Three-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 is a human, CD38-targeted, IgGκ monoclonal antibody with both direct on-tumor and immunomodulatory mechanisms of action. In the phase 3 POLLUX study, D-Rd reduced the risk of disease progression or death by 63% and significantly increased the overall response rate (ORR) versus Rd alone (93% vs 76%; P <0.001) in RRMM patients (pts). When combined with standard of care regimens across three phase 3 studies including POLLUX, daratumumab demonstrated ≥50% reductions in the risk of progression or death, doubled complete response (CR) rates, and tripled minimal residual disease (MRD)-negative rates at the 10-5 sensitivity threshold in pts with RRMM or newly diagnosed MM (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). Improvements in deeper responses gained from novel MM treatments have led to interest in sustained MRD negativity as a potential surrogate endpoint (Kumar S, et al. Lancet Oncol 2016. 17[8]:e328-e346; Anderson KC. Blood Adv 2017. 1[8]:517-521). Here, we present updated efficacy and safety analyses of POLLUX, including sustained MRD negativity, after >3 years of median follow-up. Methods: Pts with ≥1 prior line of therapy were randomized (1:1) to receive 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). High risk cytogenetic abnormalities included t(4;14), t(14;16), and del17p. At the time of suspected CR and at 3 and 6 months after confirmed CR (and every 12 months thereafter if CR was maintained), bone marrow aspirates were assessed for MRD using clonoSEQ® V2.0 (Adaptive Biotechnologies, Seattle, WA). Sustained MRD negativity was defined as maintenance of MRD negativity at the 10-5 threshold for ≥6 or ≥12 months. 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 39.5 months, D-Rd significantly prolonged progression-free survival (PFS) versus Rd (median, not reached [NR] vs 17.5 months; hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.35-0.55; P <0.0001); 36-month PFS rate was 55% versus 28%. D-Rd also prolonged PFS versus Rd among pts with 1 prior line of therapy and pts with 1-3 prior lines of therapy (Table 1). A PFS benefit for D-Rd versus Rd was also observed regardless of cytogenetic risk status (Table 1). D-Rd was associated with a significantly higher ORR versus Rd (93% vs 76%), including higher rates of ≥very good partial response (80% vs 49%) and ≥CR (56% vs 23%; all P <0.0001). At the 10-5 sensitivity threshold, MRD-negativity was achieved by 87 (30%) D-Rd pts versus 15 (5%) Rd pts (P <0.000001). Among the ITT population, sustained MRD negativity was achieved by 47 (16%) D-Rd pts versus 2 (0.7%) Rd pts for ≥6 months and 37 (13%) D-Rd pts versus 1 (0.4%) Rd pt for ≥12 months (both P <0.0001). Median time to next therapy for D-Rd versus Rd was NR in the D-Rd group versus 22.8 months in the Rd group (HR, 0.38; 95% CI, 0.29-0.49; P <0.0001). In the D-Rd group, 98 (34%) overall survival (OS) events were observed versus 118 (42%) OS events in the Rd group; OS follow-up 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 are described in Table 2. No differences were observed for D-Rd versus Rd in discontinuations due to TEAEs (14% of pts in each treatment group) or incidences of second primary malignancies (7% of pts in each treatment group). Updated data including PFS2 will be presented at the meeting. Conclusion: After >3 years of median follow-up, D-Rd continued to demonstrate a significant PFS benefit and higher rates of deeper responses versus Rd alone in RRMM pts. The higher rate of sustained MRD negativity with D-Rd compared with Rd suggests that continued D-Rd treatment drives these deep responses and delays progression. No new safety signals were observed following a median of 34 months of D-Rd exposure. Disclosures Bahlis: Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Dimopoulos:Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. White:Amgen: 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; Janssen: 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. Cook:Amgen, Bristol-Myers Squibb, GlycoMimetics, Celgene, Janssen and Takeda and Sanofi: Honoraria; Celgene, Janssen and Takeda: Research Funding. Ho:Takeda: Honoraria, Other: Travel to meeting; Novartis: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Other: Travel to meeting. Moreau:Janssen: 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; Takeda: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Krevvata:Janssen Research & Development, LLC: Employment. Chiu:Janssen Research & Development, LLC: Employment. Qin:Janssen Research & Development, LLC: Employment. Okonkwo:Janssen Research & Development, LLC: Employment. Trivedi:Janssen Research & Development, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. San-Miguel:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria.

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

“…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.…”

“…Furthermore, when combined with standard-of-care regimens across multiple phase III studies including POLLUX and CASTOR (borte-zomib+dexamethasone±dara), the addition of dara led to ≥50% reductions in the risk of progression or death, doubled complete response (CR) rates and tripled MRDnegative rates at the 10 -5 sensitivity threshold in patients with RRMM. [28][29][30] A 4-year follow-up analysis of POLLUX examined 569 randomized patients (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; HR 0.43; 95% CI 0.35 to 0.54; p<0.0001).…”

“…Only one patient developed neurotoxicity. 117 At data cut-off, the OS rate at 18 months was 68% (range 54%-79%) with median duration of response (mDOR) 22 months (range [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. At 18 months, the rate of PFS was 50% (range 36-63) for all treated patients and 71% (range 52-84) for MRD-negative patients with CR.…”

ASH 2018—Highlights in Multiple Myeloma

“…Updated data on the phase 3 CASTOR and POLLUX trials demonstrated a sustained significant PFS and OS benefit in relapsed and refractory multiple myeloma (RR-MM) patients treated with daratumumab containing triplets [13,14]. Also, a joint analysis from the CASTOR, POLLUX, and MMY1001 trials showed that both the combination of daratumumab with pomalidomide as wells as with carfilzomib showed similar response rates in lenalidomide-refractory patients when compared to non-refractory patients [15].…”

Moving Toward Continuous Therapy in Multiple Myeloma

“…In this setting, continuous treatment has traditionally aimed at disease control over time, with a favorable toxicity profile, and this remains true for heavily pretreated patients. In early relapses, however, the administration of newer combination regimens with novel agents-including the second-generation proteasome inhibitor (PI) carfilzomib or the anti-CD38 monoclonal antibody (mAb) daratumumab-allowed the achievement of deep responses, with complete response (CR) rates ranging from 20% to 43% [9][10][11][12][13][14]. Remarkably, with daratumumab-based combinations, the MRD-negative status was achieved in 12-26% of relapsed patients [11][12][13][14].…”