these patients. It is easy to suggest that more potent induction therapy may be necessary to achieve MRD negativity in a majority of these. Although achievement of MRD negativity has shown promise in the ability to overcome the poor prognostic impact of high risk cytogenetic abnormalities, especially when sustained over time, data are immature regarding whether MRD can safely guide management decisions and long-term outcomes of these approaches are currently unknown. In fact, in high risk myeloma, the challenge has never been whether patients will achieve a rapid response, but whether that response is maintained over time. As of today, the approach that has the best long-term data for extending progression free survival among patients with high risk cytogenetics has been continuous therapy with proteasome inhibitors (PI) and immunomodulatory agents (IMiD)4. Although this approach has not been established for +1q in particular, and a reasonable argument could be made that this no overall survival benefit for PI/IMiD maintenance has been demonstrated compared to lenalidomide, we are left with the challenge of trying to improve outcomes for a large group of patients who often have inferior outcomes to standard approaches, but for whom no randomized prospective data clearly demonstrate an alternative approach that improves survival. As such, for now our recommendation is to use PI/IMiD maintenance therapy in patients with +1q MM for whom this is feasible and who are able to tolerate it.

I am grateful to Dr. Usmani and Dr. Fonseca for including me in this effort to summarize what is known about +1q in MM. Our work together in this area is not done. Forthcoming will be an analysis of the impact of +1q in two Phase 3 frontline myeloma trials. In the Phase 3 ECOG E1A11 (ENDURANCE), patients with standard risk myeloma and t(4;14) were randomized to VRd or KRd induction, followed by a second randomization to lenalidomide maintenance therapy for 2 years or indefinite therapy5. A concurrent Phase 2 study done through SWOG randomized patients with high risk myeloma to receive RVd or RVd plus elotuzumab for induction and maintenance therapy6. Although the patient populations enrolled in these studies were intentionally different, each study enrolled patients with +1q, and it will be interesting to see if any of the interventions in these studies were impacted by +1q, as well as the prognostic impact of 1q copy number in each subset. Although these data are not yet known, this analysis should help to further clarify the impact of +1q in patients with MM and to help solve the puzzle of how to improve survival for these patients.

 

1              Schmidt, T. M. et al. Gain of Chromosome 1q is associated with early progression in multiple myeloma patients treated with lenalidomide, bortezomib, and dexamethasone. Blood Cancer J 9, 94, doi:10.1038/s41408-019-0254-0 (2019).

2              Schmidt, T. M., Fonseca, R. & Usmani, S. Z. Chromosome 1q21 abnormalities in multiple myeloma. Blood Cancer Journal 11, 83, doi:10.1038/s41408-021-00474-8 (2021).

3              Shaughnessy, J. D., Jr. et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 109, 2276-2284, doi:10.1182/blood-2006-07-038430 (2007).

4              Nooka, A. K. et al. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia 28, 690-693, doi:10.1038/leu.2013.335 (2014).

5              Kumar, S. K. et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol, doi:10.1016/S1470-2045(20)30452-6 (2020).

6              Usmani, S. Z. et al. Bortezomib, lenalidomide, and dexamethasone with or without elotuzumab in patients with untreated, high-risk multiple myeloma (SWOG-1211): primary analysis of a randomised, phase 2 trial. The Lancet Haematology 8, e45-e54, doi:10.1016/S2352-3026(20)30354-9 (2021).

Timothy Schmidt

Assistant Professor, University of Wisconsin Carbone Cancer Center