Kaufman et al. Blood Cancer Journal (2020)10:111 https://doi.org/10.1038/s41408-020-00375-2 Blood Cancer Journal ARTICLE Open Access Daratumumab, lenalidomide, and dexamethasone in relapsed/refractory myeloma: a cytogenetic subgroup analysis of POLLUX Jonathan L. Kaufman 1, Meletios A. Dimopoulos 2, Darrell White3, Lotfi Benboubker4, Gordon Cook5, Merav Leiba6, James Morton7, P. Joy Ho8, Kihyun Kim9, Naoki Takezako10, Philippe Moreau11, Heather J. Sutherland12, Hila Magen 13, Shinsuke Iida14, Jin Seok Kim 15, H. Miles Prince16, Tara Cochrane17, Albert Oriol18, Nizar J. Bahlis19, Ajai Chari20, Lisa O’Rourke21, Sonali Trivedi21, Tineke Casneuf22, Maria Krevvata21, Jon Ukropec23, Rachel Kobos24, Hervé Avet-Loiseau25, Saad Z. Usmani 26 and Jesus San-Miguel 27 Abstract High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/ lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10–5) was assessed via the clonoSEQ® assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression- free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk. Introduction line of therapy, in combination with bortezomib/mel- Daratumumab is a human IgGκ monoclonal antibody phalan/prednisone or Rd in patients with transplant- targeting CD38 with a direct on-tumor1–4 and immuno- ineligible newly diagnosed MM, and in combination with modulatory5–7 mechanism of action. Intravenous dar- bortezomib, thalidomide, and dexamethasone in patients atumumab 16 mg/kg is approved in the USA in with transplant-eligible newly diagnosed MM8. Dar- combination with lenalidomide and dexamethasone (Rd) atumumab is also approved in the USA as monotherapy in or bortezomib and dexamethasone (Vd) in patients with patients with heavily pretreated relapsed or refractory multiple myeloma (MM) who received at least one prior MM (RRMM) and in combination with pomalidomide/ dexamethasone for patients with at least two prior therapies, including lenalidomide and a proteasome Correspondence: Jonathan L. Kaufman (jlkaufm@emory.edu) 1 inhibitor8. Winship Cancer Institute, Emory University, Atlanta, GA, USA 2 The National and Kapodistrian University of Athens, Athens, Greece Full list of author information is available at the end of the article © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Blood Cancer Journal Kaufman et al. Blood Cancer Journal (2020)10:111 Page 2 of 10 In the phase 3 POLLUX study in patients with RRMM, therapy for MM, achieved at least a partial response to at adding daratumumab to Rd (D-Rd) more than doubled least one prior MM therapy, and had documented evidence complete response (CR) or better rates, induced a > four- of progressive disease based on IMWG criteria on or after fold increase in the rate of minimal residual disease their last regimen. Patients were excluded if they were (MRD) negativity at the 10–5 sensitivity threshold, and refractory to or intolerant of lenalidomide or had a creati- reduced the risk of disease progression or death by 63% nine clearance of <30 mL/min/1.73 m2. versus Rd alone at a median follow-up of 13.5 months9. With longer follow-up (median: 44.3 months), D-Rd Study design and treatment continued to reduce the risk of disease progression or POLLUX is a phase 3, randomized, open-label, active- death by 56% and significantly increased the overall controlled, multicenter study in patients with RRMM. response rate (ORR; 93% vs 76%; P < 0.0001) and rates of Randomization was stratified according to International CR or better (57% vs 23%; P < 0.0001), very good partial Staging System (ISS) disease stage (I vs II vs III) at response (VGPR) or better (80% vs 49%; P < 0.0001), and screening, number of prior lines of therapy (1 vs 2 or 3 vs MRD negativity (10–5 sensitivity threshold; 30% vs 5%; >3), and prior lenalidomide exposure (no vs yes). P < 0.000001) versus Rd alone10. Exploratory analyses were conducted for subgroups of Patients with MM and high cytogenetic risk abnormal- patients based on cytogenetic risk status. Patients were ities including IgH translocations (e.g., t[4;14]) and geno- randomized 1:1 to Rd (lenalidomide: 25 mg orally on Days mic imbalance (e.g., del17p) have worse progression-free 1–21 of each 28-day cycle; dexamethasone: 40 mg orally survival (PFS) and overall survival outcomes compared weekly) with or without daratumumab (16 mg/kg IV with patients with standard cytogenetic risk11,12. Although weekly for 8 weeks, every 2 weeks for 16 weeks, and then high cytogenetic risk abnormalities are most relevant as a every 4 weeks) until progression. prognostic marker prior to relapse, several