Introduction: Daratumumab is a human monoclonal antibody targeting CD38 that demonstrated superior efficacy in combination with lenalidomide and dexamethasone (DRd) versus lenalidomide and dexamethasone alone (Rd) in a pre-specified interim analysis of a randomized phase 3 study of relapsed or refractory multiple myeloma (RRMM; Dimopoulos MA, et al. N Engl J Med 2016; in press). We report subgroup analyses from this study in patients (pts) who received 1 to 3 prior lines of therapy (1-3 PL), including outcomes based on high-risk cytogenetics within these subgroups.

Methods: Patients (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 PO weekly) with or without daratumumab (16 mg/kg IV qw for 8 weeks, q2w for 16 weeks, then q4w until progression). The primary endpoint was progression-free survival (PFS). The site investigator determined the number of prior lines of therapy according to IMWG consensus guidelines. Treatment-free interval (TFI) was defined as the duration between the end/start date of last line of prior therapy and the date of randomization. Pts with high-risk cytogenetic status had at least one of the following abnormalities as assessed via fluorescence in-situ hybridization or karyotyping by local laboratory assessment: t(4;14), t(14;16), or del17p.

Results: In the 1-3 PL subgroup (DRd, n=272; Rd, n=264), PFS was significantly improved with DRd vs Rd (median: not reached [NR] vs 18.4 months; HR, 0.36; 95% CI, 0.25-0.50; P<0.0001), with estimated 12-month PFS rates of 83.2% vs 60.4%, respectively. Time to progression was also significantly longer with DRd vs Rd (median: NR vs 18.4 months; HR, 0.32; 95% CI, 0.22-0.46; P<0.0001). ORR (94% vs 77%), rates of very good partial response (VGPR) or better (76% vs 45%) and complete response (CR) or better (44% vs 20%) were significantly higher with DRd vs Rd, respectively (P<0.0001 for all). Among responders, median time to VGPR or better was 2.8 months in DRd vs 2.9 months in Rd; median time to CR or better was 6.7 months vs 7.5 months, respectively. For pts in the 1-3 PL subgroup with high-risk cytogenetics (n=33 in each treatment group), significantly longer PFS was observed in DRd vs Rd (median: NR vs 8.3 months; HR, 0.30; 95% CI, 0.14-0.67; P=0.0019). Significantly higher ORR (91% vs 69%; P=0.0267), rate of VGPR or better (73% vs 28%; P=0.0004), and rate of CR or better (36% vs 9%; P=0.0104) were achieved in pts with high-risk cytogenetic status treated with DRd vs Rd, respectively.

For 1-3 PL pts who had a TFI of >12 months (DRd, n=138; Rd, n=145), median PFS was NR in DRd vs 18.4 months in Rd (HR, 0.42; 95% CI, 0.24-0.74; P=0.0019; Figure A); the estimated 12-month PFS rate was 88.0% vs 74.5%, respectively. ORR was significantly higher with DRd vs Rd (96% vs 86%, P=0.0084), along with rate of VGPR or better (77% vs 56%; P=0.0008) and rate of CR or better (43% vs 27%; P=0.0083). Among pts with a TFI of ≤12 months (DRd, n=134; Rd, n=119), median PFS was NR in DRd vs 10.3 months in Rd (HR, 0.32; 95% CI, 0.21-0.51; P<0.0001; Figure B); the estimated 12-month PFS rate was 78.1% vs 43.1%, respectively. ORR (92% vs 67%), rate of VGPR or better (76% vs 32%), and rate of CR or better (44% vs 10%) were all significantly higher with DRd vs Rd (P<0.0001 for all).

Among pts with 1-3 PL who were refractory to their last line of therapy (DRd, n=73; Rd, n=67), PFS was significantly prolonged with DRd vs Rd (median: NR vs 10.3 mo; HR, 0.42; 95% CI, 0.25-0.72; P=0.0010). ORR (92% vs 66%; P=0.0002), rate of VGPR or better (72% vs 34%; P<0.0001), and rate of CR or better (47% vs 14%; P<0.0001) were significantly higher with DRd vs Rd.

Data for all subgroup analyses will be updated for the meeting.

Conclusions: Responses with DRd were deep and durable which translated into significantly improved clinical outcomes vs Rd in 1-3 PL pts with RRMM. The results of these subgroup analyses suggest that the treatment benefit of DRd vs Rd was maintained across these subgroups, including pts with TFI of ≤12 months and those who were refractory to their last line of therapy.

Figure
Figure. Progression-free survival in patients with 1 to 3 prior lines of therapy and treatment-free interval of (A) >12 months (B) ≤12 months prior to randomization
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Progression-free survival in patients with 1 to 3 prior lines of therapy and treatment-free interval of (A) >12 months (B) ≤12 months prior to randomization

Figure
Figure. Progression-free survival in patients with 1 to 3 prior lines of therapy and treatment-free interval of (A) >12 months (B) ≤12 months prior to randomization
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Progression-free survival in patients with 1 to 3 prior lines of therapy and treatment-free interval of (A) >12 months (B) ≤12 months prior to randomization

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Disclosures

Usmani:Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Dimopoulos:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Belch:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria. White:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria. Benboubker:Celgene: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cook:Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Glycomimetics: Consultancy. Ho:Amgen: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Khokhar:Janssen: Employment. Guckert:Janssen: Employment; Johnson & Johnson: Equity Ownership. Wu:Janssen: Employment. Qin:Janssen: Employment. Casneuf:Johnson & Johnson: Equity Ownership; Janssen R&D, Beerse, Belgium: Employment. Chiu:Janssen: Employment. Sasser:Janssen: Employment; Johnson & Johnson: Equity Ownership. San-Miguel:Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Topics:
daratumumab, dexamethasone, lenalidomide, multiple myeloma, thumb, brachial plexus neuritis, complete remission, karyotype determination procedure, monoclonal antibodies, partial response

Author notes

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© 2016 by The American Society of Hematology
2016
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