"Clinical Question"
In patients with high-risk smoldering multiple myeloma, does early intervention with lenalidomide and dexamethasone delay progression to active disease and improve overall survival compared to observation?

"Bottom Line"
Early treatment with lenalidomide and dexamethasone in patients with high-risk smoldering multiple myeloma significantly delays progression to symptomatic disease and improves overall survival with manageable toxicity.

"Major Points"
- Standard care for smoldering multiple myeloma has been observation until symptoms develop. However, this does not identify high-risk patients who may benefit from early intervention.
- This phase 3 study randomized 119 high-risk smoldering myeloma patients to early treatment with lenalidomide and dexamethasone followed by maintenance lenalidomide or to observation.
- Early treatment significantly increased time to progression to symptomatic myeloma and overall survival rate at 3 years (94% vs. 80%).
- Response rates were high, with 79% after induction phase and 90% during the maintenance phase.
- Treatment toxic effects were mainly low-grade, consisting primarily of grade 1 or 2 infections, asthenia, and hematologic adverse events.

"Guidelines"
As of the knowledge cutoff date, there are no updated guidelines reflecting the results of this study.

"Design"
- Open-label, phase 3 randomized controlled trial
- N=119
- Early treatment (n=57)
- Observation (n=62)
- Median follow-up: 40 months

"Population"
- Inclusion criteria: Diagnosis of high-risk smoldering multiple myeloma within the previous 5 years.
- Exclusion criteria: Symptoms of active myeloma such as hypercalcemia, bone lesions, renal failure, or anemia.

"Interventions"
- Treatment: 9 cycles of lenalidomide (25 mg/day for days 1-21) and dexamethasone (20 mg/day on days 1-4 and 12-15), followed by maintenance with lenalidomide (10 mg/day on days 1-21 of each 28-day cycle) for 2 years.
- Observation: No treatment until progression to symptomatic disease.

"Outcomes"
- Primary: Time to progression to symptomatic disease.
- Secondary: Response rate, overall survival, and safety.

"Criticisms"
- Open-label design may introduce bias.
- Did not assess the quality of life impact of early treatment.
- Some patients received other treatments off-protocol at the time of symptomatic progression.

"Funding"
The study was funded by Celgene with an unrestricted grant.

"Further Reading"
The full study details and results are published in The New England Journal of Medicine, NCT00480363.