Evaluation of Minimal Residual Disease (MRD) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients Treated With Daratumumab in Combination With Lenalidomide Plus Dexamethasone or Bortezomib Plus Dexamethasone Hervé Avet-Loiseau, 1 Tineke Casneuf, 2 Christopher Chiu, 3 Jacob Laubach, 4 Je-Jung Lee, 5 Philippe Moreau, 6 Torben Plesner, 7 Hareth Nahi, 8 Nushmia Z. Khokhar, 3 Ming Qi, 3 Jordan Schecter, 9 Victoria Carlton, 1 Xiang Qin, 3 Kevin Liu, 9 Kaida Wu, 3 Sen Hong Zhuang, 9 Tahamtan Ahmadi, 3 A. Kate Sasser, 3 Jesus San-Miguel 11 1 Unite de Genomique du Myelome, CHU Rangueil, Toulouse, France; 2 Oncology Heme Translational Research Group, Janssen Research & Development, Beerse, Belgium; 3 Janssen Research & Development, LLC, Spring House, PA, USA; 4 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 5 Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, South Korea; 6 Hematology, University Hospital Hôtel-Dieu, Nantes, France; 7 Vejle Hospital and University of Southern Denmark, Vejle, Denmark; 8 Karolinska Institute and the Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, Stockholm, Sweden; 9 Janssen Research & Development, LLC, Raritan, NJ, USA; 1 Adaptive Biotechnologies, Seattle, WA, USA; 11 Clínica Universidad de Navarra-CIMA, IDISNA, Pamplona, Spain. ClinicalTrials.gov Identifiers: NCT2136134 and NCT2769
Daratumumab Daratumumab Human monoclonal antibody that targets CD38 Direct on-tumor and immunomodulatory mechanisms of action 1-5 Daratumumab is approved by the FDA as monotherapy and in combination with standard of care regimens for patients with multiple myeloma (MM) with 1 prior line of treatment Daratumumab + standard of care regimens Resulted in a >6% reduction in the risk of disease progression or death 6,7 The immunomodulatory effects of daratumumab may drive deep responses CDC, complement-dependent cytotoxicity; ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cell-mediated phagocytosis. 1. Lammerts van Bueren J, et al. Blood. 214;124. Abstract 3474. 2. Overdijk MB, et al. J Immunol. 216;197(3):87-813. 3. de Weers M, et al. J Immunol. 211;186(3):184-1848. 4. Overdijk MB, et al. MAbs. 2;7(2):311-321. 5. Krejcik J, et al. Blood. 216;128(3):384-394. 6. Dimopoulos MA, et al. New Engl J Med. 216;375(14):1319-1331. 7. Palumbo A, et al. New Engl J Med. 216;375(8):754-766. 2
Minimal Residual Disease Minimal residual disease (MRD) is a more sensitive measure of disease burden than traditional definitions of clinical response 1,2 MRD-negative status is associated with prolonged progressionfree survival (PFS) and overall survival (OS) in newly diagnosed MM patients 1,2 In the future, MRD may be a primary endpoint for clinical studies International Myeloma Working Group guidelines recommend an MRD-sensitivity threshold of at least 1 5 using next-generation sequencing (NGS) or next-generation flow cytometry 3 This study is the first evaluation of MRD in relapsed and refractory (RR) MM using a randomized, controlled, and prospective analysis 1. Munshi NC, et al. JAMA Oncol. 216. [Epub ahead of print.] 2. Landgren O, et al. Bone Marrow Transplant. 216. [Epub ahead of print.] 3. Kumar S, et al. Lancet Oncol. 216;17(8):e328-e346. 3
POLLUX and CASTOR Multicenter, randomized (1:1), open-label, active-controlled, phase 3 studies in 1 prior line of therapy for MM POLLUX CASTOR R A N D O M I Z E DRd (n = 286) D 16 mg/kg IV Every week: Cycles 1-2 Every 2 weeks: Cycles 3-6 Every 4 weeks until PD R 25 mg PO (similar to Rd alone) d 4 mg Rd (n = 283) R 25 mg PO Days 1-21 of each cycle until PD d 4 mg weekly until PD R A N D O M I Z E DVd (n = 251) D 16 mg/kg IV Every week: Cycles 1-3 Every 3 weeks: Cycles 4-8 Every 4 weeks: Cycles 9+ V1.3 mg/m 2 SC (similar to Vd alone) d 2 mg Vd (n = 247) V1.3 mg/m 2 SC on Days 1, 4, 8, and 11 for 8 cycles d 2 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 for 8 cycles MRD assessments At suspected CR 3 & 6 months after CR MRD assessments At suspected CR 6 & 12 months after first study dose Patient characteristics Median (range) prior lines: 1 (1-11) Prior V: 84% Prior R: 18% Patient characteristics Median (range) prior lines: 2 (1-1) Prior V: 66% Prior R: 42% DRd, daratumumab, lenalidomide, and dexamethasone; D, daratumumab; IV, intravenous; PD, progressive disease; R, lenalidomide; PO, orally; Rd, lenalidomide and dexamethasone; d, dexamethasone; CR, complete response; DVd, daratumumab, bortezomib, and dexamethasone; V, bortezomib; SC, subcutaneously; Vd, bortezomib and dexamethasone. 4
