Marc J. Braunstein
Smoldering multiple myeloma (SMM) is a heterogeneous disease in which patients have between 10% and 59% clonal bone marrow plasma cells without additional myeloma-defining criteria. Approximately one-third of patients are categorized as high risk for progression within 2 years. There is no standard of care for management and, outside of the context of a clinical trial, most patients typically are closely observed for signs of progression.
Considering that incidence of high-risk SMM is relatively low, Lonial and colleagues should be commended for contributing the second and largest randomized study supporting the benefit of lenalidomide for delaying progression to symptomatic disease.
Data from a prior randomized study of 119 patients led by Maria-Victoria Mateos, MD, PhD, showed an OS benefit with lenalidomide and dexamethasone induction for nine cycles, followed by lenalidomide maintenance until progression. The regimen reduced risk for death by 69% compared with observation.
In the current study, Lonial and colleagues randomly assigned 182 patients with intermediate- or high-risk disease to single-agent lenalidomide or observation. At median follow up of 35 months, results showed a 72% reduction in risk for progression, with 3-year PFS rates of 91% with lenalidomide vs. 66% with observation.
In both studies, grade 1 to grade 3 adverse events were higher in the experimental arm; however, there were no significant differences in treatment-related mortality or secondary malignancies.
One of the critiques of these studies is how higher-risk SMM was defined. After revision of the diagnostic criteria for symptomatic multiple myeloma in 2014, in which patients with ultra-high-risk SMM were classified as symptomatic myeloma, various risk models have been proposed to classify high-risk SMM.
The study by Mateos and colleagues included patients who would not be considered to have symptomatic disease. In the study by Lonial and colleagues, patients were defined by slightly differing Mayo 2008 and 2018 criteria for intermediate- or high-risk disease. Although subgroup analysis showed a benefit of lenalidomide across different criteria, interestingly, patients categorized as high risk by Mayo 2018 stratification — which includes a higher percentage of plasma cells or higher serum free light chains than the 2008 criteria — showed the most significant benefit of single-agent lenalidomide. This suggests that patients with higher-risk SMM have the most to gain from earlier intervention, which is both intuitive and practical in terms of weighing costs vs. benefit of treatment.
Data from these studies clearly indicate that a watch-and-wait approach is no longer ideal for patients with high-risk SMM. However, the question remains whether lenalidomide alone or combined with dexamethasone is the optimal regimen to prevent progression of SMM.
At the most recent ASH Annual Meeting and Exposition, several abstracts that focused on treatment for patients with high-risk SMM were presented. They included a phase 2 study by Bustoros and colleagues — which evaluated the combination of ixazomib (Ninlaro, Takeda), lenalidomide and dexamethasone — and an update of the phase 2 GEM-CESAR study, which evaluated carfilzomib (Kyprolis, Amgen) with lenalidomide and dexamethasone along with stem cell transplantation and maintenance therapy.
As we await maturation of data from these studies, we have mounting evidence from two randomized studies that suggest the path to delaying progression of SMM begins with extinguishing plasma cell clones early in high-risk patients.
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Marta Wronska, DO
NYU Winthrop Hospital
NYU Langone Health
Marc J. Braunstein, MD, PhD
NYU Long Island School of Medicine
NYU Perlmutter Cancer Center
NYU Langone Health
Disclosures: Braunstein reports research funding from Janssen, as well as scientific advisory board roles with Amgen, AstraZeneca, Celgene, Janssen, Karyopharm Therapeutics, Takeda and Verastem. Wronska reports no relevant financial disclosures.