Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma

Abstract

Purpose: Observation is the current standard of care for smoldering multiple myeloma. We hypothesized that early intervention with lenalidomide could delay progression to symptomatic multiple myeloma.

Methods: We conducted a randomized trial that assessed the efficacy of single-agent lenalidomide compared with observation in patients with intermediate- or high-risk smoldering multiple myeloma. Lenalidomide was administered orally at a dose of 25 mg on days 1 to 21 of a 28-day cycle. The primary end point was progression-free survival, with disease progression requiring the development of end-organ damage attributable to multiple myeloma and biochemical progression.

Results: One hundred eighty-two patients were randomly assigned-92 patients to the lenalidomide arm and 90 to the observation arm. Median follow-up is 35 months. Response to therapy was observed in 50% (95% CI, 39% to 61%) of patients in the lenalidomide arm, with no responses in the observation arm. Progression-free survival was significantly longer with lenalidomide compared with observation (hazard ratio, 0.28; 95% CI, 0.12 to 0.62; P = .002). One-, 2-, and 3-year progression-free survival was 98%, 93%, and 91% for the lenalidomide arm versus 89%, 76%, and 66% for the observation arm, respectively. Only six deaths have been reported, two in the lenalidomide arm versus four in the observation arm (hazard ratio for death, 0.46; 95% CI, 0.08 to 2.53). Grade 3 or 4 nonhematologic adverse events occurred in 25 patients (28%) on lenalidomide.

Conclusion: Early intervention with lenalidomide in smoldering multiple myeloma significantly delays progression to symptomatic multiple myeloma and the development of end-organ damage.

Trial registration: ClinicalTrials.gov NCT01169337.

FIG 1.

CONSORT diagram for phase III. FLC, free light chain; SPEP, serum protein electropheresis; UPEP, urine protein electropheresis.

FIG 2.

Time to event estimates by treatment arm in phase III: (A) progression-free survival, (B) cumulative incidence of progression, and (C) overall survival in patients with smoldering multiple myeloma. Len, lenalidomide; Obs, observation.

FIG 3.

Treatment hazard ratio (HR) for progression-free survival in subgroups in phase III. ECOG PS, Eastern Cooperative Oncology Group performance status.

FIG 4.

Kaplan-Meier estimates of progression-free survival by treatment arm within Mayo 2008 risk subgroups in phase III: (A) high risk, (B) intermediate risk, and (C) low risk.

FIG 5.

Kaplan-Meier estimates of progression-free survival by treatment arm within Mayo 2018 risk subgroup: (A) high risk, (B) intermediate risk, and (C) low risk.

FIG A1.

CONSORT diagram for phase II. FLC, free light chain; SPEP, serum protein electropheresis; UPEP, urine protein electropheresis.

FIG A2.

Time to event estimates in phase II: (A) progression-free survival, (B) cumulative incidence of progression, and (C) overall survival in patients with smoldering multiple myeloma. Len, lenalidomide.

FIG A3.

Kaplan-Meier estimates of progression-free survival by treatment arm within fluorescence in situ hybridization risk subgroups in phase III: (A) high risk, (B) intermediate risk, and (C) low risk.

FIG A4.

Swimmer’s plot patterns of treatment duration and follow-up by reason off-treatment (Tx): (A) Patients off-treatment phase II. (B) Patients off treatment phase III. AE, adverse event; PFS, progression-free survival; WD, withdrawal.

FIG A5.

Kaplan-Meier estimates of progression-free survival within prognostic subgroups in phase III: (A) Mayo 2008 risk stratification, (B) Mayo 2018 risk stratification, and (C) fluorescence in situ hybridization risk stratification.

FIG A6.

Health-related quality of life scores over time in phase III by Functional Assessment of Cancer Therapy-General (FACT-G): (A) FACT-G: Physical plus functional (P+F) well-being score (range, 0-56). (B) FACT-multiple myeloma (MM) score (range, 0-56). (C) FACT-G: Physical (P) well-being score (range, 0-28). (D) FACT-G: Functional (F) well-being score (range, 0-28).