Treatment of Relapsed/Refractory Multiple Myeloma in the Era of Novel Agents
Several novel therapies have been approved by the US Food and Drug Administration for relapsed/refractory multiple myeloma, including the immunomodulatory drug (IMiD) pomalidomide, the proteasome inhibitors (PIs) carfilzomib and ixazomib, the histone deacetylase inhibitor panobinostat, and the monoclonal antibodies elotuzumab and daratumumab. Our featured experts discuss the treatment of patients with relapsed/refractory multiple myeloma with novel agents.
Q: How do you approach the treatment of relapsed disease, and how are the novel agents impacting multiple myeloma?
Clinical Program Leader and Director of Clinical Research
“Treating multiple myeloma is a marathon, not a sprint, and acute and long-term toxicities have significant bearing on what we do."
The tempo of a patient’s relapse while on prior therapies is important, and I am particularly concerned about the triplet-class–refractory patients who have failed IMiDs, PIs, and CD38-targeting agents. I would underscore the importance of continuous therapy in the relapsed/refractory multiple myeloma setting—it is a critical paradigm to appreciate. Treating multiple myeloma is a marathon, not a sprint, and acute and long-term toxicities have significant bearing on what we do. We must move quickly in patients with relapsed/refractory multiple myeloma while we still have a reasonable chance of salvage. In the absence of an exciting, feasibly deployed protocol that these patients would be eligible for, I look at combinations, with different classes of antibody, for example. I also return to different classes of drugs. When daratumumab fails a patient, using a carfilzomib-based platform appears attractive, based on data presented at the 60th American Society of Hematology Annual Meeting & Exposition in 2018—and I have seen that anecdotally in my own practice. Early intervention with off-protocol therapies is important. For example, elotuzumab was initially regarded as a less powerful antibody on its own, but elotuzumab combined with the IMiD pomalidomide has demonstrated efficacy in relapsed/refractory multiple myeloma. We do not yet know whether that combination will salvage a patient after daratumumab failure. In my clinical experience, the results have been mixed, off protocol. Sometimes I will use elotuzumab to augment control as we bridge to the next platform. Part of the mechanism with elotuzumab may lie with the enhanced antibody-dependent cellular cytotoxicity leading anti-myeloma activity, and that likely explains some of our findings from the ELOQUENT-3 study, which was published in The New England Journal of Medicine in 2018: Adding elotuzumab to pomalidomide and dexamethasone improved progression-free survival and overall response rate in patients with multiple myeloma who had relapsed from or were refractory to lenalidomide and a PI. The B-cell maturation antigen (BCMA)–based platforms appear to be quite promising, and I am referring not only to chimeric antigen receptor T-cell therapy—which remains a highly selective population and a challenge to deploy, in my experience—but also to other novel agents, particularly selinexor, which inhibits chromosomal maintenance protein exportin-1 (XPO1), has anti-tumor effects, and is being tested as part of a combination therapy in pretreated patients with relapsed/refractory multiple myeloma.
“Outside of a clinical trial, we often make treatment decisions based on the patient’s response trend; we do not always wait to fully meet International Myeloma Working Group criteria for true progression before intervening.”
Several key considerations guide my decision making with respect to treating patients with relapsed/refractory multiple myeloma. These include the speed of recurrence, previously employed lines of therapy, and the patient’s functional status and genetic profile. Those with a favorable genetic profile and a slow rise in proteins or markers might be considered for a single- or 2-drug change, while those with high-risk cytogenetics and who progress through triplet therapy would proceed to combinations that include, ideally, 2 new therapies. I will cycle back to different combinations because, even if a particular agent is not effective in 1 combination, there may be an increased response with the same agent in a different combination. Outside of a clinical trial, we often make treatment decisions based on the patient’s response trend; we do not always wait to fully meet International Myeloma Working Group criteria for true progression before intervening. Patients who are refractory to triplet therapy (ie, IMiD-PI-dexamethasone) and to CD38-targeting are particularly challenging to treat and are in need of newer therapies. The BCMA approaches and XPO1 inhibition are particularly exciting developments.
Founder, President, and Chief Executive Officer
“There is a danger in being too relaxed in monitoring patients for changes in clinical status. More frequent and tighter monitoring early on, as patients are receiving novel treatments during relapse, allows for speedier changes to therapy, thereby likely improving their outcomes and quality of life.”
Karyotype and chromosome cytogenetics may tell us how poorly our patients are going to do, but, with the possible exception of t(11;14), for which the data support adding venetoclax, they really do not tell us which particular agents to use. Having said that, the failure of a drug in 1 combination does not mean that that same drug will not work in another combination. The same is often true of drug classes (ie, the failure of 1 PI does not mean that a different PI will not work, the failure of 1 IMiD does not mean that a new IMiD will not work). Tolerability is important, and that means looking at not only objective measures such as blood counts and perhaps renal function, but also at how patients tolerate treatment in terms of their quality of life, which is certainly a major issue for my patients. There is a danger in being too relaxed in monitoring patients for changes in clinical status. More frequent and tighter monitoring early on, as patients are receiving novel treatments during relapse, allows for speedier changes to therapy, thereby likely improving their outcomes and quality of life. Soluble BCMA may be a marker that can help with timely response assessments, although more data are needed. The serum half-life of BCMA is much shorter than that of immunoglobulin G, so the hope is that changes in BCMA levels might better reflect real-time disease characteristics. Close monitoring is crucial. In addition, it is also true that you risk adversely impacting the patient’s ability to tolerate additional therapy by waiting for changes in the conventional myeloma markers. We have quite a bit of experience with single-agent elotuzumab; we use it in patients with biochemical relapses and we have seen it active in patients who have failed daratumumab-based therapies. In fact, sometimes replacing daratumumab with elotuzumab has led to very long responses, and I agree that elotuzumab may be more active than some originally thought.
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Cornell RF, Gandhi UH, Lakshman A, et al. Subsequent treatment outcomes of multiple myeloma refractory to CD38-monoclonal antibody therapy. Abstract 2015. Abstract presented at: 60th ASH Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA.
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