Results of a randomized placebo-controlled phase 2 study of metformin for the prevention of progression of precursor multiple myeloma

Multiple myeloma (MM) is an incurable plasma cell malignancy that is preceded by a presymptomatic state of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), conditions that together affect over 5% of adults over age 50. Although daratumumab was recently approved for the treatment of high-risk SMM, most individuals with MGUS or SMM undergo close observation alone, rendering an unmet need for the identification of alternative safe and cost-effective strategies to prevent disease progression. Metformin has demonstrated anti-myeloma activity in preclinical models and has been associated with reduced risk of progression to MM in observational studies; however, it's efficacy has not been evaluated in a prospective trial. We conducted a phase II, single-center, randomized, placebo-controlled trial to assess the effect of metformin on serologic markers of disease progression in patients with high-risk MGUS and low-risk SMM (NCT04850846). Participants were randomized 1:1, stratified by heavy versus light chain disease and MGUS versus SMM, to 1500 mg daily metformin or placebo. The primary objective was to determine whether metformin reduced or stabilized serum monoclonal (M-) protein concentrations from baseline to 6 months, which is an established biomarker of disease burden. A total of 60 participants were randomized with a median age of 65 years. Half were male, 85% self-identified as White and 62% had SMM at study entry. Baseline characteristics and laboratory values were balanced across arms. The most commonly reported adverse events were nausea, diarrhea, and constipation. Forty-six participants had evaluable heavy-chain M-protein measurements at baseline and 6 months (median baseline M-protein, 0.94 g/dL). Among these participants, there was a median 3.2% decrease in serum M-protein among those randomized to the metformin group compared to a 7.7% increase in serum M-protein concentration among those randomized to placebo (p=0.015). Ten participants were only evaluable by serum-free light chains (sFLCs), and there was no difference across randomization arms in the changes in either sFLC ratios or difference between involved and uninvolved FLCs (both p > 0.79). While clinical management for MGUS and many individuals with SMM has traditionally emphasized observation until progression to symptomatic MM, there remains strong interest among patients and clinicians in strategies to prevent or delay malignant transformation and subsequent end-organ damage. Short-term metformin use resulted in modest, but statistically significant changes in M-protein evolution in patients with heavy-chain MGUS and SMM. Although the magnitude of effect was smaller than those that can be achieved with cancer-directed therapies, these findings support further evaluation of metformin with longer follow up, as well as other metabolic interventions, as prevention strategies in precursor plasma cell disorders, especially among asymptomatic patients who are not candidates for and/or are unwilling to accept the risks of active treatment.