LenDex in High-Risk Smoldering Myeloma

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Mateos MV, et al. "Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma". The New England Journal of Medicine. 2013. 369(5):438-47.
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Clinical Question

Among patients with high-risk smoldering myeloma, does early treatment with lenalidomide plus dexamethasone improve progression-free survival compared to observation?

Bottom Line

Among patients with smoldering myeloma fitting a specific definition of high-risk disease, early therapy with lenalidomide plus dexamethasone improved progression-free and overall survival compared to observation, with several caveats.

Major Points

Multiple myeloma is a plasma-cell malignancy that leads to characteristic features of hypercalcemia, renal dysfunction, anemia, and lytic bone disease. Observational studies revealed that nearly all patients diagnosed with myeloma have a prephase of disease starting with monoclonal gammopathy of undetermined significance (MGUS) and progressing to asymptomatic ("smoldering") multiple myeloma over a period of years. Efforts to delay symptomatic progression and death have focused on early initiation of therapy for patients with these precursor conditions. A logical group of patients to focus on has been patients with patients with smoldering myeloma who are estimated to have a high risk of progression to symptomatic myeloma based on biomarkers.

Published in 2013, this phase 3 study by Maria-Vitoria Mateos and sponsored by Celgene randomly assigned 119 patients with high-risk smoldering myeloma to either early treatment with lenalidomide and dexamethasone (LenDex) or to observation. High-risk smoldering myeloma was defined as (1) both bone marrow plasma cells ≥10% and sufficient monoclonal protein or (2) either one of these criteria plus an abnormal immunophenotype in ≥95% of marrow plasma cells and a ≥25% reduction in one or two of the uninvolved immunoglobulins; patients with symptomatic multiple myeloma were excluded. Treatment patients were given nine 28-day induction cycles of LenDex followed by maintenance lenalidomide monotherapy for up to 2 years. Dexamethasone was added to patients with asymptomatic biochemical progression during maintenance lenalidomide. Importantly, patients in the observation arm only received therapy for symptomatic disease progression. At a median follow-up of 40 months, the primary outcome of progression-free survival was not reached in the treatment arm and was 21 months in the observation arm. Overall survival at 3 years was improved in the treatment arm (94% vs. 80%; P=0.03), and toxicity was relatively mild. The authors conclude that early initiation of LenDex improves progression-free and overall survival in patients with high-risk smoldering myeloma.

Despite the impressive overall survival benefit to early initiation of therapy, several caveats require discussion. First is the choice of progression-free survival (PFS) as the primary endpoint for this trial, when overall survival (OS) is the more relevant endpoint for patients with premalignant conditions. Second is that the design of this trial was biased to favor the experimental LenDex arm. For example, patients receiving lenalidomide monotherapy who developed biochemical progression were given dexamethasone, whereas patients in the control arm were given no therapy for biochemical progression. Third is that the trial likely enrolled a very high-risk population — approximately 20% of patients in the control arm progressed to overt myeloma within the first year — and these patients would be recategorized as having overt myeloma on the basis of the current International Myeloma Working Group (IMWG) 2014 consensus criteria which incorporate biomarkers not reported in the current study. Ultimately, despite being a provocative trial it cannot be used to support early initiation of therapy to high-risk smoldering patients as currently defined. Modern studies in patients with high-risk smoldering myeloma are evaluating a different strategy altogether, namely eradicating disease entirely with aggressive combination therapy, and time will tell if this strategy is effective in improving overall survival of this high-risk group.

Guidelines

As of October 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Open-label, randomized, multi-center, phase 3 study
  • N=119 patients with high-risk smoldering myeloma
    • Lenalidomide plus dexamethasone (n=57)
    • Observation (n=62)
  • Setting: 22 centers in Spain and Portugal
  • Enrollment: 2007-2010
  • Median follow-up: 40 months
  • Analysis: Per-protocol
  • Primary outcome: Time to progression to symptomatic disease

Population

Inclusion Criteria

  • Diagnosed with smoldering myeloma within prior 5 years
  • At high-risk for progression to symptomatic disease, based on:
    • Both of the following:
      1. Bone marrow plasma cells ≥10%
      2. IgG M-spike ≥3 g/dL, IgA M-spike ≥2 g/dL, or Bence Jones proteinuria >1 g/24h
    • Or one of the above plus:
      • ≥95% phenotypically aberrant plasma cells
      • Immunoparesis defined as a reduction in one or two of the uninvolved immunoglobulins ≥25%

Exclusion Criteria

  • Patients with CRAB criteria were excluded
    • Creatinine ≥2 mg/dL
    • Hemoglobin <10 g/dL or 2 g/dL below the normal range
    • Bone lesions

Baseline Characteristics

From the treatment arm.

  • Median age: 63 years
  • Female 56%
  • Time since diagnosis: ≤6 months 44%, >6 months 56%
  • Criteria for high-risk smoldering myeloma:
    • BMPCs plus M-protein: 18%
    • ≥95% aberrant immunophenotype plus immunoparesis 40%
    • Both criteria 42%
  • M-protein: serum 2.7 g/dL, urine 0
  • Median BMPCs 18% (range 2-48%)

Interventions

  • Randomization to treatment versus observation in a 1:1 fashion
  • Patients in the treatment arm received nine 28-day induction cycles followed by 28-day maintenance cycles. Initially maintenance was planned until disease progression but in a protocol amendment this was limited to 2 years.
  • Induction therapy:
    • Lenalidomide 25 mg/d days 1-21
    • Dexamethasone 20 mg/d days 1-4 and days 12-15
  • Maintenance therapy:
    • Lenalidomide 10 mg/d days 1-21
    • For patients with asymptomatic increase in M-protein >25%, dexamethasone 20 mg/d days 1-4 of each cycle was added.
  • Patients in the control arm were observed without therapy until the time of progression. At the time of progression, patients did not cross over to LenDex; rather they were treated off protocol.
  • Progression was defined as the development of hypercalcemia >11.5 mg/dL, renal failure with creatinine ≥2 mg/dL, or anemia with hemoglobin ≤10 g/dL or 2 g/dL below the normal range, or bone lesions.
  • M-protein monitoring was performed every month, skeletal survey was performed at study entry and thereafter only based on symptoms.

Outcomes

Comparisons are early treatment versus observation.

Primary Outcome

Timie to progression
Not reached vs. 21 months (HR 0.18, 95% CI 0.09-0.32; P<0.001)

Secondary Outcomes

Overall survival at 3 years
94% vs. 80% (HR 0.31, 95% CI 0.10-0.91; P=0.03)

Adverse Events

Serious adverse events
12% vs. 3%
Grade 5 adverse events
1 in the treatment arm (respiratory infection)
Grade 3 adverse events
Infection 6%
Asthenia 6%
Neutropenia 5%
Rash 3%
Other adverse events
Grade 1-2 infection 40%
Grade 1-2 asthenia 18%
Grade 2 neutropenia 13%
Rash 32%
DVT 5%
Secondary malignancy
6% vs. 2%

Criticisms

  • Use of progression-free survival as a primary endpoint.
  • Study design favored the treatment arm, for example in that patients receiving lenalidomide monotherapy who developed biochemical progression were given dexamethasone, whereas patients in the control arm were given no therapy for biochemical progression.
  • At least a subset of patients enrolled on this study would now be considered as having overt myeloma based on IMWG 2014 criteria, and should not be observed. This skews the results in favor of early treatment.
  • Use of medical writer and editorial support was funded by Celgene, the maker of lenalidomide.

Funding

  • Sponsored by PETHEMA/GEM with an unrestricted grant from Celgene, the maker of lenalidomide.

Further Reading