ClinicalTrials.gov Identifier: NCT

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1 Efficacy of Daratumumab, Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma Among Patients With to 3 Prior Lines of Therapy Based on Previous Treatment Exposure: Updated Analysis of POLLUX Philippe Moreau, Jonathan L. Kaufman, 2 Heather Sutherland, 3 Marc Lalancette, 4 Hila Magen, 5 Shinsuke Iida, Jin Seok Kim, 7 Miles Prince, 8 Tara Cochrane, 9 Nushmia Z. Khokhar, Mary Guckert, Xiang Qin, Albert Oriol Hematology, University Hospital Hôtel-Dieu, Nantes, France; 2 Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA; 3 Cell Separator Unit and Leukemia/Bone Marrow Transplant Program, University of British Columbia, Vancouver, BC, Canada; 4 Hotel-Dieu de Québec, Québec City, Québec, Canada; 5 Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Petah-Tikva and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel, Petah Tikva, Israel; Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; 7 Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea; 8 University of Melbourne, Peter MacCallum Cancer Centre, Melbourne, Australia; 9 Gold Coast University Hospital, Southport, QLD, Australia; Janssen Research & Development, LLC, Spring House, PA, USA; Institut Català d Oncologia, Institut Josep Carreras, Hospital Germans Trias I Pujol, Barcelona, Spain. ClinicalTrials.gov Identifier: NCT279

2 Daratumumab (D) With Lenalidomide and Dexamethasone () In a phase /2 study, 32 patients with relapsed or refractory multiple myeloma were treated with daratumumab mg/kg and lenalidomide/dexamethasone D induced rapid, deep, and durable responses Safety profile was manageable Neutropenia, the most common adverse event (AE), was managed with treatment interruptions, lenalidomide dose reduction, and growth factor administrations Patients progression-free and alive, % month PFS rate = 72% (95% CI, ) ORR, % % CR or better scr CR VGPR PR ORR = 8% % 9% 28% 3% VGPR or better 9% Patients at risk Time from first dose, months mg/kg PFS, progression-free survival; ORR, overall response rate; scr, stringent complete response; CR, complete response; VGPR, very good partial response; PR, partial response.. Plesner T, et al. Blood 2;28:

3 POLLUX: Study Design Multicenter, randomized (:), open-label, active-controlled, phase 3 study D (n = 28) Key eligibility criteria RRMM prior line of therapy Prior lenalidomide exposure, but not refractory Creatinine clearance 3 ml/min Stratification factors No. of prior lines of therapy ISS stage at study entry R A N D O M I Z E : Daratumumab mg/kg IV Qw in Cycles to 2, q2w in Cycles 3 to, then q4w until PD R mg PO Days to 2 of each cycle until PD d 4 mg PO 4 mg weekly until PD (n = 283) R mg PO Days to 2 of each cycle until PD d 4 mg PO 4 mg weekly until PD Cycles: 28 days Primary endpoint PFS Secondary endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Statistical analyses Primary analysis: ~77 PFS events Prior lenalidomide FDA approved daratumumab in patients with prior therapy based on POLLUX and CASTOR studies ISS, International Staging System; D, daratumumab/lenalidomide/dexamethasone; IV, intravenous; qw, weekly; q2w, every 2 weeks; q4w, every 4 weeks; R, lenalidomide; PO, oral; PD, progressive disease; d, dexamethasone;, lenalidomide/dexamethasone; TTP, time to progression; OS, overall survival; MRD, minimal residual disease. 3

4 POLLUX: Study Design Multicenter, randomized (:), open-label, active-controlled, phase 3 study D (n = 28) Key eligibility criteria RRMM prior line of therapy Prior lenalidomide exposure, but not refractory Creatinine clearance 3 ml/min Stratification factors No. of prior lines of therapy ISS stage at study entry R A N D O M I Z E : Daratumumab mg/kg IV Qw in Cycles to 2, q2w in Cycles 3 to, then q4w until PD R mg PO Days to 2 of each cycle until PD d 4 mg PO 4 mg weekly until PD (n = 283) R mg PO Days to 2 of each cycle until PD d 4 mg PO 4 mg weekly until PD Cycles: 28 days Primary endpoint PFS Secondary endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Statistical analyses Primary analysis: ~77 PFS events Prior lenalidomide FDA approved daratumumab in patients with prior therapy based on POLLUX and CASTOR studies ISS, International Staging System; D, daratumumab/lenalidomide/dexamethasone; IV, intravenous; qw, weekly; q2w, every 2 weeks; q4w, every 4 weeks; R, lenalidomide; PO, oral; PD, progressive disease; d, dexamethasone;, lenalidomide/dexamethasone; TTP, time to progression; OS, overall survival; MRD, minimal residual disease. 4

