Lenalidomide, an analog of thalidomide, received FDA approval as a first-line treatment for multiple myeloma in February 2015. This oral agent, marketed as Revlimid by Celgene, is now indicated for use in combination with low-dose dexamethasone for patients newly diagnosed with multiple myeloma who are not candidates for autologous stem-cell transplant (ASCT). This approval marked a significant advancement in the treatment landscape for this patient population, offering an alternative to traditional chemotherapy regimens.
Clinical Efficacy: The FIRST Trial
The approval was primarily based on the results of the Phase 3 FIRST (MM-020) trial, a randomized, open-label study involving 1623 patients. The trial compared lenalidomide plus low-dose dexamethasone to melphalan, prednisone, and thalidomide (MPT), a standard chemotherapy regimen, and to lenalidomide given for 18 cycles. Patients in the lenalidomide plus dexamethasone arm experienced a significantly longer median progression-free survival (25.5 months) compared to those receiving MPT (21.2 months; HR, 0.72; P < .001). Furthermore, the final analysis of overall survival demonstrated a significant benefit, with a median overall survival of 58.9 months in the lenalidomide plus dexamethasone group versus 48.5 months in the MPT group (HR, 0.75).
The study's findings highlighted the superiority of the lenalidomide-based combination in terms of both progression-free survival and overall survival, establishing it as a preferred first-line option for eligible patients. The overall response rate was 75.1% in the lenalidomide plus low-dose dexamethasone arm, compared to 62.3% in the MPT arm.
Mechanism of Action and Administration
Lenalidomide is an immunomodulatory agent with multiple mechanisms of action. It inhibits the proliferation and induces apoptosis of hematopoietic tumor cells, enhances T-cell-mediated and natural killer cell-mediated immunity, and blocks pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The synergistic effect of lenalidomide and dexamethasone further enhances the inhibition of cell proliferation and induction of apoptosis in multiple myeloma cells.
Lenalidomide is administered orally at a recommended dose of 25 mg daily for the first 21 days of each 28-day cycle, continuing until disease progression. It is available in various capsule strengths to facilitate dose adjustments based on individual patient needs and tolerability.
Safety Profile and Adverse Events
While lenalidomide offers significant clinical benefits, it is associated with specific adverse events that require careful monitoring and management. In the FIRST trial, the most frequently reported grade 3 or 4 adverse reactions included neutropenia, anemia, thrombocytopenia, and pneumonia. The overall rate of infections was higher in the lenalidomide-based combination arm compared to the MPT arm (75% vs 56%, respectively).
Common adverse reactions (all grades) reported at a rate >20% overall and at least 5% higher than in the MPT regimen included diarrhea (46% vs 17%), back pain (32% vs 21%), asthenia (28% vs 23%), and rash (26% vs 19%).
Lenalidomide carries a boxed warning regarding the risk of embryofetal toxicity, hematologic toxicity, and thromboembolism, necessitating strict adherence to a Risk Evaluation and Mitigation Strategy (REMS) program. Patients should be monitored closely for hematologic toxicities, and thromboprophylaxis is recommended to mitigate the risk of venous and arterial thromboembolic events.
Multiple Myeloma: An Overview
Multiple myeloma is a cancer of plasma cells in the bone marrow, characterized by bone destruction and bone marrow failure. It represents approximately 1% of all cancers and is the second most common hematologic malignancy. While the incidence of multiple myeloma has been increasing, mortality rates have declined due to advancements in therapy. The approval of lenalidomide as a first-line treatment option contributes to the ongoing efforts to improve outcomes for patients with multiple myeloma.
