62nd ASH Annual Meeting and Exposition
Research to Address Unmet Needs in Multiple Myeloma
Patients with multiple myeloma currently have more treatment options than ever before; however, there is still no cure. Researchers at the 62nd ASH Annual Meeting and Exposition presented data from several studies aiming to address unmet needs in multiple myeloma, with strategies that included novel combinations, quadruplets, and an all-oral triplet regimen.
Our featured expert, S. Vincent Rajkumar, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD, and Dr Rajkumar’s clinical perspectives on these emerging data are presented here.
Edward W. and Betty Knight Scripps Professor of Medicine
“There continues to be a need to find new treatments and to develop rational combinations in a timely manner for our current patients.”
While huge progress has been made in the treatment of multiple myeloma, there are still many unmet needs. Although patients today have many treatment options, the disease remains incurable and progression-free survival can become progressively diminished with later lines of therapy. Sometimes a patient may go through 2 lines of therapy relatively quickly. So, we need more research on how to approach the disease to produce a cure, how to optimally manage newly diagnosed and relapsed/refractory disease, and how to treat patients who are not able to tolerate available therapies. Further, there continues to be a need to find new treatments and to develop rational combinations in a timely manner for our current patients. Many different studies presented at ASH 2020 aimed to address these needs.
Ocio et al evaluated the following 2 regimens in transplant-ineligible, newly diagnosed patients: isatuximab, bortezomib, dexamethasone, and cyclophosphamide (Isa-VCd) and isatuximab, bortezomib, dexamethasone, and lenalidomide (Isa-VRd). Although this was a small, dose-finding, phase 1b study, both quadruplets showed high activity with high response rates, as reported in abstract 2288. Such studies are important for a variety of reasons. It is good to have 2 different anti-CD38 antibodies (ie, daratumumab and isatuximab). It is also valuable to demonstrate activity for additional quadruplets and additional monoclonal antibodies for reasons that potentially include differing side-effect profiles, costs, and insurance coverage. I am glad that both Isa-VCd and Isa-VRd were studied. Although VRd is a standard backbone, VCd is reasonably efficacious and less costly, so it is used in a number of countries around the world.
Another study (TOURMALINE-MM2) evaluated the all-oral regimen of ixazomib, lenalidomide, and dexamethasone (IRd) vs placebo/Rd for transplant-ineligible patients with newly diagnosed multiple myeloma. As reported in abstract 551, IRd was associated with improved progression-free survival compared with Rd (35.3 months vs 21.8 months), although the difference did not quite reach statistical significance, and so, this was reported as a trend toward improvement with IRd.
My own interpretation is that this all-oral triplet is a welcome addition to our treatment armamentarium, and I, personally, do not have any doubt that it works. It is particularly useful for patients who are struggling to come into the clinic. The downside of ixazomib is that you lose some efficacy with oral administration because of decreased bioavailability; however, this is a trade-off in exchange for the advantages of safety and the ability to dose orally, which avoids the risks of traveling. Making the trip in for treatment is quite a burden for some patients, including those who are elderly and/or at high risk for accidental injuries and exposures such as COVID-19.
A third abstract described a phase 3 study comparing the addition of isatuximab to carfilzomib and dexamethasone vs carfilzomib/dexamethasone in relapsed/refractory multiple myeloma. As reported in abstract 2316, the positive results from this trial demonstrate that this regimen is a useful option for patients who have already been on regimens such as VRd and have come to require a change in 2 of the agents in their combination.
Richardson and colleagues reported on the platform for the development of belantamab mafodotin in combination with 4 different novel agents in patients with relapsed/refractory multiple myeloma, as noted in abstract 2299. Belantamab mafodotin is an exciting advance in the treatment of multiple myeloma, and it will be great to see how we can build on it with the addition of novel agents. The design allows the evaluation of multiple combinations in parallel, enabling you to take promising combinations to a controlled trial quickly, thus increasing the speed of development.
Finally, abstract 2293 described the HORIZON trial, which evaluated the use of melflufen plus dexamethasone in a heavily pretreated population of elderly patients with relapsed/refractory multiple myeloma. The results showed that the combination is effective, with a response rate of approximately 30%. The value of this trial is that it demonstrates the activity of an alkylating agent in these patients, but it is as yet unknown whether this agent has any advantages over existing alkylators, such as cyclophosphamide or melphalan. This study reminds us not to forget about the alkylators. These agents often get overlooked because no pharmaceutical company is promoting cyclophosphamide or melphalan.
Overall, these studies highlight the need for new treatment options in many patient groups (eg, high-risk cytogenetics, elderly or frail, or multiple refractory disease). The abstracts also provide new information on how to expand beyond triplets through the use of quadruplets and how to effectively bring new drugs into the treatment armamentarium quickly by running multiple parallel trials simultaneously. Finally, we are developing more convenient regimens for patients who cannot travel and for those who cannot take a drug every day.
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. doi:10.1016/S0140-6736(19)32556-5
Dimopoulos MA, Gay F, Schjesvold F, et al; TOURMALINE-MM3 Study Group. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2019;393(10168):253-264. doi:10.1016/S0140-6736(18)33003-4
Facon T, Venner CP, Bahlis N, et al. The phase 3 TOURMALINE-MM2 trial: oral ixazomib, lenalidomide, and dexamethasone (IRd) vs placebo-Rd for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) [abstract 551]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Larocca A, Richardson PG, Oriol A, et al. HORIZON (OP-106): melflufen plus dexamethasone in patients with relapsed/refractory multiple myeloma—age subgroup analysis of elderly patients [abstract 2293]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221. doi:10.1016/S1470-2045(19)30788-0
Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3, randomized, open-label study [abstract 2316]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Ocio EM, Bringhen S, Oliva S, et al. Updates from a phase Ib study of isatuximab, bortezomib and dexamethasone plus cyclophosphamide or lenalidomide in transplant ineligible newly diagnosed multiple myeloma [abstract 2288]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548-567. doi:10.1002/ajh.25791
Richardson PG, Nooka A, Quach H, et al. DREAMM-5 platform trial: belantamab mafodotin (belamaf) in combination with four different novel agents in patients with relapsed/refractory multiple myeloma (RRMM) [abstract 2299]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
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