5 Baseline Demographic and Clinical Characteristics Characteristic Age, y Median (range) 75, % ISS stage, % a I II III D (n = 28) 5 (34-89) (n = 283) 5 (42-87) Characteristic Prior lines of therapy, % Median (range) 2 3 >3-3 c D (n = 28) (-) (n = 283) (-8) Median (range) time from diagnosis, y Creatinine clearance (ml/min), % N >3- > 3.48 (.4-27.) (.4-2.7) Prior ASCT, % 3 4 Prior PI, % Prior bortezomib, % Prior IMiD, % Prior lenalidomide, % Prior PI + IMiD, % Cytogenetic profile, % b N Standard risk High risk Refractory to bortezomib, % 2 2 Refractory to last line of therapy, % ASCT, autologous stem cell transplantation; PI, proteasome inhibitor; IMiD, immunomodulatory drug. a ISS staging is derived based on the combination of serum β2-microglobulin and albumin. b Centralized analysis using next-generation sequencing. High-risk patients had any of t(4;4), t(4;), or del7p. Standard-risk patients had an absence of high-risk abnormalities. c Exploratory. 5

6 Baseline Demographic and Clinical Characteristics Characteristic Age, y Median (range) 75, % ISS stage, % a I II III D (n = 28) 5 (34-89) (n = 283) 5 (42-87) Characteristic Prior lines of therapy, % Median (range) 2 3 >3-3 c D (n = 28) (-) (n = 283) (-8) Median (range) time from diagnosis, y Creatinine clearance (ml/min), % N >3- > 3.48 (.4-27.) (.4-2.7) Prior ASCT, % 3 4 Prior PI, % Prior bortezomib, % Prior IMiD, % Prior lenalidomide, % Prior PI + IMiD, % Cytogenetic profile, % b N Standard risk High risk Refractory to bortezomib, % 2 2 Refractory to last line of therapy, % ASCT, autologous stem cell transplantation; PI, proteasome inhibitor; IMiD, immunomodulatory drug. a ISS staging is derived based on the combination of serum β2-microglobulin and albumin. b Centralized analysis using next-generation sequencing. High-risk patients had any of t(4;4), t(4;), or del7p. Standard-risk patients had an absence of high-risk abnormalities. c Exploratory.

7 Efficacy in the to 3 Prior Lines Subgroup P <. 8-month PFS a ORR = 94% b 9 % surviving without progression No. at risk HR:.3 (95% CI,.2-.49; P <.) 77% 5% D Median: 8.4 months Months ORR, % CR: 47% c CR: 2% 24 3 D (n = 27) VGPR: 78% c ORR = 77% b (n = 7) VGPR: 4% scr CR VGPR PR D Responses continue to deepen in the D group with longer follow-up HR, hazard ratio; CI, confidence interval. a Kaplan-Meier estimate. b Response-evaluable population. c P <. for D vs. 7

8 Lenalidomide-naïve in to 3 Prior Lines P <. 8-month PFS a ORR = 93% b 9 % surviving without progression No. at risk HR:.37 (95% CI,.2-.5; P <.) 7% 49% D Median: 7. months Months ORR, % CR: 4% c CR: 2% D (n = 22) VGPR: 7% c ORR = 77% b (n = 29) VGPR: 4% scr CR VGPR PR D D maintains treatment benefit in lenalidomide-naïve patients a Kaplan-Meier estimate. b Response-evaluable population. c P <. for D vs. 8

9 Lenalidomide-exposed in to 3 Prior Lines % surviving without progression No. at risk HR:.45 (95% CI,.2-.99; P =.42) 8-month PFS a 79% 59% D Months ORR, % ORR = 87% b 22 CR: 48% c CR: % D (n = 4) P =.22 VGPR: 8% d ORR = 7% b (n = 45) VGPR: 4% scr CR VGPR PR D D improves outcomes regardless of prior treatment with lenalidomide a Kaplan-Meier estimate. b Response-evaluable population. c P =. for D vs. d P <. for D vs. 9

10 Refractory to Last Line of Therapy: to 3 Prior Lines 8-month PFS a 9 ORR = 89% b P =.3 % surviving without progression No. at risk HR:.45 (95% CI, ; P =.4) Median: 8.8 months Months 5% 37% D ORR, % CR: 49% c 23 CR: 5 2 3% VGPR: 9 74% c D (n = 73) ORR = 3% b 9 3 (n = 7) VGPR: 33% scr CR VGPR PR D D treatment benefit observed in patients refractory to last line of therapy a Kaplan-Meier estimate. b Response-evaluable population. c P <. for D vs.

