Four-Year Follow-up of the Phase 3 Pollux Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) Alone in Relapsed or Refractory Multiple Myeloma (RRMM)

Abstract

Introduction: Daratumumab, a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, is approved in combination with standard-of-care regimens for the treatment of newly diagnosed multiple myeloma (NDMM) and RRMM. When combined with standard of care regimens across four phase 3 studies, daratumumab demonstrated ≥44% reductions in the risk of progression or death, nearly doubled complete response (CR) or better rates, and tripled minimal residual disease (MRD)-negative rates at the 10-5 sensitivity threshold in pts with RRMM or NDMM (Palumbo A, et al. N Engl J Med 2016. 375[8]:754-766; Dimopoulos MA, et al. N Engl J Med 2016. 375[14]:1319-1331; Mateos MV, et al. N Engl J Med 2018. 378[6]:518-528; Facon T, et al. N Engl J Med 2019. 380[22]2104-2015). In the phase 3 POLLUX study (median follow-up 44.3 months), D-Rd reduced the risk of disease progression or death by 56% and significantly increased the overall response rate (ORR) versus Rd alone (93% vs 76%; P <0.0001) in patients (pts) with RRMM. Here, we present updated efficacy and safety analyses of POLLUX after >4 years of median follow-up. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to Rd (lenalidomide 25 mg PO on Days 1-21 of each 28-day cycle; dexamethasone 40 mg per week) ± daratumumab (16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, then Q4W until disease progression). Cytogenetic risk was determined by local fluorescence in situ hybridization or karyotyping; pts with high cytogenetic risk had t(4;14), t(14;16), and del17p abnormalities. PFS on subsequent line of therapy (PFS2), an exploratory endpoint, was defined as time from randomization to progression after next line of subsequent therapy or death. Results: A total of 569 pts were randomized (D-Rd, n = 286; Rd, n = 283). At a median follow-up of 51.3 months, D-Rd significantly prolonged progression-free survival (PFS) versus Rd (median 45.8 vs 17.5 months; hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.35-0.54; P <0.0001; Figure). D-Rd also prolonged PFS versus Rd among pts with 1 prior line of therapy, among pts with 1-3 prior lines of therapy, and regardless of cytogenetic risk status (Table). A PFS benefit with D-Rd was also observed among pts who received prior lenalidomide (median 38.8 vs 18.6 months; HR, 0.34; 95% CI, 0.19-0.59; P <0.0001) and among pts refractory to bortezomib (median 34.3 vs 11.3 months; HR, 0.41; 95% CI, 0.25-0.68; P = 0.0004). D-Rd was associated with a significantly higher ORR versus Rd (93% vs 76%), including higher rates of ≥very good partial response (81% vs 49%) and ≥CR (57% vs 24%; all P <0.0001). Median time to next therapy for D-Rd versus Rd was not reached in the D-Rd group versus 22.8 months in the Rd group (HR, 0.39; 95% CI, 0.30-0.49; P <0.0001). D-Rd significantly prolonged PFS2 versus Rd (median 53.3 vs 31.6 months; HR, 0.54; 95% CI, 0.43-0.68; P <0.0001). In the D-Rd group, 121 deaths were observed versus 133 deaths in the Rd group; follow-up for overall survival is ongoing. The median duration of treatment was 34.3 months in the D-Rd arm versus 16.0 months in the Rd arm. The most common (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs) observed with D-Rd versus Rd included neutropenia (56% vs 42%), anemia (18% vs 22%), thrombocytopenia (15% vs 16%), pneumonia (16% vs 10%), and diarrhea (10% vs 4%). Similar rates of discontinuations due to TEAEs were observed for D-Rd versus Rd (16% vs 15%). The incidence of invasive second primary malignancies was 4.9% and 5.7% for the D-Rd and Rd groups, respectively. Additional efficacy data, including minimal residual disease, and safety analyses will be presented at the meeting. Conclusion: After >4 years of median follow-up, D-Rd continues to demonstrate a significant PFS benefit and higher rates of deeper responses versus Rd alone in pts with RRMM. Although significant PFS benefit was observed with D-Rd in RRMM pts regardless of prior lines of therapy or cytogenetic risk status, the greatest benefit was observed when used in patients treated earlier with D-Rd. The significant improvement in PFS2 suggests a potential survival benefit, but OS data is still immature. No new safety concerns were identified with this additional follow-up. Disclosures Kaufman: Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Takeda: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AbbVie: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Amgen: Consultancy. Usmani:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Bahlis:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. White:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Cook:Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding. Ho:Novartis: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs. Moreau:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Krevvata:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Renaud:Janssen: Employment, Equity Ownership. Trivedi:Janssen: Employment, Equity Ownership. Kobos:Janssen: Employment. Dimopoulos:Sanofi Oncology: Research Funding.

Shaping the Treatment Paradigm Based on the Current Understanding of the Pathobiology of Multiple Myeloma: An Overview

“…Combination with mAbs appears tolerable with improvements in PFS with both elotuzumab (19.4 vs. 14.9 months, HR 0.70, p < 0.01; Elo-Rd vs. Rd; ELOQUENT-2) and daratumumab (45.8 vs. 17.5 months, HR 0.43, p < 0.0001; Dara-Rd vs. Rd; POLLUX) [ 124 , 125 ]. The greatest benefit of Dara-Rd is when given at first relapse (mPFS 53.3 months) suggesting incorporation of mAbs early in treatment of relapse is crucial [ 132 ].…”

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma

“…At a median follow-up of 51.3 months, D-Rd significantly prolonged progression-free survival (PFS) versus Rd (median 45.8 vs 17.5 months; HR 0.43; 95% CI 0.35 to 0.54; p<0.0001). 31 A PFS benefit for D-Rd versus Rd was also observed regardless of cytogenetic risk status. In the phase III CASTOR trial evaluating dara in combination with bortezomib and dexamethasone (D-Vd) compared with Vd alone, the 12-month rate of PFS was 60.7% in the dara group vs 26.9% in the control group.…”

“…Among patients with keratopathy worse than baseline at the end of treatment, the events resolved in 9 (36%) of 25 patients in the 2.5 mg/kg cohort, with a median time to resolution of 71 days (interquartile range (IQR) 57-99), and 8 (28%) of 29 patients in the 3.4 mg/kg cohort, with a median time to resolution of 96 days . No benefit was observed for prophylactic steroid eyedrop administration, as median time to keratopathy was similar between eyes treated prophylactically with corticosteroid eye drops and without (24 (IQR 21-30) and 27 days, respectively in the 2.5 mg/kg cohort and 25 (9-40) and 25 (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) days, respectively in the 3.4 mg/kg cohort). 203 Panel recommendations ► Prior to receiving belantamab mafodotin the patient should receive a complete ophthalmological examination.…”

Multiple Myeloma: An Overview of the Current and Novel Therapeutic Approaches in 2020

“…A triplet association with lenalidomide is probably the better option. To date, as still only few patients would have received daratumumab, the triplet dara-Rd is a valid choice based on the data of the phase 3 POLLUX trial, with an impressive median PFS of 45.8 months for dara-Rd vs. 17.5 month for Rd ( p < 0.0001) [ 26 ], and a ≥CR rate of 57% vs. 24%, respectively. Interestingly, dara-Rd also performed well for patients exposed to lenalidomide, although it concerned a quite small cohort of patients ( n = 50).…”