Updated PFS: POLLUX and CASTOR 1 POLLUX 18-month PFS a 1 CASTOR 12-month PFS a Patients surviving without progression, % 8 6 4 2 3 6 9 12 18 21 24 27 PFS, months 76% 49% Rd DRd Median (range) follow-up: 17.3 (-24.5) months Median PFS DRd: not reached; Rd: 17.5 months HR:.37 (95% CI,.28-.5; P <.1) HR, hazard ratio; CI, confidence interval. a Kaplan-Meier estimates. Clinical cut-off: June 3, 216. Patients surviving without progression, % 8 6 4 2 6% 22% Vd DVd 3 6 9 12 18 21 24 PFS, months Median (range) follow-up: 13. (-21.3) months Median PFS DVd: not reached; Vd: 7.1 months HR:.33 (95% CI,.26-.43; P <.1) 5
ClonoSEQ MRD Assay Collect fresh or archived non-decalcified bone marrow V to DJ recombination Transcription, splicing 3 BP AAA MRD positive Targeted IgH- VDJ sequencing library Sequence ~1M 1 bp reads Index clone Calibration (screening) Index clone identification MRD negative MRD evaluation High-sensitivity index clone evaluation MRD was assessed at suspected CR using bone marrow aspirate samples and evaluated by ClonoSEQ NGS-based assay a MRD, minimal residual disease; BP, base pair; IgH, immunoglobulin H; 1M, 1 million. a Version 1.3; Adaptive Biotechnologies. 6
Criteria for MRD Negativity MRD was evaluated at 3 sensitivity thresholds: 1 4, 1 5, and 1 6 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 i.e., MRD at 1 6 required that 1 million cells were evaluated 7
Proportion of MRD-negative Patients at 1 4, 1 5, and 1 6 Thresholds POLLUX CASTOR 35 31.8 *** 3.6X *** 4.4X *** 4.8X 35 *** 5.1X ** 4.3X * 5.5X 3 3 25 24.8 25 MRD negative, % 2 1 8.8 11.9 MRD negative, % 2 1 18.3 1.4 5 5.7 2.5 5 3.6 2.4 4.4.8 Sensitivity threshold DRd Rd DRd Rd DRd Rd 1-4 4 1-5 5 1-6 6 DVd Vd DVd Vd DVd Vd 1-4 4 1-5 5 1-6 6 Daratumumab in combination with standard of care significantly improved MRD-negative rates at all thresholds P values calculated using likelihood-ratio chi-square test. *** P <.1 ** P <.5 * P <.5 8
MRD Negativity Among Patients With CR POLLUX CASTOR ** ** * * 25 ITT population, % 4 3 2 1 65 DRd 42 Rd 52 26 27 13 DRd Rd DRd Rd ITT population, % 2 1 5 6 DVd 35 Vd 37 16 22 9 DVd Vd DVd Vd 1 4 1 5 1 6 1 4 1 5 1 6 MRD negative MRD positive MRD negative MRD positive Values refer to the percentage of MRD-negative patients among those who achieved CR in a given treatment arm ** P <.5 * P <.5 Consistently higher MRD-negative rates in patients with CR treated with a daratumumab-containing regimen P values calculated using likelihood-ratio chi-square test. 9
Time to MRD (1 5 ) 3 POLLUX 3 CASTOR Patients with MRD negativity, % 25 2 1 5 DRd Rd Patients with MRD negativity, % 25 2 1 5 Vd DVd Patients at risk 3 6 9 12 18 21 24 27 Rd 283 DRd 286 272 271 Time to MRD negativity, months 252 247 243 229 225 22 22 169 83 71 18 1 Patients at risk Vd DVd 3 6 9 12 18 21 24 247 251 217 229 Time to MRD negativity, months 22 212 187 19 13 137 55 58 13 12 1 Rapid accumulation of MRD-negative events in patients treated with daratumumab-containing regimens versus standard of care MRD-negative patients continued to accumulate over time in both studies Majority of patients maintain MRD negativity; patients will continue to be followed annually Only 1 MRD-negative sample counted per patient. 1
MRD-negative patients per risk group, % a 35 3 25 2 1 5 MRD at 1 5 by Cytogenetic Risk by NGS 18 ** POLLUX 3 3 25 2 1 14 CASTOR *** ** ** 35 1 MRD-negative patients per risk group, % a 5 2 High risk Standard risk High risk Standard risk n = 28 n = 37 n = 133 n = 113 n = 44 n = 51 n = 123 n = 135 DRd (17% high risk b ) Rd (25% high risk b ) DVd (26% high risk b ) Vd (27% high risk b ) 12 No high-risk MRD negative patients have progressed or converted to MRD positive High risk = any of t(4;14), t(14;16), del17p Standard risk = conclusive absence of all 3 markers In high-risk patients, MRD-negative status was achieved only in those treated with daratumumab-containing regimens P values calculated using likelihood-ratio chi-square test. a Percentage of patients within a given risk group and treatment arm. b Percentage of patients within a given treatment arm within the biomarker-evaluable population. *** P <.1 ** P <.5 11
