Adapting to the Evolving Treatment Landscape for Multiple Myeloma

The treatment landscape for multiple myeloma (MM) is evolving rapidly. For many years, there were only a few different classes of agents available for our patients with MM, and treatment options were limited. Now, we have multiple classes of agents that can be used in the newly diagnosed and relapsed MM settings, with the choice of optimal therapy at each disease stage having its own challenges. The backbone of therapy for newly diagnosed MM continues to be immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and corticosteroids used in various combinations, with or without the monoclonal antibody daratumumab. For relapsed disease, there are new agents with novel mechanisms of action that are very effective treatment options.

Diagnosis of Smoldering vs Active MM
The diagnosis of active MM and when to initiate therapy for patients with MM continues to evolve as we learn more about the biology of this disease and how we can use various biomarkers to determine the risk of progression to active disease.

Currently, some healthcare professionals consider beginning therapy for patients with smoldering MM once they have >50% risk of progression to active disease based on the 20/2/20 model (at least 2 of the 3 risk factors: free light chain ratio of >20, serum M-protein of >2 g/dL, or >20% bone marrow plasma cells). The E3A06 and QuiRedex trials have shown that lenalidomide or lenalidomide plus dexamethasone (Rd) can reduce the risk of end organ damage and delay disease progression. For those patients who want to start treatment, a clinical trial is ideal; therapy with Rd would also be reasonable. For those who feel uncomfortable and do not wish to start treatment for high-risk smoldering MM, ongoing monitoring for an accumulation of risk factors is essential, and therapy should be initiated immediately when a patient progresses to active disease or shows evolving biomarkers associated with active disease.

Treatment for Newly Diagnosed Active MM
Triplet therapy continues to be standard of care for patients with newly diagnosed active MM. For patients who are eligible for autologous stem cell transplant (ASCT), therapy with bortezomib plus Rd followed by ASCT and then lenalidomide maintenance remains the mainstay, and ongoing trials are exploring whether we should incorporate quadruplet regimens into our routine practice. For patients who are not eligible for ASCT, we do not have randomized data comparing bortezomib plus Rd vs daratumumab plus Rd. However, the MAIA trial has shown promising efficacy with the daratumumab-based triplet.

For patients with newly diagnosed disease, it may also be important to tailor therapy based on risk assessment—those with higher risk due to either cytogenetics, other tumor-related characteristics, or patient characteristics may be treated differently than those patients with standard-risk disease. Risk‑adapted therapy may include choice of the optimal PI (carfilzomib vs bortezomib) as part of initial treatment, addition of daratumumab for quadruplet therapy, tandem ASCT, or more aggressive maintenance therapy (with the addition of a PI to standard lenalidomide-based treatment). On the other end of the spectrum, risk-adapted therapy for frail patients may include starting with a doublet regimen and adding additional agents based on individual tolerability or selecting combination agents based on comorbidities.

Therapy Selection and Sequencing for Relapsed/Refractory MM
One of the biggest advances in the past few years for MM is the expanding treatment paradigm for relapsed/refractory (R/R) MM. The introduction of monoclonal antibodies for R/R MM changed how we can treat patients with R/R MM with the approval of daratumumab, which targets CD38 on the surface of MM cells, followed by elotuzumab, which targets SLAMF7, and isatuximab, which also targets CD38.

Now, we also have various anti-BCMA–targeted agents approved along with the XPO1 inhibitor selinexor. Both belantamab mafodotin, an antibody–drug conjugate targeting BCMA, and idecabtagene vicleucel, a CAR T-cell therapy targeting BCMA, are approved by the FDA for patients with R/R MM who have received ≥4 previous therapies, which must include an anti-CD38 monoclonal antibody, a PI, and an IMiD (our triple class–refractory patient population). Selinexor is approved by the FDA in combination with bortezomib/dexamethasone for patients with R/R MM after ≥1 previous therapy or with dexamethasone after ≥4 previous therapies with disease that is refractory to ≥2 PIs, ≥2 IMiDs, and an anti-CD38 monoclonal antibody.

There are numerous factors to consider when selecting therapy at relapse, including previous therapy, how soon patients need to start therapy, fitness and age, and any specific comorbidities. Patients who have preexisting corneal disease are at higher risk of ocular toxicity from belantamab mafodotin. Patients with neurologic disorders or cardiac risk factors may be at higher risk of immune effector cell–associated neurotoxicity syndrome (ICANS) or CRS, respectively, from idecabtagene vicleucel. Patients with gastrointestinal or constitutional comorbidities may not tolerate gastrointestinal adverse events associated with selinexor, like nausea, decreased appetite, diarrhea, and vomiting.

Many times, it is not a question of which therapy to use but when to use each different class of agents. With each relapse or progression, the next treatment should incorporate ≥1 agent with a novel mechanism of action, if possible, and understanding optimal sequencing for individual patients can be a challenge in clinical practice. In addition to considering a patient’s disease and physical limitations, it is important to educate patients about their different treatment options (eg, administration and adverse events) and discuss patient preferences and individual circumstances that may affect treatment recommendations.

Your Thoughts?
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To learn more about optimizing the care of patients with MM, sign up here to attend a live symposium at ASH 2021 or a live stream webinar of the symposium “Adapting Clinical Practice to a Rapidly Changing Therapeutic Landscape in Multiple Myeloma” on Friday, December 10, 2021, at 11:30 AM Eastern time with program chair and moderator, Brian G.M. Durie, MD,along with international expertsThomas G. Martin, MD; Philippe Moreau, MD; S. Vincent Rajkumar, MD; and Jesús F. San-Miguel, MD, PhD.