studies have shown that they have a negative effect on survival for Cytogenetic risk evaluation RRMM11,12. The 2009 International Myeloma Working Cytogenetic abnormalities were detected by local FISH Group (IMWG) guidelines define high cytogenetic risk as or karyotyping on bone marrow aspirates collected at having at least one of the following abnormalities: t(4;14), screening visits. Determination of each abnormality and t(14;16), or del17p, determined by fluorescence in situ threshold of frequencies to consider a positive finding was hybridization (FISH)13. More recently, and after the determined locally and varied by site. Patients in the POLLUX study was initiated, updated IMWG guidelines intent-to-treat (ITT) population who had at least one were published in 2016, wherein the definition of high assessment from FISH or karyotyping were included in cytogenetic risk was expanded to include t(14;20) and the analysis. Patients with high cytogenetic risk status had gain1q abnormalities11. In patients with high cytogenetic at least one of the following cytogenetic abnormalities risk, treatment choice is driven by the duration, quality, identified: t(4;14), t(14;16), or del17p. and depth of response offered; updated IMWG guidelines recommend treatment with regimens containing borte- MRD evaluation zomib or lenalidomide in these patients. MRD was assessed at the time of the suspected CR After a median follow-up of 25.4 months, D-Rd sig- (including stringent CR; blinded to treatment group), and nificantly prolonged PFS and increased ORR in patients if CR was maintained, at 3 months, 6 months, and every with RRMM in POLLUX; improvement was also seen 12 months after confirmation of CR. MRD testing was regardless of cytogenetic risk status14. Here, we report the performed via the clonoSEQ® assay V2.0 (Adaptive Bio- updated efficacy and safety findings after a median follow- technologies, Seattle, WA, USA) at the 10–5 sensitivity up of more than 3 years for patients with standard and threshold (one cancer cell per 100,000 nucleated cells). high cytogenetic risk RRMM. Patients with an MRD-negative test result were con- sidered to be MRD negative, and patients with only MRD- Methods positive or indeterminate test results or who had not Patients undergone MRD testing were considered to be MRD A total of 439 patients who underwent cytogenetic testing positive. Sustained MRD negativity was defined as con- from phase 3 POLLUX study (ClinicalTrials.gov identifier: firmed maintenance of MRD-negative status at a sensi- NCT02076009) were included in this analysis. The study tivity threshold of 10–5 for ≥6 or ≥12 months. design, complete eligibility criteria, and primary and sub- group analysis results have been previously published9,14. Statistical analyses and assessments Briefly, eligible patients were ≥18 years of age with an PFS analyses for the cytogenetic risk groups included Eastern Cooperative Oncology Group performance status patients in the ITT population who met the biomarker score of 0 to 2. Patients had received at least one prior line of criteria for risk assessment. Patients with measurable Blood Cancer Journal Kaufman et al. Blood Cancer Journal (2020)10:111 Page 3 of 10 disease at baseline or at the screening visit who received at patients underwent cytogenetic testing; 324 (57%) patients least one study treatment and had undergone at least one were evaluated using FISH, 261 (46%) patients were post-baseline disease assessment were included in the evaluated using karyotyping, and 146 (26%) were eval- response-evaluable population. Patients who received at uated using both. Of these, high cytogenetic risk least one administration of study treatment were included abnormalities were reported in 35 (12%) patients in the in the safety population. D-Rd group and 35 (12%) patients in the Rd group. The PFS and time to response were compared between the D- standard cytogenetic risk was reported in 193 (68%) Rd and Rd treatment groups using a stratified log-rank test. patients in the D-Rd group and 176 (62%) patients in the Hazard ratios (HRs) and 95% confidence intervals (CIs) were Rd group. Among patients assessed for cytogenetic risk, estimated using a Cox proportional hazards model with patient demographics, baseline disease, and clinical treatment as the sole explanatory variable. The characteristics based on cytogenetic status are shown in Kaplan–Meier method was used to estimate the distribu- Table 1. Among patients achieving CR or better, MRD tions. PFS on the subsequent line of therapy (PFS2) was was not evaluated in 48 (22%) patients. At the time of the defined as the time from randomization to disease pro- clinical cutoff (October 10, 2018), 253 (69%) and 57 (83%) gression after the next line of subsequent therapy or death. patients discontinued treatment in the standard and high Differences in ORRs, rates of CR or better, and rates of cytogenetic risk subgroups, respectively (Table 2). VGPR or better between treatment groups were measured using a stratified Cochran–Mantel–Haenszel chi-square test. Updated efficacy results MRD and sustained MRD negativity were evaluated for After a median follow-up of 44.3 months, D-Rd pro- patients in the entire ITT population who met the bio- longed PFS versus Rd in patients with standard cytoge- marker criteria for risk assessment to allow for a stringent netic risk (median: not estimable [NE] vs 18.6 months; and unbiased evaluation of MRD negativity. MRD- HR, 0.43; 95% CI, 0.32–0.57; P < 0.0001; Fig. 1A) and high negativity rates were defined as the proportion of cytogenetic risk (median: 26.8 months vs 8.3 months; HR, patients who achieved MRD-negative status at any time 0.34; 95% CI, 0.16–0.72; P = 0.0035; Fig. 1B) in the ITT point following the first treatment dose. A Fisher’s exact population. The 42-month PFS rates were 53% with D-Rd test was used to compare MRD-negativity rates between versus 25% with Rd in the standard cytogenetic risk the D-Rd and Rd treatment groups. subgroup and 35% versus 13%, respectively, in the high cytogenetic risk subgroup. Among patients with 1 prior Study oversight line of therapy, D-Rd prolonged PFS versus Rd in patients Institutional review boards or ethics committees with standard cytogenetic risk (median: NE vs approved the research at each clinical study site. All 20.2 months; HR, 0.41; 95% CI, 0.27–0.63; P < 0.0001; 42- patients provided written informed consent. The study month PFS rate: 58% vs 27%; Fig. 1C) and high cytoge- design and analyses were devised by the investigators and netic risk (median: 29.6 months vs 6.6 months; HR, 0.26; sponsor, and study data were collected by the investigators 95% CI, 0.09–0.75; P = 0.0083; 42-month PFS rate: 43% vs and their research teams. Final data analysis and verifica- 12%; Fig. 1D). tion of accuracy were conducted by Janssen. The investi- The ORR and rates of VGPR or better and CR or better gators were not restricted by confidentiality agreements were higher with D-Rd compared with Rd, regardless of and had full accessibility to all the data. Writing assistance cytogenetic risk status (Table 3). Among patients with was funded by Janssen Global Services. The study was standard cytogenetic risk, time to VGPR or better (med- sponsored by Janssen Research & Development, LLC and ian: 3.7 vs 8.3 months; HR, 1.98; 95% CI, 1.52–2.59; was registered at ClinicalTrials.gov (NCT02076009). P < 0.0001) and CR or better (median: 13.9 months vs NE; HR, 2.38; 95% CI, 1.66–3.43; P < 0.0001) were decreased Data-sharing statement with D-Rd versus Rd. Time to VGPR or better (median: The data-sharing policy of Janssen Pharmaceutical 3.7 months vs 18.7 months; HR, 3.45; 95% CI, 1.41–8.39; Companies of Johnson & Johnson is available at https:// P = 0.0040) and CR or better (median: 14.4 months vs NE; www.janssen.com/clinical-trials/transparency. As noted HR, 2.07; 95% CI, 0.51–8.48; P = 0.3011) were also on this site, requests for access to the study data can be decreased with D-Rd versus Rd for patients with high submitted through the Yale Open Data Access Project site cytogenetic risk. at http://yoda.yale.edu. At a sensitivity threshold of 10–5, MRD-negativity rates were higher with D-Rd compared with Rd, regardless of Results cytogenetic risk (Table 3). Nine patients with high-risk Patients and treatments cytogenetics in the D-Rd group achieved MRD negativity; A total of 569 patients were randomized, with 286 however, only one of these patients was able to sustain assigned to D-Rd and 283 to Rd. A total of 439 (77%) this response. No patients in the Rd group who had a Blood Cancer Journal Kaufman et al. Blood Cancer Journal (2020)10:111 Page 4 of 10 Table 1 Patient demographics, baseline disease, and Table 2 Patient disposition based on cytogenetic risk* clinical characteristics. status. Standard cytogenetic risk* High cytogenetic risk*,† Standard risk High risk† Characteristic D-Rd Rd (n = 176) D-Rd Rd (n = 35) Treatment discontinuation,‡ D-Rd Rd D-Rd Rd (n = 193) (n = 35) n (%) (n = 192) (n = 176) (n = 35) (n = 34) Age, y Patients who discontinued 105 (55) 148 (84) 26 (74) 31 (91) Median (range) 66 (36–89) 64 (42–85) 67 (50–80) 67 (50–81) treatment ≥75 y, n (%) 21 (11) 17 (10) 4 (11) 6 (17) Reason for discontinuation Sex, n (%) Progressive disease 57 (30) 104 (59) 17 (49) 25 (74) Male 114 (59) 102 (58) 19 (54) 19 (54) Adverse event 28 (15) 22 (13) 7 (20) 4 (12) Race, n (%) Noncompliance with study 7 (4) 4 (2) 0 2 (6) drug§ White 131 (68) 120 (68) 28 (80) 23 (66) Withdrawal by patient 2 (1) 8 (5) 1 (3) 0 Asian 47 (24) 35 (20) 4 (11) 8 (23) Physician decision 6 (3) 3 (2) 1 (3) 0 Black or African American 4 (2) 5 (3) 1 (3) 2 (6) Death 3 (2) 5 (3) 0 0 Unknown/not reported 11 (6) 16 (9) 2 (6) 2 (6) ‡ Other 2 (1) 2 (1) 0 0 ISS stage, n (%) I 96 (50) 92 (52) 13 (37) 14 (40) D-Rd daratumumab plus lenalidomide/dexamethasone, Rd lenalidomide/dex- II 62 (32) 50 (28) 15 (43) 13 (37) amethasone, FISH fluorescence in situ hybridization. *Based on FISH/karyotyping. III 35 (18) 34 (19) 7 (20) 8 (23) † Patients with high cytogenetic risk had a t(4;14), t(14;16), or del17p abnormality. ECOG performance status score, n (%) ‡ Safety population. 0 94 (49) 90 (51) 15 (43) 22 (63) § Based on reason, “patient refused to further study treatment” at “end of 1 91 (47) 78 (44) 18 (51) 12 (34) treatment.” 2 8 (4) 8 (5) 2 (6) 1 (3) Cytogenetic profile,*,† n (%) D-Rd prolonged PFS2 versus Rd in both standard t(4;14) – – 10 (29) 15 (43) t(14;16) – – 2 (6) 6 (17) cytogenetic risk (median: NE vs 33.3 months; HR, 0.54; del17p – – 25 (71) 20 (57) 95% CI, 0.40–0.74; P < 0.0001; Fig. 2A) and high cytoge- ≥2 risk factors§ – – 2 (6) 5 (14) netic risk (median: 37.7 months vs 20.8 months; HR, 0.38; Median (range) time from diagnosis, y 3.7 (0.6–22.5) 4.0 (0.4–18.3) 3.2 (0.4–27.0) 2.3 (0.4–14.6) 95% CI, 0.18–0.83; P = 0.0121) subgroups (Fig. 2B). Prior lines of therapy, n (%) Among patients with one prior line of therapy, PFS2 was 1 96 (50) 90 (51) 22 (63) 20 (57) prolonged with D-Rd versus Rd in patients with standard 2 62 (32) 47 (27) 6 (17) 9 (26) cytogenetic risk (median: NE vs 38.2 months; HR, 0.53; 3 24 (12) 24 (14) 5 (14) 4 (11) 95% CI, 0.34–0.83; P = 0.0049; Fig. 2C) and high cytoge- >3 11 (6) 15 (9) 2 (6) 2 (6) Median (range) 2 (1–11) 1 (1–8) 1 (1–6) 1 (1–6) netic risk (median: 36.2 months vs 16.9 months; HR, 0.26; Prior ASCT, n (%) 115 (60) 115 (65) 22 (63) 19 (54) 95% CI, 0.09–0.74; P = 0.0082; Fig. 2D). Prior PI, n (%) 162 (84) 148 (84) 31 (89) 31 (89) At the time of the analysis, among patients with stan- Bortezomib 160 (83) 145 (82) 30 (86) 31 (89) dard cytogenetic risk, 71 (36.8%) deaths were observed in Prior IMiD, n (%) 103 (53) 102 (58) 22 (63) 15 (43) the D-Rd group versus 68 (38.6%) deaths in the Rd group. Lenalidomide 27 (14) 33 (19) 10 (29) 4 (11) Prior PI + IMiD, n (%) 79 (41) 80 (46) 18 (51) 12 (34) Among patients with high cytogenetic risk, 18 (51.4%) Refractory to PI only, n (%) 42 (22) 29 (17) 8 (23) 9 (26) deaths were observed in the D-Rd group versus 22 (62.9%) Refractory to IMiD only, n (%) 7 (4) 10 (6) 3 (9) 1 (3) deaths in the Rd group. The overall survival data were Refractory to PI and IMiD, n 6 (3) 7 (4) 1 (3) 3 (9) immature, and follow-up for overall survival is ongoing. (%) Refractory to last line of 62 (32) 50 (28) 11 (31) 13 (37) therapy, n (%) Safety D-Rd daratumumab plus lenalidomide/dexamethasone, Rd lenalidomide/dex- The most common (≥25% of patients) any-grade treat- amethasone, ISS International Staging System, ECOG Eastern Cooperative ment-emergent adverse events (TEAEs) and most com- Oncology Group, ASCT autologous stem cell transplant, PI proteasome inhibitor, IMiD immunomodulatory drug, FISH fluorescence in situ hybridization. mon (≥5% of patients) grade 3/4 TEAEs are summarized Note: percentages may not equal 100% due to rounding. in Table 4. The most common hematologic adverse event *Based on FISH/karyotyping. † Patients with high cytogenetic risk had a t(4;14), t(14;16), or del17p abnormality. was neutropenia, followed by anemia and thrombocyto- ‡ ISS stage is derived based on the combination of serum β2-microglobulin and penia. The most common infection was upper respiratory albumin. § Patients with ≥2 of the t(4;14), t(14;16), or del17p risk factors. tract infection, followed by nasopharyngitis and pneumonia. high-risk cytogenetic feature achieved MRD negativity. MRD negativity was sustained for at least 6 months and at Discussion least 12 months in 18% and 14% of patients treated with After more than 3 years of follow-up, D-Rd continued D-Rd, respectively, versus 1% of patients treated with Rd to demonstrate improved efficacy versus Rd alone