11 Bortezomib-refractory in to 3 Prior Lines P =.24 8-month PFS a 9 ORR = 92% b % surviving without progression No. at risk D HR:.5 (95% CI,.28-.9; P =.2) 5% 4% D Median:.3 months Months ORR, % CR: 5% c CR: 3% 29 VGPR: 77% c 27 D (n = 52) ORR = 8% b (n = 47) VGPR: 3% scr CR VGPR PR D significantly improves outcomes irrespective of bortezomib refractoriness a Kaplan-Meier estimate. b Response-evaluable population. c P <. for D vs.

12 Criteria for MRD Negativity MRD was evaluated at 3 sensitivity thresholds: 4, 5, and MRD-negativity rate = proportion of patients with negative MRD test results at any time during treatment A stringent, unbiased MRD evaluation was applied MRD-negativity counts were evaluated against the intent-to-treat (ITT) population Any patient in the ITT population not determined to be MRD negative was scored as MRD positive A minimum cell input equivalent to the given sensitivity threshold was required to determine MRD negativity ie, MRD at required that million cells were evaluated Assessed at suspected CR and 3 and months after CR 2

13 3 MRD-negative Rates ( 5 ) *** *** *** ** * 28 *** P <.. ** P <.. * P < MRD-negative rate, % D (n = 28) (n = 283) D (n = 272) (n = 24) D (n = 22) (n = 29) D (n = 4) (n = 45) D (n = 54) (n = 49) Total evaluable ITT -3-3 prior plline Len-naïve Len-naive Len-exposed Bort-refractory population population (-3 prior lines) (-3 prior lines) (-3 prior lines) (ITT) Patients achieved deeper responses including MRD negativity irrespective of prior lenalidomide exposure or bortezomib refractoriness P values calculated using likelihood-ratio chi-square test. 3

14 MRD-negative Rate ( 5 ) by Prior Treatment Status P <. 3 MRD negative MRD-negative rate, % 2 5 % surviving without progression D MRD negative D MRD positive MRD positive D (n = 272) (n = 24) -3 prior -3 pllines population No. at risk Months MRD negative D MRD negative MRD positive D MRD positive MRD-negative patients achieve prolonged PFS 4

15 Responses and PFS by Cytogenetic Status Total population (response evaluable) to 3 prior lines population ORR, % ORR = 85% D (n = 27) ORR = 7% High risk 3 (n = 3) ORR = 95% D (n = 32) (n = ) Standard risk ORR = 82% scr CR VGPR PR % surviving without progression No. at risk standard risk D standard risk high risk D high risk D std risk D high risk std risk high risk Months D improves outcomes in high-risk and standard-risk patients

16 Most Common AEs: to 3 Prior Lines D (n = 29) (n = 22) Hematologic, % All grade Grade 3/4 All grade Grade 3/4 % a 5% a % a 5% a Neutropenia Febrile neutropenia Anemia Thrombocytopenia Lymphopenia Nonhematologic, % Diarrhea Fatigue Upper respiratory tract Infection Cough 3 3 Constipation Muscle spasms Nausea Nasopharyngitis 2 7 Pneumonia No new safety signals reported a Common treatment-emergent AEs listed are either % all grade OR 5% grade 3/4.

17 Key Takeaways D significantly improves outcomes for patients with relapsed/refractory myeloma with to 3 prior lines of treatment This treatment benefit of D versus was maintained regardless of prior treatment with lenalidomide or refractoriness to bortezomib Higher MRD-negative rates ( 5 ) in D versus for all subgroups D is superior to in both standard- and high-risk cytogenetic patients Safety profile remains unchanged These data support use of D, irrespective of prior lenalidomide treatment or bortezomib refractoriness 7

18 Acknowledgments Patients who participated in this study Investigators Data and safety monitoring committee Staff members involved in data collection and analyses Tineke Casneuf, David Soong, Christopher Velas 8 countries This study was funded by Janssen Research & Development, LLC Medical writing and editorial support were provided by Jason Jung, PhD, of MedErgy, and were funded by Janssen Global Services, LLC 8