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Lenalidomide versus observation in patients with smoldering multiple myeloma: a randomized trial

Nov 27, 2019

Multiple myeloma (MM) often progresses from an asymptomatic phase, called smoldering multiple myeloma (SMM). The risk of progression is 10% per year, however the presence of adverse prognostic factors can lead this to increase to 25%. The current standard of care for SMM is observation. Early interventions, from a preventative approach with low-intensity therapy, through to a more intensive approach, might prevent end-organ damage.

In this paper, Sagar Lonial, Emory University, Atlanta, GA, and colleagues hypothesized that early interventions could delay progression to MM. They conducted a randomized trial wherein patients with intermediate- or high-risk SMM received either lenalidomide or observation. The results of this trial were previously presented by Sagar Lonial at the American Society of Clinical Oncology (ASCO) meeting earlier this year and covered by the MM Hub.

Study design and patients

  • Before the phase III trial, the authors conducted a safety phase II run-in where patients were treated with lenalidomide
    • Forty-four patients were enrolled between January 2011 and January 2013; out of these, 34 were eligible (measurable levels of monoclonal protein, ≥1g/dL in the serum and/or ≥200mg/24h in the urine; baseline skeletal survey and magnetic resonance imaging of the spine and pelvis to exclude myeloma bone lesions or plasmacytomas) and were treated
    • The overall median treatment duration was 33.5 cycles
  • In the phase III trial, 182 patients were randomly assigned to the lenalidomide arm (n= 90) or to the observation arm (n= 92)
    • Of these 182 patients, 139 (lenalidomide arm [n= 73]; observation arm [n= 66]) received a diagnosis of asymptomatic intermediate or high-risk SMM within the past 60 months and were eligible
    • The dose of oral lenalidomide was 25mg on Days 1 to 21 of every 28-day cycle
    • The overall median treatment duration was 23 cycles


  • In the safety phase II run in:
    • The median overall survival (OS) follow-up was 82 months (95% confidence interval [CI], 72─84 months)
    • The 5-year progression-free survival (PFS) was 78% (95% CI, 65─93%)
    • The 5-year OS was 88% (95% CI, 78─98%)
    • Grade ≥3 adverse events (AEs) occurred in 22 patients, and one patient died from pulmonary embolism
    • The incidence of invasive second primary cancers at 4 years was 4.9%
  • In the phase III trial:
    • The median follow-up was 35 months (95% CI, 30─37 months)
    • Partial response (PR) to therapy was 50% (95% CI, 39─61%) for the lenalidomide arm and no responses were observed in the observation arm. The time to response was a median of 5 months (1─23 months)
    • PFS for the lenalidomide arm versusthe observation arm was significantly longer (treatment hazard ratio [HR], 0.28; 95% CI, 0.12–0.62; p= 0.002):
      • One-year PFS: 98% vs 89%
      • Two-year PFS: 93% vs76%
      • Three-year PFS: 91% vs66%
    • Cumulative incidence of progression at 3 years was 7.3% vs31.6% in the lenalidomide arm versusthe observation arm
    • Two deaths were reported in the lenalidomide arm and four in the observation arm (HR for death, 0.46; 95% CI, 0.08─2.53)
    • In 36 (41%) patients, grade 3 or 4 hematologic and nonhematologic AEs occurred. Among the off treatment (n= 45) patients, 18 came off therapy as a result of AEs
    • The cumulative incidence of invasive second primary cancers at 3 years was 5.2% vs3.5% in the lenalidomide arm versusthe observation arm
    • End-organ damage occurred more frequently in the observation arm than in the treatment arm, with bone progression as the most common cause for progression (observation arm [n= 11] vstreatment arm [n= 3])


  • Early intervention with lenalidomide in SMM patients prolongs PFS, delays progression to MM, and prevents end-organ damage
  • To test whether more aggressive therapies may be more effective in treating patients with SMM, an ongoing trial ( NCT03937635) is comparing lenalidomide and dexamethasone versuslenalidomide and dexamethasone plus daratumumab (triplet regimen approved for MM)
  1. Lonial S. et al., Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma. J Clin Oncol. 2019 Oct 25; JCO1901740. DOI: 10.1200/JCO.19.01740

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