in in the standard cytogenetic risk subgroup (Table 3). patients with RRMM regardless of cytogenetic risk status; Blood Cancer Journal Kaufman et al. Blood Cancer Journal (2020)10:111 Page 5 of 10 A. Standard risk: HR, 0.43; 95% CI, 0.32–0.57; P < 0.0001 B. High risk: HR, 0.34; 95% CI, 0.16–0.72; P = 0.0035 100 100 80 80 % surviving without progression % surviving without progression 60 60 D-Rd standard risk 40 40 D-Rd high risk: Median 26.8 mo Rd standard risk: 20 Median 18.6 mo 20 Rd high risk: Median 8.3 mo 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Months Months No. at risk No. at risk Rd standard risk 176 157 135 120 106 94 84 72 67 58 54 49 42 40 33 14 1 0 Rd high risk 35 28 19 13 11 11 8 6 5 5 5 4 4 4 4 1 0 0 D-Rd standard risk 193 180 171 165 157 146 137 133 128 117 109 106 102 96 85 38 5 0 D-Rd high risk 35 31 27 26 25 24 23 21 17 16 14 13 11 10 9 6 1 0 C. Standard risk: HR, 0.41; 95% CI, 0.27–0.63; P < 0.0001 D. High risk: HR, 0.26; 95% CI, 0.09–0.75; P = 0.0083 100 100 80 80 % surviving without progression % surviving without progression 60 D-Rd standard risk 60 D-Rd high risk: 40 40 Median 29.6 mo Rd standard risk: 20 Median 20.2 mo 20 Rd high risk: Median 6.6 mo 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Months Months No. at risk No. at risk Rd standard risk 90 84 73 66 59 49 45 39 38 32 28 25 22 21 17 8 1 0 Rd high risk 20 14 9 6 6 6 4 3 2 2 2 2 2 2 2 0 0 0 D-Rd standard risk 96 89 85 83 79 75 69 67 66 62 59 57 56 52 44 21 4 0 D-Rd high risk 22 19 18 17 16 15 15 14 11 11 10 9 8 8 8 5 1 0 Fig. 1 PFS based on cytogenetic risk status. PFS in the ITT/biomarker risk population:* A standard and B high cytogenetic risk patients. PFS in patients with one prior line of therapy: C standard and D high cytogenetic risk patients. PFS progression-free survival, HR hazard ratio, CI confidence interval, D-Rd daratumumab plus lenalidomide/dexamethasone, Rd lenalidomide/dexamethasone, ITT intent-to-treat. *Patients in the ITT population who met the biomarker criteria for risk assessment. Table 3 Response and MRD-negativity rates in patients with standard and high cytogenetic risk. Standard risk High risk* Response,† n (%) D-Rd (n = 190) Rd (n = 172) P D-Rd (n = 35) Rd (n = 34) P ORR 178 (94) 135 (79) <0.0001 31 (89) 23 (68) 0.0145 ≥CR 111 (58) 43 (25) 15 (43) 3 (9) Stringent CR 61 (32) 23 (13) 10 (29) 1 (3) CR 50 (26) 20 (12) 5 (14) 2 (6) ≥VGPR 156 (82) 92 (54) <0.0001 25 (71) 10 (29) 0.0004 VGPR 45 (24) 49 (29) 10 (29) 7 (21) PR 22 (12) 43 (25) 6 (17) 13 (38) MRD negative (10–5)‡ n = 193 n = 176 n = 35 n = 35 n (%) 63 (33) 15 (9) <0.0001 9 (26) 0 0.0022 Sustained MRD negativity (≥6 months), n (%) 35 (18) 2 (1) <0.0001 1 (3) 0 Sustained MRD negativity (≥12 months), n (%) 27 (14) 1 (1) <0.0001 1 (3) 0 MRD minimal residual disease, D-Rd daratumumab plus lenalidomide/dexamethasone, Rd lenalidomide/dexamethasone, ORR overall response rate, CR complete response, VGPR very good partial response, PR partial response, ITT intent-to-treat. *Patients with high cytogenetic risk had a t(4;14), t(14;16), or del17p abnormality. † Response-evaluable population. ‡ ITT population. Blood Cancer Journal Kaufman et al. Blood Cancer Journal (2020)10:111 Page 6 of 10 A. Standard risk: HR, 0.54; 95% CI, 0.40–0.74; P < 0.0001 B. High risk: HR, 0.38; 95% CI, 0.18–0.83; P = 0.0121 100 100 % surviving without progression on % surviving without progression on 80 80 the subsequent line of therapy the subsequent line of therapy D-Rd standard risk 60 60 D-Rd high risk: Median 37.7 mo 40 40 Rd standard risk: Median 33.3 mo 20 20 Rd high risk: Median 20.8 mo 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Months Months No. at risk No. at risk Rd standard risk 176 169 159 151 146 137 119 107 98 93 86 78 71 63 56 27 1 0 Rd high risk 35 33 28 26 22 19 17 15 13 13 11 6 6 6 5 1 0 0 D-Rd standard risk 193 188 183 176 172 163 152 150 143 137 130 122 117 111 97 45 7 0 D-Rd high risk 35 33 30 30 29 27 24 23 22 21 18 16 16 12 11 6 1 0 C. Standard risk: HR, 0.53; 95% CI, 0.34–0.83; P = 0.0049 D. High risk: HR, 0.26; 95% CI, 0.09–0.74; P = 0.0082 100 100 % surviving without progression on % surviving without progression on 80 80 the subsequent line of therapy D-Rd standard risk the subsequent line of therapy 60 60 D-Rd high risk: Median 36.2 mo 40 40 Rd standard risk: Median 38.2 mo 20 20 Rd high risk: Median 16.9 mo 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Months Months No. at risk No. at risk Rd standard risk 90 88 83 78 76 70 63 58 52 49 46 42 40 34 28 14 1 0 Rd high risk 20 19 15 14 12 10 9 8 7 7 6 3 