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At the iwMyeloma 2023 meeting, Pieter Sonneveld, MD, PhD, of the Erasmus University, Rotterdam, Netherlands, and Sagar Lonial, MD, of the Winship Cancer Institute of Emory University, Atlanta, GA, debated the efforts being undertaken, both in Europe and the US, to support the development of a cure for multiple myeloma. In doing so, they highlighted key ongoing studies they hope will advance the treatment of patients with multiple myeloma, as well as current pitfalls in the therapy and research paradigms.
European research initiatives
In this video, commenting from the European perspective, Prof. Sonneveld emphasizes the unmet need in the relapsed/refractory (R/R) setting, highlighting how, in recent trials such as LocoMMotion (NCT04035226), CASSIOPEIA (NCT02541383), KarMMa-3 (NCT03651128), and CARTITUDE-1 (NCT03548207), those with high-risk disease features continue to derive less benefit from treatments, which suggests it is unlikely novel agents will be curative for these patients.
Prof. Sonneveld discusses the role of the European Myeloma Network (EMN) in bringing countries together to design clinical trials that focus on advancing various aspects of therapy, including optimizing first-line treatment; moving effective agents earlier in the paradigm; intensifying treatment for those with high-risk disease; and establishing the use of measurable residual disease (MRD) monitoring. “From the pioneering work of the Spanish group, we know that MRD-negative (MRD-) status is predictive for progression-free survival (PFS) and overall survival (OS) in the long term, so in all the EMN trials we have a strong focus on MRD monitoring,” Prof. Sonneveld explains, highlighting the EMN26 trial (NCT04564703) evaluating MRD- conversion rates following autologous stem cell transplant (autoSCT) as a secondary endpoint, and the EM17 trial (NCT03652064) utilizing sustained MRD- to discontinue daratumumab maintenance therapy.
Another focus of research, according to Prof. Sonneveld, is risk-adapted therapy; he discusses the MIDAS trial (NCT04934475) as a key study exploring the impact of this approach. In the trial patients are randomized based on risk classification to adapted or non-adapted therapy.
Other trials highlighted by Prof. Sonneveld in his presentation are evaluating the role of autoSCT, chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAbs) in newly diagnosed patients with multiple myeloma. These include the CARTITUDE-6 trial (NCT05257083) comparing autoSCT and CAR-T head-to-head in transplant-eligible patients, and EMN30 (NCT05243797) evaluating whether earlier intervention with the BsAb teclistamab negates the need for autoSCT.
While discussing these trials Prof. Sonneveld also explains the importance of the academic collaborative side studies that aim to optimize the quantity of data generated from the trial participants. Ongoing correlative studies implementing gene expression profiling or single-cell sequencing of patient samples are helping identify novel prognostic factors and high-risk populations, while others are attempting to establish the role of the bone marrow immune and inflammatory microenvironment in treatment response.
Development in the US
Meanwhile, from the US perspective, Prof. Lonial highlights how a lack of ingenuity may be holding up the development of a cure: “Our clinical trial designs are not very innovative… we need to change the paradigm or model, to get us away from our current continuous therapy, continuous maintenance, suppression of a clone for as long as we can, to perhaps a curative option.”
Prof. Lonial explains why, in his opinion, obtaining long OS and PFS through continuous therapy is no longer an optimal approach, since more effective immunotherapies result in more severe immunosuppression, which is becoming of greater concern to patients: “Now that we’re using bispecifics and CARs, pretty much everybody in the clinic is coming in on some form of gamma globulin, antibiotic prophylaxis, antiviral prophylaxis, in some cases antifungal prophylaxis.”
According to Prof. Lonial, unusual infections are becoming more common, and that given this is in the context of COVID-19 and other viral infections, “the idea of continuous suppression just doesn’t make sense in 2023, we’ve got to think about how to give short bursts of therapy that allow us to stop and allow for normal immune recovery over time.”
In the video, Prof. Lonial also describes the importance of combining therapies, and stresses how trials need to evolve to advance towards a cure: “Many of the trials that we are seeing are single-agent continuous, or single-agent for two years… that’s not really how we’re ultimately going to cure the disease. We have to put drugs together to ultimately get to curative intent, and that’s going to require companies coming together to combine their drugs.”
Prof. Lonial further comments on the importance of adapting our approach to using MRD, noting that duration of response is crucial, and that “not just shooting for MRD-, but really pushing to maintain MRD- over time is going to be important. I would say we shouldn’t even be talking about stopping or changing therapy until you know whether or not that depth of response is in fact sustainable.”
According to Prof. Lonial, “The future looks like combination therapy, mixing targets, limited duration therapy.” He describes the design of the CURE trial, which is currently being developed to test this hypothesis, and evaluate how effective utilizing numerous drugs with multiple targets in combination over a short duration of time will be in eliminating multiple myeloma.
Prof. Lonial concludes: “When you ask me, ‘how are we going to cure myeloma?’… this is the answer: everything, everywhere all at once. This really is the optimal way to think about how to cure myeloma, is to put all of our best drugs together in a short burst of therapy.”
So, while novel agents are improving outcomes for patients, a cure without the requirement for continuous maintenance therapy remains an unmet need – especially for those patients who relapse or have higher-risk disease features. However, as our understanding of multiple myeloma continues to expand, innovation in agents, target combinations and trial designs will hopefully lead to truly curative approaches for patients with multiple myeloma.
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