NEW ORLEANSResults of the FIRST trial have established continuous treatment with lenalidomide and low-dose dexamethasone (Rd) as a new standard of care in patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for stem cell transplantation (SCT), a phase 3 study presented at the 55th American Society of Hematology Annual Meeting and Exposition concluded.

The multicenter FIRST (Frontline Investigation Of Lenalidomide + Dexamethasone Versus Standard Thalidomide) trial found that the all-oral Rd doublet significantly improved progression-free survival (PFS) compared with the standard triplet (melphalan, prednisone, and thalidomide [MPT]), said Thierry Facon, MD, Service des Maladies du Sang, Hopital Claude Huriez, CHRU Lille, Lille, France, and colleagues.

The study randomly assigned 1,623 patients 65 years of age or older in 18 countries to Rd in 28-day cycles until disease progression (Arm A); Rd in 28-day cycles for 72 weeks (18 cycles, Arm B); or MPT in 42-day cycles for 72 weeks (12 cycles, Arm C). Patients with renal impairment were eligible; however, those on dialysis were excluded.

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“Starting doses of lenalidomide and dexamethasone were adjusted based on renal function and age, respectively. Melphalan starting dose was adjusted based on age, absolute neutrophil count, platelet count, and renal function; and thalidomide was adjusted for age,” Dr. Facon said. Dose adjustments were permitted for adverse events, and all patients were required to receive antithrombotic prophylaxis.

After each cycle, patients were assessed using International Myeloma Working Group criteria. Stratification factors included age, International Staging System (ISS) stage, and country. Primary end point was a comparison of PFS in Arm A versus Arm C. Secondary end points included overall survival (OS), overall response rate (ORR), time to response, duration of response (DOR), safety, and quality of life (QOL).

A preplanned additional analysis included time from randomization to second progression event or death (PFS2). Dr. Facon’s presentation provided results of a final preplanned analysis of independently adjudicated progressive disease (PD) events in Arm A versus Arm C conducted after 960 events of death or PD, and an interim of OS in 64% of survival events (574/896 events).

Median age was 73 years (range, 40-92 years), with 35% of patients 75 years of age or older. A total of 41% of patients had ISS stage 3 disease.

“After a median follow-up of 37 months, the trial met its primary end point, demonstrating a 28% reduction in risk of progression or death (hazard ratio [HR], 0.72; P = 0.00006),” Dr. Facon said. Median PFS was 25.5 months in Arm A and 21.2 months in Arm C. Although the preplanned interim analysis of OS demonstrated a 22% reduction in risk of death in favor of Arm A versus Arm C (HR, 0.78; P = 0.01685), the prespecified boundary (P < 0.0096) was not crossed. At 4 years, OS was 59.4% in Arm A and 51.4% in Arm C.

All other secondary end points consistently showed improvement in favor of Arm A compared with Arm C: ORR (partial response or better) 75.1% versus 62.3% (P < 0.00001), median DOR 35.0 versus 22.3 months (HR, 0.63; P < 0.00001), and PFS2 (HR, 0.78; P = 0.0051).

Grade 3/4 adverse events in Arm A compared with Arm C were neutropenia (27.8% vs. 44.9%), infection (28.9% vs. 17.2%), thrombocytopenia (8.3% vs. 11.1%), peripheral sensory neuropathy (1.1% vs. 9.4%), and febrile neutropenia (1.1% vs. 2.6%). When incidence of secondary primary malignancies was evaluated, hematologic malignancies were 0.4% (one patient with AML and one with MDS) in Arm A versus 2.2% in Arm C (12 patients; four with AML, six with MDS, and two with MDS to AML), and the overall incidence of solid tumors was 2.8% in each arm, respectively.“All secondary end points support the clinical benefit of continuous Rd treatment,” Dr. Facon said. The safety profile of Rd was manageable, with reduced hematologic secondary primary malignancies compared with MPT.

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