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305 Efficacy and Feasibility of Dose/Schedule-Adjusted Rd-R Vs. Continuous Rd in Elderly and Intermediate-Fit Newly Diagnosed Multiple Myeloma (NDMM) Patients: RV-MM-PI-0752 Phase III Randomized Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Novel Targeted Combinations in Myeloma
Hematology Disease Topics & Pathways:
Diseases, multiple myeloma, Biological, Non-Biological, Plasma Cell Disorders, Lymphoid Malignancies
Sunday, December 2, 2018: 8:30 AM
Grand Ballroom 7 (Marriott Marquis San Diego Marina)

Alessandra Larocca, MD1, Marco Salvini, MD1*, Lorenzo De Paoli, MD1*, Nicola Cascavilla, MD1, Giulia Benevolo, MD1*, Monica Galli, MD1*, Vittorio Montefusco, MD1*, Tommaso Caravita di Toritto, MD1*, Anna Baraldi, MD1*, Stefano Spada1*, Nicola Giuliani, MD, PhD 1, Chiara Pautasso1*, Stefano Pulini, MD1*, Sonia Ronconi, MD1*, Norbert Pescosta, MD1*, Anna Marina Liberati, MD1*, Francesca Patriarca, MD1*, Claudia Cellini, MD1*, Patrizia Tosi, MD1*, Massimo Offidani, MD1, Michele Cavo, MD1*, Antonio Palumbo, MD2, Mario Boccadoro, MD1,3 and Sara Bringhen, MD1

1GIMEMA, European Myeloma Network, Italy
2University of Torino - Currently Takeda Pharmaceuticals Co., Torino, Italy - Zurich, Switzerland
3Città della Salute e della Scienza, Università di Torino, Division of Hematology, Torino Italy, Torino, Italy

INTRODUCTION: Elderly patients with newly diagnosed multiple myeloma (NDMM) are highly heterogeneous and their outcome is influenced by many factors: beside age, also comorbidities, general physical fitness, and cognitive function play a crucial role. The IMWG frailty score combines age, functional status, and comorbidities, and it identifies fit, intermediate-fit and frail patients, with different risk of toxicity, treatment discontinuation, and mortality (Palumbo A et al. Blood 2015). Until now, evidence-based tailored treatments according to patients’ frailty are still lacking. Therefore, this phase III study investigated the efficacy and feasibility of dose/schedule-adjusted lenalidomide-dexamethasone therapy followed by lenalidomide maintenance (Rd-R) versus continuous lenalidomide-dexamethasone (Rd) in elderly, intermediate-fit NDMM patients.

METHODS: Intermediate-fit NDMM patients, with a total frailty score (age, Charlson Index, ADL and IADL) of 1 (http://www.myelomafrailtyscorecalculator.net/), were enrolled and randomized to receive Rd-R or continuous Rd. To better approximate a real-world older population, patients usually excluded from clinical trials or with abnormal laboratory values could be included in the trial.

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 for 21 days, until disease progression. Continuous Rd consisted of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, until disease 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 adverse events (AEs), including Secondary Primary Malignancies (SPMs), whichever came first.

RESULTS: 199 patients (98 in Rd-R arm and 101 in continuous Rd arm) could be evaluated. Patients characteristics were well balanced between the 2 arms. 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 Charlson Index, ADL or IADL (p=ns).

In intention-to-treat analysis, after a median follow-up of 25 months, 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 (Figure 1).

Best response rates were not significantly different 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 (p=ns).

No difference in progression-free survival (PFS) and overall survival (OS) was observed. Median PFS was 18.3 vs 15.5 months (HR 0.93, 95% CI 0.64-1.34, p=ns) (Figure 1), 18 month-OS was 85% versus 81% (HR 0.73, 95% CI 0.40-1.33, p=ns).

Adverse events accounting for EFS (any hematologic grade 4, non-hematologic grade 3-4) were less frequent in the Rd-R group (30% vs 39%) than in the continuous Rd group (p=ns). The most frequent adverse events were neutropenia, infection and skin reactions (less than 10% in each arm). After 9 treatment cycles, these adverse events were less frequent in Rd-R vs continuous Rd group (3% vs 7%, p=ns).

Lenalidomide dose reduction after 9 treatment cycles was required in 1% of Rd-R patients and 21% of continuous Rd patients (p =0.06). Dexamethasone dose reduction was required in 17% vs 29% of patients, respectively (p=0.06).

CONCLUSION: This is the first prospective randomized phase III trial specifically designed for real-life intermediate-fit NDMM patients. A dose/schedule-adjusted Rd-R treatment was more feasible compared to full dose continuous Rd treatment in elderly intermediate-fit NDMM patients, with no negative impact but rather a comparable outcome. These results confirm the need for an appropriate definition of patient frailty, and pave the way to a frailty-adjusted treatment approach to better balance efficacy and safety in elderly NDMM patients.

Disclosures: Larocca: Celgene: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Amgen: Honoraria; Janssen-Cilag: Honoraria, Other: Advisory Board; Takeda: Other: Advisory Board. De Paoli: Amgen: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Other: Advisory Board; Gilead: Other: Advisory Board. Galli: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Sigma-Tau: Honoraria. Montefusco: Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Caravita di Toritto: Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Amgen: Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Takeda: Other: Advisory Board; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding. Giuliani: Celgene Italy: Other: Avisory Board, Research Funding; Takeda Pharmaceutical Co: Research Funding; Janssen Pharmaceutica: Other: Avisory Board, Research Funding. Patriarca: Jazz: Other: Travel, accommodations, expenses; Janssen: Other: Advisory role; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; MSD Italy: Other: Advisory Role. Offidani: Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. Cavo: GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo: Takeda: Employment. Boccadoro: Janssen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Bringhen: Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria.

*signifies non-member of ASH