3 3 2 0 0 0 D-Rd standard risk 96 95 91 89 87 84 80 79 76 72 68 63 61 58 52 25 6 0 D-Rd high risk 22 21 19 19 19 17 15 15 14 14 11 9 9 8 8 5 1 0 Fig. 2 PFS2 based on cytogenetic risk status. PFS2 in the ITT/biomarker risk population:* A standard and B high cytogenetic risk patients. PFS2 in patients with one prior line of therapy: C standard and D high cytogenetic risk patients. PFS2 progression-free survival on the next subsequent line of therapy, D-Rd daratumumab plus lenalidomide/dexamethasone, Rd lenalidomide/dexamethasone, HR hazard ratio, CI confidence interval, ITT intent- to-treat. *Patients in the ITT population who met the biomarker criteria for risk assessment. however, as has been observed previously for high-risk MRD-negativity (10–5) rates were higher with D-Rd ver- patients, this subgroup had poorer outcomes in both sus Rd, and more patients treated with D-Rd achieved a treatment arms. At a median follow-up of 44.3 months, sustained MRD response, which translates into better D-Rd reduced the risk of disease progression or death by patient outcomes15, suggesting that achievement of MRD 57% versus Rd alone in patients with standard cytogenetic negativity can predict clinical benefit across all patient risk risk and by 66% in patients with high cytogenetic risk. groups. In addition, PFS2 was prolonged with D-Rd Median PFS for patients treated with D-Rd was NE in compared with Rd in the ITT population and in patients those with standard cytogenetic risk (vs 18.6 months with with one prior line of therapy, regardless of cytogenetic Rd; P < 0.0001) and was 26.8 months in those with high risk status. Of note, although favorable outcomes were cytogenetic risk (vs 8.3 months with Rd; P = 0.0035). achieved by D-Rd in patients with high cytogenetic risk, Similar results were observed in the subset of patients clinical benefits were of lesser magnitude than in patients with one prior line of therapy. Deep responses were with standard cytogenetic risk, demonstrating that D-Rd observed with D-Rd in both patients with standard cyto- reduces but does not abrogate the adverse impact of high- genetic risk (≥CR: 58% vs 25% with Rd) and high cyto- risk cytogenetics. genetic risk (≥CR: 43% vs 9% with Rd). Time to reach This extended follow-up of POLLUX complements the VGPR or better and CR or better was decreased with results reported after a median follow-up of D-Rd compared with Rd in both the standard and high 25.4 months14. In the earlier analysis, D-Rd reduced the cytogenetic risk subgroups. Regardless of cytogenetic risk, risk of disease progression or death by 70% versus Rd Blood Cancer Journal Kaufman et al. Blood Cancer Journal (2020)10:111 Page 7 of 10 Table 4 Most common any-grade (≥25% of patients) and Grade 3/4 (≥5% of patients) TEAEs. Any grade Grade 3/4 Standard risk High risk* Standard risk High risk* TEAE, n (%) D-Rd Rd D-Rd Rd D-Rd Rd D-Rd Rd (n = 192) (n = 176) (n = 35) (n = 34) (n = 192) (n = 176) (n = 35) (n = 34) Hematologic Neutropenia 116 (60) 80 (46) 22 (63) 18 (53) 103 (54) 69 (39) 17 (49) 16 (47) Febrile neutropenia 10 (5) 4 (2) 2 (6) 0 10 (5) 4 (2) 2 (6) 0 Anemia 71 (37) 62 (35) 13 (37) 15 (44) 31 (16) 32 (18) 7 (20) 10 (29) Thrombocytopenia 55 (29) 46 (26) 13 (37) 14 (41) 25 (13) 24 (14) 8 (23) 10 (29) Leukopenia 18 (9) 15 (9) 3 (9) 4 (12) 6 (3) 4 (2) 1 (3) 3 (9) Lymphopenia 10 (5) 10 (6) 5 (14) 3 (9) 8 (4) 7 (4) 5 (14) 3 (9) Nonhematologic Diarrhea 104 (54) 53 (30) 18 (51) 16 (47) 20 (10) 5 (3) 3 (9) 4 (12) Upper respiratory tract 82 (43) 56 (32) 10 (29) 8 (24) 4 (2) 3 (2) 0 0 infection Fatigue 74 (39) 52 (30) 12 (34) 12 (35) 13 (7) 9 (5) 4 (11) 2 (6) Cough 65 (34) 23 (13) 11 (31) 6 (18) 0 0 0 0 Nasopharyngitis 64 (33) 37 (21) 11 (31) 9 (27) 0 0 0 0 Constipation 57 (30) 46 (26) 12 (34) 10 (29) 0 1 (1) 2 (6) 1 (3) Insomnia 54 (28) 41 (23) 9 (26) 4 (12) 5 (3) 3 (2) 0 1 (3) Muscle spasms 52 (27) 36 (21) 12 (34) 7 (21) 2 (1) 3 (2) 1 (3) 0 Pneumonia 51 (27) 30 (17) 10 (29) 6 (18) 32 (17) 20 (11) 4 (11) 4 (12) Nausea 48 (25) 37 (21) 14 (40) 8 (24) 5 (3) 2 (1) 1 (3) 0 Peripheral edema 47 (25) 24 (14) 8 (23) 3 (9) 1 (1) 1 (1) 0 0 Pyrexia 48 (25) 18 (10) 10 (29) 5 (15) 5 (3) 5 (3) 1 (3) 1 (3) Dyspnea 37 (19) 23 (13) 7 (20) 4 (12) 2 (1) 1 (1) 4 (11) 0 Hypokalemia 37 (19) 19 (11) 7 (20) 4 (12) 14 (7) 5 (3) 2 (6) 1 (3) Cataract 35 (18) 24 (14) 4 (11) 2 (6) 13 (7) 8 (5) 1 (3) 1 (3) Bronchitis 32 (17) 24 (14) 10 (29) 4 (12) 6 (3) 5 (3) 0 0 Arthralgia 27 (14) 22 (13) 10 (29) 5 (15) 2 (1) 1 (1) 1 (3) 0 Influenza 20 (10) 9 (5) 5 (14) 2 (6) 2 (1) 0 2 (6) 0 Hyperglycemia 18 (9) 14 (8) 6 (17) 3 (9) 5 (3) 7 (4) 4 (11) 2 (6) Hypophosphatemia 12 (6) 7 (4) 4 (11) 2 (6) 9 (5) 5 (3) 3 (9) 0 Hypertension 12 (6) 8 (5) 9 (26) 2 (6) 5 (3) 2 (1) 4 (11) 0 Increased alanine 12 (6) 7 (4) 5 (14) 3 (9) 6 (3) 2 (1) 2 (6) 1 (3) aminotransferase Syncope 9 (5) 2 (1) 2 (6) 1 (3) 9 (5) 2 (1) 2 (6) 1 (3) Pulmonary embolism 4 (2) 8 (5) 2 (6) 2 (6) 4 (2) 7 (4) 2 (6) 2 (6) Hypercalcemia 2 (1) 6 (3) 3 (9) 2 (6) 1 (1) 2 (1) 2 (6) 2 (6) TEAE treatment-emergent adverse event, D-Rd daratumumab plus lenalidomide/dexamethasone, Rd lenalidomide/dexamethasone. *Patients with high cytogenetic risk had a t(4;14), t(14;16), or del17p abnormality. Blood Cancer Journal Kaufman et al. Blood Cancer Journal (2020)10:111 Page 8 of 10 alone in patients with standard cytogenetic risk (D-Rd, among high-risk patients, MRD negativity was only n = 133; Rd, n = 113) and by 47% in patients with high achieved in patients treated with D-Vd. cytogenetic risk (D-Rd, n = 28; Rd, n = 37), with cytoge- Although high cytogenetic risk patients in the POLLUX netic abnormalities assessed by central next-generation study were defined using the 2009 IMWG criteria avail- sequencing14. The next-generation sequencing and FISH able at the time of study design instead of the updated methods have been shown to have high concordance 2016 criteria, the definition used to determine high (88%–98%) in identifying high-risk cytogenetics16. cytogenetic risk status (t[4;14], t[14;16], or del17p The safety profile of D-Rd in the standard and high abnormality) is consistent with the previously mentioned cytogenetic risk subgroups was consistent with the overall studies. Additionally, the fact that among the patients population of POLLUX9,10. No new safety concerns were with high cytogenetic risk in this study, patients who observed following a median follow-up of more than received Rd had a lower PFS further confirms the correct 3 years. categorization of patients. Although cross-trial comparisons are limited by differ- This subgroup analysis was limited by incomplete ences in risk-group definitions (due to lack of consensus cytogenetic abnormality data collected for patients criteria on cutoffs), patient populations, and clinical enrolled in the POLLUX study; cytogenetic testing was settings, they allow for a comprehensive assessment of a not performed in 23% of patients. Also, the cytogenetic treatment regimen’s clinical benefit. The efficacy results testing for t(4;14), t(14;16), and del17p abnormalities was in terms of HR of PFS from this study are similar to performed locally, and threshold levels for a positive those for other studies of the immunomodulatory drug finding were not uniform for all patients. Although (IMiD)–containing regimens in patients with RRMM additional abnormalities were requested, they were not and high cytogenetic risk. In a subgroup analysis of the required by the protocol and were not always reported. phase 3 ASPIRE study, among patients with high cyto- About two-thirds of patients with high cytogenetic risk in genetic risk (defined as the presence of t[4;14], t[14;16], or this study had del17p abnormalities. The presence of del17p according to FISH), median PFS was 23.1 months TP53 mutation status in del17p patients is known to with carfilzomib plus Rd versus 13.9 months with Rd adversely affect clinical outcomes; however, details on alone (HR, 0.70; 95% CI, 0.43–1.16; P = 0.0829)17. In the TP53 mutational status were not collected and thus a phase 3 study of elotuzumab (ELOQUENT-2), at a potential for bias based on TP53 mutation status cannot median follow-up of 46 months, median PFS among high- be ruled out. Small sample sizes in the cytogenetic risk risk patients (defined as ISS stage II or III disease and a t subgroups precluded us from conducting additional sub- [4;14] or del17p abnormality) was 15 months with elo- group analyses. MRD results were not available in 22% of tuzumab plus Rd compared with 7 months with Rd alone patients with CR or better. Patients without MRD (HR, 0.64; 95% CI, 0.43–0.97; P = 0.0331)18. In a post hoc assessment were considered as MRD positive, potentially analysis of the TOURMALINE-MM1 study according to underestimating the rate of MRD negativity. cytogenetic risk status, median PFS in high-risk patients In conclusion, the results from this updated subgroup (defined as t[4;14], t[14;16] or del17p abnormality) was analysis of POLLUX show that D-Rd in comparison with 21.4 months with ixazomib plus Rd versus 9.7 months the standard of care alone improves the outcome of with Rd alone (HR, 0.543; 