PFS According to MRD Status at 1 5 POLLUX CASTOR Patients progression free and alive (%) Patients at risk 1 Rd MRD negative DRd MRD negative Rd MRD positive DRd MRD positive 8 6 4 2 3 6 9 12 18 21 24 27 16 71 267 2 16 71 233 195 16 71 19 178 7 166 167 Months 66 144 161 12 57 12 137 1 28 38 54 Rd MRD DRd MRD 6 5 9 1 DRd MRD + Rd MRD + Patients progression free and alive (%) Patients at risk 1 Vd MRD negative DVd MRD negative Vd MRD positive DVd MRD positive 8 6 4 2 Vd MRD + 3 6 9 12 18 21 24 6 26 241 225 6 26 176 189 6 26 123 172 5 26 68 134 Months 3 2 76 2 7 7 26 1 4 Vd MRD DVd MRD 1 DVd MRD + Lower risk of progression in MRD-negative patients PFS benefit in MRD-positive patients who received daratumumabcontaining regimens versus standard of care 12
Conclusions Daratumumab induced MRD negativity in over 3 times as many patients as standard of care regimens Daratumumab led to rapid and durable achievement of MRD negativity Patients continued to achieve MRD negativity over time Daratumumab allowed high-risk patients to achieve MRD-negative status MRD-negative status was associated with a lower risk of progression The high rate of MRD negativity and deep clinical responses induced by daratumumab may lead to improved long-term clinical benefit 13
The magnitude of daratumumab-induced MRD negativity in the RRMM setting is unprecedented The potential benefit of MRD-negative status induced by daratumumab in newly diagnosed MM is being explored in ongoing studies 14
Acknowledgments POLLUX 18 countries CASTOR 16 countries Patients who participated in these studies Investigators Data and safety monitoring committee Staff members involved in data collection and analyses David Soong, PhD for his work on the NGS cytogenetic analyses This study was funded by Janssen Research & Development, LLC Medical writing and editorial support were provided by Erica Chevalier-Larsen, PhD, of MedErgy, and were funded by Janssen Global Services, LLC
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Baseline Bone Marrow Plasma Cell Percentages From Daratumumab Phase 3 Trials NDMM RRMM Calibrates Fails to calibrate Baseline bone marrow plasma cell percentages of the 238 samples that successfully calibrated were significantly higher than the 75 samples that failed to calibrate (median of 25% vs 11%, respectively; P <.1) NDMM, newly diagnosed multiple myeloma. Calibration using ClonoSEQ Version 1.3 17
MRD Threshold Samples with input cell equivalents below the MRD-sensitivity level were considered MRD positive in the analysis of MRD-negativity rate POLLUX CASTOR MRD ambiguous MRD negative MRD positive 18
Bone Marrow Processing Considerations RBC hypotonic lysis Ficoll enrichment ClonoSEQ analysis RBC, red blood cell. Ficoll enrichment removes the granulocytic cell population that makes up 25-5% of nucleated cells in the sample Calculations of MRD-negative rate in Ficoll-enriched samples are more stringent than those using RBC lysates, which would include all of the leukocytes in the sample 19
Assessment by MRD MRD assessment is a more sensitive measure of disease burden than traditional definitions of clinical response 1,2 PD 1. Munshi NC, et al. JAMA Oncol. 216. [Epub ahead of print.] 2. Landgren O, et al. Bone Marrow Transplant. 216. [Epub ahead of print.] 2
ORR by Cytogenetic Risk a : POLLUX P =.14 P =.2 1 9 ORR = 85% ORR = 95% ORR = 82% ORR, % 8 7 6 5 4 3 2 1 19 3 22 DRd (n = 27) ORR = 67% 6 25 36 Rd (n = 36) 29 23 33 11 DRd (n = 132) 7 17 27 31 Rd (n = 111) scr CR VGPR PR High risk Std risk P values calculated using Mantel-Haenszel estimate of common odds ratios. a Central NGS. High-risk patients had any of t(4;14), t(14;16), del17p. Standard-risk patients had an absence of high-risk abnormalities. 21
ORR by Cytogenetic Risk a : CASTOR P =.39 P =.3 1 9 ORR = 82% ORR = 85% ORR, % 8 7 6 5 4 3 11 18 34 4 ORR = 62% 21 9 26 38 ORR = 64% 2 6 18 scr CR VGPR PR 2 1 18 28 21 37 DVd (n = 44) Vd (n = 47) DVd (n = 118) Vd (n = 131) High risk Std risk P values calculated using Mantel-Haenszel estimate of common odds ratios. a Central NGS. High-risk patients had any of t(4;14), t(14;16), del17p. Standard-risk patients had an absence of high-risk abnormalities. 22