conference reporter

Virtual Edition of the 25th EHA Annual Congress

Novel Agents in the Approach to Patients With High-Risk Multiple Myeloma

by Robert Z. Orlowski, MD, PhD

Overview

Several abstracts presented at the Virtual Edition of the 25th EHA Annual Congress focused on the incorporation of novel agents into treatment regimens for relapsed/refractory multiple myeloma. In particular, updated analyses from studies such as ICARIA-MM and OPTIMISMM showed improved outcomes in high-risk patients.

Following the presentation, our featured expert, Robert Z. Orlowski, MD, PhD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Orlowski’s perspectives on these abstracts are presented here.

Robert Z. Orlowski, MD, PhD

Director of Myeloma Section
Department of Lymphoma/Myeloma
Florence Maude Thomas Cancer Research Professor
Department of Experimental Therapeutics
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX

“Individuals with higher-risk molecular features have myeloma subtypes that remain a challenge, so we need to continue to optimize treatments and incorporate novel agents.”

Robert Z. Orlowski, MD, PhD

Individuals with higher-risk molecular features have myeloma subtypes that remain a challenge, so we need to continue to optimize treatments and incorporate novel agents. In general, patients with t(14;14), 17p deletion, t(14;16), t(14;20), or gain or amplification of 1q21 (gain[1q21]) are considered high risk, but there are a few subtleties to these definitions and sample size limitations can arise when high-risk subsets from clinical trials are analyzed.

In abstract EP1017, data from the phase 1b study of isatuximab, pomalidomide, and dexamethasone and the phase 3 ICARIA-MM trial were combined to examine outcomes in patients with gain(1q21). The ICARIA-MM study led to the approval of isatuximab for relapsed/refractory multiple myeloma. Isatuximab and daratumumab are both anti-CD38 monoclonal antibodies, but they recognize different epitopes on CD38 and also differ somewhat with respect to mechanisms of action. Gain(1q21) is among the most common cytogenic abnormalities in multiple myeloma. Further, 1q21 is a large region, with several genes as potential drivers of higher risk (eg, MCL1, IL6R, ILF2). In this analysis, patients with isolated gain(1q21) receiving isatuximab, pomalidomide, and dexamethasone showed a median progression-free survival (PFS) of 11.2 months, compared with 4.3 months in the pomalidomide-dexamethasone group. This was a big improvement in PFS, suggesting that this combination would be an effective therapy for patients with gain(1q21). This presentation also dovetails well with the recently published meta-analysis of data from daratumumab-based combination trials by Giri et al, showing that anti-CD38 monoclonal antibodies can help outcomes in high-risk patients. Whether isatuximab or daratumumab is better for high-risk patients remains to be seen.

The 3-drug combination of pomalidomide, bortezomib, and dexamethasone was the focus of abstract EP957. One of the positive things about this combination is that it can be used as a second-line therapy for patients who, for example, are progressing on lenalidomide as their maintenance after autologous stem cell transplantation. This was an update from the OPTIMISMM trial, which previously reported that the 3-drug combination of pomalidomide, bortezomib, and dexamethasone resulted in an improved PFS compared with pomalidomide and dexamethasone. This abstract focused, in particular, on patients with high-risk features, defined as 17p deletion, t(14;14), or t(14;16), after 1 prior line of therapy. High-risk patients had a median PFS of 14.7 months with the 3-drug regimen (n=18) vs 9.9 months with the 2-drug regimen (n=14). This was definitely an improvement and a significant increase in PFS. Further, the 3-drug combination is US Food and Drug Administration approved and would be a good option for high-risk patients. We should remember, however, that this was a relatively small analysis and that high-risk patients still do not do as well as standard-risk patients.

References

An G, Xu Y, Shi L, et al. Chromosome 1q21 gains confer inferior outcomes in multiple myeloma treated with bortezomib but copy number variation and percentage of plasma cells involved have no additional prognostic value. Haematologica. 2014;99(2):353‐359.

Attal M, Richardson PG, Rajkumar SV, et al; ICARIA-MM Study Group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study [published correction appears in Lancet. 2019;394(10214):2072]. Lancet. 2019;394(10214):2096‐2107.

Dimopoulos M, Weisel K, Moreau P, et al. OPTIMISMM subanalysis: pomalidomide, bortezomib, dexamethasone after 1 prior line of therapy in relapsed or refractory multiple myeloma by age, prior transplant, and high-risk cytogenetics. Accessed June 12, 2020. https://library.ehaweb.org/eha/2020/eha25th/294874/meletios.dimopoulos.optimismm.subanalysis.pomalidomide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D2%2Asearch%3Dep957

Giri S, Grimshaw A, Bal S, et al. Efficacy of daratumumab in the treatment of multiple myeloma with high-risk cytogenetics: meta-analysis of randomized phase III trials [abstract 8540]. J Clin Oncol. 2020;38(15 suppl):8540. Accessed June 12, 2020. https://meetinglibrary.asco.org/record/187638/abstract

Mikhael J, Richardson P, Usmani SZ, et al. A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma. Blood. 2019;134(2):123‐133.

Richardson PG, Oriol A, Beksac M, et al; OPTIMISMM Trial Investigators. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(6):781‐794.

Richardson P, Harrison S, Facon T, et al. Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with 1q21 gain: insights from phase 1 and phase 3 studies. Accessed June 12, 2020. https://library.ehaweb.org/eha/2020/eha25th/293508/paul.g.richardson.isatuximab.plus.pomalidomide.and.dexamethasone.in.relapsed.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3Dep1017

Schmidt TM, Barwick BG, Joseph N, et al. Gain of chromosome 1q is associated with early progression in multiple myeloma patients treated with lenalidomide, bortezomib, and dexamethasone. Blood Cancer J. 2019;9(12):94.

Walker BA, Mavrommatis K, Wardell CP, et al. A high-risk, double-hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia. 2019;33(1):159‐170.

This information is brought to you by Engage Health Media and is not sponsored by, nor a part of, the European Hematology Association. 

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