95% CI, 0.321–0.918; P = patients with high-risk RRMM. Moreover, the analysis of 0.021)19. None of these analyses reported the effects of all the previously mentioned trials confirms that dar- these combinations on MRD negativity according to atumumab is effective in patients with MM, regardless of cytogenetic risk status. cytogenetic risk status. Improvement in PFS with a daratumumab-based regi- men versus standard of care was also observed in the Acknowledgements This study was sponsored by Janssen Research & Development, LLC. The phase 3 CASTOR study of daratumumab plus Vd (D-Vd) authors would like to thank the patients who participated in this study and versus Vd alone in RRMM, regardless of cytogenetic risk their families, as well as the study co-investigators, research nurses, and status20. In an updated subgroup analysis after a median coordinators at each of the clinical sites. The authors thank Nikki DeAngelis, PhD, of Janssen Research & Development, LLC for her insights on the study. follow-up of more than 3 years, treatment with D-Vd Medical writing and editorial support were provided by Kristin Runkle, PhD, of prolonged PFS compared with Vd in patients with stan- MedErgy, and were funded by Janssen Global Services, LLC. dard cytogenetic risk (16.6 vs 6.6 months; HR, 0.26; 95% CI, 0.19–0.37) as well as those with high cytogenetic risk Author details 1 Winship Cancer Institute, Emory University, Atlanta, GA, USA. 2The National (12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21–0.83)21. The and Kapodistrian University of Athens, Athens, Greece. 3Dalhousie University benefits of D-Vd over Vd in the high-risk population were and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada. 4 not only maintained but strengthened, demonstrating Service d’Hématologie et Thérapie Cellulaire, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire, Tours, France. 5St James’s Institute of improved clinical benefit in terms of PFS, ORR, rate of Oncology, Leeds Teaching Hospitals National Health Service Trust and VGPR or better, and MRD-negativity rate. Moreover, University of Leeds, Leeds, UK. 6Assuta Ashdod University Hospital, Faculty of Blood Cancer Journal Kaufman et al. Blood Cancer Journal (2020)10:111 Page 9 of 10 Health Science Ben-Gurion University of the Negev, Beer Sheva, Israel. 7Icon Celgene, Skyline, Amgen, AbbVie, Mundipharma, Seattle Genetics, and Janssen; Cancer Care, South Brisbane, QLD, Australia. 8Institute of Haematology, Royal and received grants from Sanofi, Takeda, Celgene, Skyline, Amgen, AbbVie, Prince Alfred Hospital, Camperdown, NSW, Australia. 9Department of Medicine, Mundipharma, Seattle Genetics, Janssen, Bristol-Myers Squibb, and Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Pharmacyclics. J.S.-M. served in a consulting or advisory role for Amgen, Bristol- South Korea. 10Department of Hematology, National Hospital Organization Myers Squibb, Celgene, Janssen, Merck Sharp & Dohme, Novartis, Takeda, Disaster Medical Center of Japan, Tachikawa, Japan. 11Hematology, University Sanofi, Roche, AbbVie, GlaxoSmithKline, and Karyopharm. M.L., J.M., K.K., N.T., Hospital Hôtel-Dieu, Nantes, France. 12Leukemia/Bone Marrow Transplant H.M., J.S.K., and H.A.-L. declare no competing financial interests. Program, University of British Columbia, Vancouver, Canada. 13Department of Hematology Chaim Sheba Medical Center, Ramat-Gan, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 14Department of Hematology and Publisher’s note Oncology, Nagoya City University Graduate School of Medical Sciences, Springer Nature remains neutral with regard to jurisdictional claims in Nagoya, Japan. 15Yonsei University College of Medicine, Severance Hospital, published maps and institutional affiliations. Seoul, South Korea. 16Cabrini Hospital, Epworth HealthCare and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. 17Gold Coast University Hospital and Griffiths University, Southport, Received: 18 June 2020 Revised: 27 August 2020 Accepted: 1 October 2020 QLD, Australia. 18Institut Català d’Oncologia i Institut Josep Carreras, Hospital Germans Trias I Pujol, Barcelona, Spain. 19University of Calgary, Arnie Charbonneau Cancer Institute, Calgary, AB, Canada. 20Icahn School of Medicine at Mount Sinai, New York, NY, USA. 21Janssen Research & Development, Spring House, PA, USA. 22Janssen Research & Development, Beerse, Belgium. References 23 Janssen Global Medical Affairs, Horsham, PA, USA. 24Janssen Research & 1. de Weers, M. et al. 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