Prospective, Multicenter Clinical Trial of Everolimus As Primary Therapy in Waldenstrom Macroglobulinemia (WMCTG 09-214)

Purpose: Everolimus inhibits mTOR, a component of PI3K/AKT pro-survival signaling triggered by MYD88 and CXCR4 activating mutations in Waldenstrom's Macroglobulinemia (WM).

Experimental design: We evaluated everolimus in a prospective, multicenter study of 33 symptomatic, previously untreated WM patients. Intended therapy consisted of everolimus (10 mg/day) until progression or unacceptable toxicity. Dose de-escalation was permitted. The study was registered at www.clinicaltrials.gov(NCT01470196).

Results: At best response, median serum IgM levels declined from 4,440 to 1,360 mg/dL (p<0.0001); median hemoglobin rose from 10.8 to 12 g/dL (p=0.001); and median bone marrow disease burden declined from 75% to 52.5% in serially biopsied patients. The ORR and major response rates were 72.7% and 60.6%, respectively. Among genotyped patients, non-responders associated with wild-type MYD88 and mutated CXCR4 status. Median time to response was 4 weeks. Discordance between serum IgM levels and BM disease burden was common. With a median follow-up of 13.1 (range 1.6-64.6 months), median time to progression was 21 months, and 33 months for major responders. Discontinuation of everolimus led to rapid serum IgM rebound in 7 patients, and symptomatic hyperviscosity in two patients. Toxicity led to treatment discontinuation in 27% of patients, including 18% for pneumonitis.

Conclusions: Everolimus is active as primary therapy in WM. IgM discordance is common, and treatment cessation can often lead to rapid serum IgM rebound. Pneumonitis also appears more pronounced in untreated versus previously treated WM patients. The risks and benefits of everolimus should carefully be weighed against other primary WM therapy options.