Lenalidomide plus dexamethasone demonstrates efficacy in the treatment of relapsed or refractory multiple myeloma

In 2 studies assessing the combination of lenalidomide plus dexamethasone, the treatment regimen was demonstrated to be an effective therapy for relapsed and/or refractory multiple myeloma. Both studies were published in the New England Journal of Medicine (NEJM).

The studies were similar in many respects. Both were multicenter, randomized, placebo-controlled, phase 3 trials. The first study was also double blinded. All patients in both trials had previously received ≥1 treatment for multiple myeloma. The primary end point (time to disease progression, measured from randomization to the first date that disease progression was noted during assessment) was the same in both trials. Disease progression was defined as a >500-mg/dL absolute increase in serum monoclonal protein compared with the nadir value; a >200-mg increase in urinary monoclonal protein per 24-hour period; plasmacytoma (or increased size of such lesions) or a new bone lesion; or a >11.5-mg/dL serum calcium level. The first trial also defined a ≥25% increase from nadir in monoclonal protein as an indication of disease progression. In both trials, patients were randomized to receive lenalidomide 25 mg or placebo on Days 1 to 21 of each 28-day cycle. All patients received oral dexamethasone 40 mg on Days 1 to 4, 9 to 12, and 17 to 20 for the first 4 cycles. Patients received dexamethasone 40 mg only on Days 1 to 4 after the fourth cycle. This treatment regimen continued until the occurrence of disease progression or unacceptable toxic effects.

Patients in both trials were assessed (blood counts and physical examination) on Days 1 and 15 (and Day 8 of Cycle 1) during Cycles 1 to 3 and on the first day of each subsequent cycle. Researchers also evaluated the patients' serum and urinary protein levels on Day 1 of each cycle and at the end of therapy.

Lenalidomide plus dexamethasone was associated with a longer median time to progression compared with placebo plus dexamethasone (11.1 months vs 4.7 months; P<.001).

The incidence of complete, near-complete, or partial responses was greater among patients in the lenalidomide group compared with those in the placebo group (61.0% vs 19.9%; P<.001). A total of 14.1% of patients in the lenalidomide group achieved a complete response compared with 0.6% of patients in the placebo group (P<.001).

The length of median overall survival was greater among patients in the lenalidomide group compared with those in the placebo group (29.6 months vs 20.2 months; P<.001).

The most commonly reported nonhematologic adverse events in study patients were fatigue, insomnia, diarrhea, constipation, muscle cramps, and infection. A greater percentage of patients treated with lenalidomide plus dexamethasone experienced infections (primarily upper respiratory tract infections and pneumonia) compared with patients who received placebo plus dexamethasone (67.8% vs 44.0%; P<.001). More patients in the lenalidomide group experienced venous thromboembolic events compared with those in the placebo group (14.7% vs 3.4%; P<.001); of these events, none was fatal. Grade 3 and 4 hematologic toxic effects were more common among patients in the lenalidomide group compared with those in the placebo group (52.5% vs 13.7%; P<.001). Grade 3 or 4 neutropenia and thrombocytopenia were more common with lenalidomide treatment versus placebo.

In the second trial, 176 patients received lenalidomide plus dexamethasone and 175 patients received placebo plus dexamethasone. Secondary end points included response rate, overall survival, and safety.

Lenalidomide plus dexamethasone therapy was associated with a longer median time to progression compared with placebo plus dexamethasone (11.3 months vs 4.7 months; P<.001).

The incidence of complete, near-complete, or partial responses was greater among patients in the lenalidomide group compared with those in the placebo group (60.2% vs 24.0%; P<.001). A total of 15.9% of patients treated with lenalidomide plus dexamethasone achieved a complete response compared with 3.4% of patients who received placebo plus dexamethasone (P<.001).

The length of median overall survival was greater among patients in the lenalidomide group compared with those in the placebo group. This end point had not been reached at the time of the last analysis among patients treated with lenalidomide plus dexamethasone; the median overall survival for patients who received placebo plus dexamethasone was 20.6 months (HR for death among patients treated with lenalidomide plus dexamethasone=0.66; 95% CI, 0.45–0.96; P=.03).

The most commonly reported nonhematologic adverse events in this trial were muscle cramps, constipation, nausea, tremor, and dizziness. More patients treated with lenalidomide plus dexamethasone experienced deep-vein thrombosis (4.0% vs 3.5%) and pulmonary embolism (4.5% vs 1.2%) compared with those who received placebo plus dexamethasone. Grade 3 neutropenia was more prevalent among patients in the lenalidomide group compared with those in the placebo group (25.0% vs 2.3%); 3.4% of patients who received lenalidomide plus dexamethasone experienced grade 3 or 4 febrile neutropenia compared with no patients who received placebo plus dexamethasone.

In both studies, granulocyte colony-stimulating factor (G-CSF) was administered only if grade 3 or 4 myelosuppression occurred. In the first study, a total of 33.9% of patients who received lenalidomide plus dexamethasone were treated with G-CSF; 21.6% of patients who received lenalidomide plus dexamethasone in the second study also received G-CSF.

In an accompanying editorial, Alan F List, MD, stated, "Lenalidomide and the immunomodulatory drugs stand as prime examples of potentially dangerous chemical compounds that have been granted a second life with powerful therapeutic applicability."

SOURCES

Weber DM, Chen C, Niesvizky R, et al; for the Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133–2142.

Dimopoulos M, Spencer A, Attal M, et al; for the Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123–2132.

List AF. Lenalidomide-the phoenix rises [editorial]. N Engl J Med. 2007;357:2183–2186.