PF586 SPARING STEROIDS IN ELDERLY INTERMEDIATE‐FIT NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS TREATED WITH A DOSE/SCHEDULE‐ADJUSTED RD‐R VS. CONTINUOUS RD: RESULTS OF RV‐MM‐PI‐0752 PHASE III RANDOMIZED STUDY
Authors: Larocca A. , Salvini M. , Gaidano G. , Cascavilla N. , Baldini L. , Aglietta M. , Bosi A. , Marasca R. , Spada S. , Ledda A. , Bernardini A. , Falco P. , De Rosa L. , Guglielmelli T. , Zambello R. , Petrucci M.T. , Di Renzo N. , Benevolo G. , Cavo M. , Palumbo A. , Boccadoro M. , Bringhen S. 
Published: June 2019

Background:Continuous lenalidomide‐dexamethasone (Rd) is an effective and safe treatment for elderly newly diagnosed multiple myeloma (NDMM) patients. However, the outcome of patients >75 years is still inferior to younger patients, and not only advanced age but also the occurrence of severe adverse events (AEs) may negatively affect duration of treatment and survival.Aims:In order to further optimize Rd treatment, we investigated the efficacy and feasibility of sparing continuous dexamethasone in a dose/schedule‐adjusted Rd therapy followed by lenalidomide maintenance (Rd‐R) compared with standard continuous Rd in intermediate‐fit NDMM patients.Methods:The IMWG frailty score combines age, functional status (ADL and IADL), and comorbidities (Charlson index, CCI), and it identifies fit, intermediate‐fit and frail patients, with different risk of toxicity, treatment discontinuation and mortality (Palumbo A et al. Blood 2015). Intermediate‐fit NDMM patients (Age 76–80 years or ADL≤4 or IADL≤5 or CCI≥2), with a frailty score = 1 (http://www.myelomafrailtyscorecalculator.net/) were randomized to receive Rd‐R or continuous Rd.Rd‐R treatment consisted of nine 28‐day cycles of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, followed by lenalidomide maintenance 10 mg/day (21 days), until progression. Continuous Rd consisted of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, until progression. The dose and schedule of continuous Rd was the one adopted in patients >75 years in the FIRST trial (Hulin C et al. JCO 2016).The primary endpoint was event‐free survival (EFS), defined as progression or death for any cause or discontinuation of lenalidomide or occurrence of any hematological grade 4 or non‐hematological grade 3–4 AEs, including Secondary Primary Malignancies, whichever comes first.Results:Of 199 evaluable patients, 98 were randomized to Rd‐R and 101 to continuous Rd. Median age was 75 and 76 years (p = 0.06); 47% in Rd‐R vs 57% in continuous Rd were defined intermediate‐fit for age (≥76 years), 53% vs 43% due to an impairment in CCI, ADL or IADL (p = ns). The median follow‐up was 25 months.Best response rates were comparable between the 2 groups: ≥PR rates were 73% vs 63%, and ≥VGPR rates were 43% vs 35% in the Rd‐R vs Rd continuous group, respectively. EFS was 9.3 vs 6.6 months (HR 0.72, 95% CI 0.52–0.99, p = 0.04), in Rd‐R versus continuous Rd, respectively. No difference in progression‐free survival (PFS) and overall survival (OS) was observed. 20‐month PFS was 43% vs 42% (HR 0.93, 95% CI 0.64–1.34, p = 0.681), 20 month‐OS was 84% versus 79% (HR 0.73, 95% CI 0.40–1.33, p = 0.306; Figure 1).At least 1 non‐hematologic grade 3–4 AE rate was 31% vs 39%. The most frequent grade3–4 AEs were neutropenia (17% vs 14%), infections (9% vs 11%) and skin rash (3% vs 7%). Lenalidomide dose reduction was required in 33% of Rd‐R patients and 43% of continuous Rd patients, and lenalidomide was discontinued in 19% vs 23% of patients, respectively. Lenalidomide median relative dose intensity was 100% in Rd‐R and 90% in continuous Rd group.Summary/Conclusion:Switching to lenalidomide maintenance after 9 cycles of Rd – thus sparing steroid in this dose/schedule‐adjusted Rd‐R treatment ‐ was feasible, without a negative impact but with outcome comparable to standard continuous Rd. This is the first prospective randomized phase III trial specifically designed for intermediate‐fit NDMM patients in which a frailty‐adjusted treatment approach to balance efficacy and safety was investigated.image