Phase III trial shows survival benefit for early multiple myeloma

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1. Treatment with lenalidomide and dexamethasone significantly delayed disease progression in patients with smoldering multiple myeloma who were at high risk for progression.

2. Treatment with lenalidomide and dexamethasone improved survival in such patients.

3. The treatment was associated with more adverse events than observation (current standard).

Evidence Rating Level: 1 (Excellent) 

Study Rundown: Smoldering multiple myeloma (SMM) is a premalignant stage of multiple myeloma. Patients with SMM have a 10% annual risk of disease progression. Such patients are closely followed but not treated because studies thus far have failed to show that early treatment reduces mortality.

In this study, the authors tested the efficacy of oral lenalidomide and dexamethasone therapy among SMM patients with a high risk for progression. Since there is no consensus on how to identify high-risk SMM, the authors used their own interpretation of current criteria.

The authors found that the lenalidomide and dexamethasone therapy not only significantly delayed disease progression, but also produced a survival benefit. At three years, 77% of the patients who received lenalidomide had progression-free survival, compared with 30% in the observation group. However, this benefit must be balanced against the risk of adverse effects, which included serious infections, rashes, constipation and diarrhea.

This small study is notable as it has succeeded in showing a survival benefit from early treatment of SMM where other trials have failed. This success may be related to the purposeful selection of high-risk SMM patients, which had not been done before. Further studies should address the impact of this regimen on quality of life, which was not assessed.

Click to read the study, published today in NEJM

Relevant Reading: Early versus deferred treatment for early stage multiple myeloma

In-Depth [randomized controlled trial]: 119 patients with high-risk SMM in Spain and Portugal were randomized to either observation or treatment. Treatment included an induction phase consisting of nine four-week cycles of lenalidomide and dexamethasone followed by maintenance therapy with lenalidomide until progression or until two years from the start of treatment. Dexamethasone was added to the maintenance regimen if asymptomatic progression occurred.

The primary end point was time to progression to symptomatic myeloma. Secondary end points were response rate, overall survival, and safety. Median time to progression was 21 months in the observation group. Less than 50% of the patients in the treatment group had disease progression by the end of the trial, so the median was not reached. The hazard ratio for progression was 0.18 (95% CI, 0.09 to 0.32, P<0.001). Median overall survival was not reached in either group. At 3 years, 94% of patients in the treatment group remained alive versus 80% in the observation group, resulting in a hazard ratio for death of 0.31 (95% CI, 0.10 to 0.91; P=0.03).

The incidence of infection did not differ between the treatment and observation group, but the rate of serious adverse events due to infection was higher in the treatment group.

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