Leukemia & Lymphoma ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ilal20 Efficacy and safety of weekly carfilzomib (70 mg/ 2 m ), dexamethasone, and daratumumab (KdD70) is comparable to twice-weekly KdD56 while being a more convenient dosing option: a cross-study comparison of the CANDOR and EQUULEUS studies Xavier Leleu , Meral Beksac , Takaaki Chou , Meletios Dimopoulos , Sung- Soo Yoon , H. Miles Prince , Ludek Pour , Tatiana Shelekhova , Ajai Chari , Monica Khurana , Jianqi Zhang , Mihaela Obreja , Ming Qi , Albert Oriol & David Siegel To cite this article: Xavier Leleu , Meral Beksac , Takaaki Chou , Meletios Dimopoulos , Sung-Soo Yoon , H. Miles Prince , Ludek Pour , Tatiana Shelekhova , Ajai Chari , Monica Khurana , Jianqi Zhang , Mihaela Obreja , Ming Qi , Albert Oriol & David Siegel (2021) Efficacy 2 and safety of weekly carfilzomib (70 mg/m ), dexamethasone, and daratumumab (KdD70) is comparable to twice-weekly KdD56 while being a more convenient dosing option: a cross-study comparison of the CANDOR and EQUULEUS studies, Leukemia & Lymphoma, 62:2, 358-367, DOI: 10.1080/10428194.2020.1832672 To link to this article: https://doi.org/10.1080/10428194.2020.1832672 © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. View supplementary material Published online: 28 Oct 2020. Submit your article to this journal Article views: 1158 View related articles View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ilal20 LEUKEMIA & LYMPHOMA 2021, VOL. 62, NO. 2, 358–367 https://doi.org/10.1080/10428194.2020.1832672 ORIGINAL ARTICLE Efficacy and safety of weekly carfilzomib (70 mg/m2), dexamethasone, and daratumumab (KdD70) is comparable to twice-weekly KdD56 while being a more convenient dosing option: a cross-study comparison of the CANDOR and EQUULEUS studies Xavier Leleua , Meral Beksacb, Takaaki Chouc, Meletios Dimopoulosd , Sung-Soo Yoone, H. Miles Princef, Ludek Pourg, Tatiana Shelekhovah, Ajai Charii , Monica Khuranaj, Jianqi Zhangk, Mihaela Obrejak, Ming Qil, Albert Oriolm and David Siegeln a Service d’Hematologie et Therapie cellulaire, CHU and Inserm, Poitiers, France; bDepartment of Hematology, Ankara University, Ankara, Turkey; cDepartment of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan; dHematology and Medical Oncology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; e Department of Internal Medicine, Seoul National University, Seoul, South Korea; fEpworth Healthcare and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; gDepartment of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic; hClinic of Professional Pathology, Saratov, Russian Federation; iTisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; jClinical Development, Oncology, Amgen Inc., Thousand Oaks, CA, USA; kGlobal Biostatistical Science, Amgen Inc., Thousand Oaks, CA, USA; lHematology and Oncology, Janssen Research and Development, LLC, Spring House, PA, USA; mInstitut Catala d’Oncologia and Josep Carreras Research Leukaemia Institute, Hospital Germans Trias i Pujol, Barcelona, Spain; nJohn Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA ABSTRACT ARTICLE HISTORY The regimen of carfilzomib, daratumumab, and dexamethasone (KdD) shows activity in patients Received 7 August 2020 with relapsed/refractory multiple myeloma. KdD at the twice-weekly 56 mg/m2 carfilzomib dose Accepted 26 September 2020 (KdD56) was used in the randomized phase 3 CANDOR study (NCT03158688), whereas KdD at KEYWORDS the once-weekly 70 mg/m2 carfilzomib dose (KdD70) was used in the phase 1 b EQUULEUS study Carfilzomib; daratumumab; (NCT01998971). We analyzed efficacy data from comparable CANDOR and EQUULEUS patients multiple myeloma; using inverse probability of treatment weighting (IPTW)–adjusted models. These weights were weekly regimen calculated from propensity scores derived to balance prespecified baseline covariates. The side- by-side and adjusted comparisons showed similar efficacy for overall response rates and pro- gression-free survival in the two groups, with a series of sensitivity analyses showing consistent findings. Safety data were generally consistent with the known safety profiles of each individual drug. Once-weekly KdD70 is comparable to twice-weekly KdD56 in terms of efficacy and safety while being a more convenient dosing option. Introduction and alterations in the bone marrow microenvironment Regimens containing immunomodulatory imide drugs [10]. The second-generation proteasome inhibitor (PI) (IMiDs) are standard of care for the treatment of newly carfilzomib and the anti-CD38 monoclonal antibody diagnosed multiple myeloma [1–5]. With the adoption daratumumab are potent agents in their respective of lenalidomide maintenance therapy until disease classes [11–15]. In the phase 3 ENDEAVOR study, carfil- progression, there is a further need for effective and zomib plus dexamethasone (Kd) showed superiority tolerable IMiD-free regimens for patients who progress over the first-generation PI bortezomib plus dexa- on lenalidomide. Worse clinical outcomes are seen in methasone (Vd) in relapsed and/or refractory multiple patients with relapse with IMiD refractoriness when myeloma [11,16]. Likewise, the phase 3 CASTOR study compared with the overall population [6–9], with demonstrated improved clinical outcomes for daratu- relapse due to various mechanisms of drug resistance mumab with bortezomib and dexamethasone CONTACT Xavier Leleu xavier.leleu@chu-poitiers.fr Chu and Inserm 1402 CIC, Poitiers University Hospital, 2 rue de la Miletrie, 86000 Poitiers, France Supplemental data for this article can be accessed here. ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. QW KdD70 COMPARABLE TO BIW KdD56 359 Figure 1. Overall response rate (ORR) and progression-free survival (PFS) analyses. (A) Unadjusted and adjusted ORR and PFS. The ORR and PFS and associated 95% confidence intervals (CIs) are shown for twice-weekly (BIW) KdD56 and once-weekly (QW) KdD70. Also shown are the odds ratios (ORs; for ORR) and hazard ratios (HRs; for PFS) and associated 95% CIs. Sensitivity analyses for ORR (B) and PFS (C), with corresponding OR for ORR and HR for PFS, and associated 95% CIs are shown for BIW KdD56 and QW KdD70. Progression-free survival (PFS) for unadjusted primary analysis (D) and IPTW-IRC analysis (E). BIW: twice-weekly; CI: confidence interval; HR: hazard ratio; IRC: Independent Review Committee; IPTW: inverse probability of treatment weighting; KdD: carfilzomib, dexamethasone, and daratumumab; NE: not estimable; QW: once weekly. compared with bortezomib and dexamethasone alone The randomized phase 3 CANDOR study demon- [17]. The regimen including carfilzomib and daratumu- strated a statistically significant improvement in progres- mab is of high interest to clinicians for relapsed and/ sion-free survival (PFS) for carfilzomib, dexamethasone, or refractory multiple myeloma. and daratumumab at the twice-weekly 56 mg/m2 360 X. LELEU ET AL. Table 1. Unadjusted baseline demographics and disease characteristics. CANDOR Subset Bortezomib and IMiD Exposure EQUULEUS 20/56 mg/m2 KdD BIW 20/70 mg/m2 KdD QW (N ¼ 185) (N ¼ 85) Sex, male, n (%) 105 (57%) 46 (54%) Age group, n (%) <65 years 100 (54%) 36 (42%) 65–74 years 73 (40%) 41 (48%) 75 years 12 (7%) 8 (9%) Race, n (%) Asian 33 (18%) 3 (4%) Black or African American 6 (3%) 3 (4%) White 132 (71%) 68 (80%) Other 14 (8%) 0 (0%) Missing 0 (0%) 11 (13%) ECOG performance status, 0 / 1–2, % 48% / 52% 38% / 62% Creatinine clearance, n (%) <50 mL/min 19 (10%) 15 (18%) 50–79 mL/min 57 (31%) 28 (33%) 80 mL/min 108 (58%) 42 (49%) Risk group by FISH, % High risk 16% 15% t(4;14) / t(14;16) / del(17p) 6.5% / 0.5% / 9.7% 7.1% / 2.4% / 8.2% Standard risk 31% 64% Unknown 53% 21% Time from diagnosis, months, mean (SD) 46 (30) 57 (30) Time from diagnosis, months, median (range) 37 (0.3–157) 49 (8.7–145) Prior regimens, 1 / 2, n (%) 62 (34%) / 123 (66%) 20 (24%) / 65 (76%) Prior transplant, n (%) 129 (70%) 62 (73%) Refractory to last prior treatment, n (%) 124 (67%) 53 (62%) Time from last relapse, months, mean (SD) 3.2 (6.3) 2.7 (5.9) Received prior IMiD, n (%) 185 (100%) 85 (100%) Received thalidomide 102 (55%) 21 (25%) Received lenalidomide 115 (62%) 81 (95%) Refractory to prior lenalidomide 94 (51%) 50 (59%) Received prior PI, n (%) 185 (100%) 85 (100%) Refractory to prior bortezomib, n (%) 57 (31%) 27 (32%) BIW: twice weekly; ECOG: Eastern Cooperative Oncology Group; FISH: fluorescence in situ hybridization; IMiD: immunomodulatory imide drug; KdD: carfil- zomib, dexamethasone, and daratumumab; PI: proteasome inhibitor; QW: once weekly; SD: standard deviation. carfilzomib dose (KdD56), with a 37% reduction in the Patient-reported outcomes from the A.R.R.O.W. study risk of progression or death versus carfilzomib and dexa- showed delayed disease symptom worsening as well methasone alone (Kd) [18]. Additionally, patients treated as greater convenience and satisfaction with once- with KdD56 achieved deep responses, with an overall weekly Kd70 as compared with twice-weekly Kd27. response rate (ORR) of 84% and a nearly 10 times higher Improved clinical outcomes for the once-weekly Kd minimal residual disease (MRD)–negative complete regimen translated into prolonged health-related qual- response (CR) rate compared with Kd-treated patients. ity of life in a cost-effective manner [21,22]. Thus, as Overall, KdD56 was associated with a favorable benefit- observed with the Kd regimen, once-weekly carfilzo- risk profile. The promising activity of the KdD regimen is mib dosing with KdD is expected to improve patients’ further supported by the non-randomized phase 1 b quality of life by allowing patients to maintain a social EQUULEUS study, in which KdD at the once-weekly role and other meaningful activities, which is key from 70 mg/m2 carfilzomib dose (KdD70) showed tolerability a patient’s perspective [23]. and efficacy, with an ORR of 84% and median PFS of While we expect that the once-weekly KdD70 regi- nearly 26 months in patients who were almost all men would provide patients a more convenient treat- exposed to lenalidomide and were mostly lenalidomide ment option and thus better adherence, the two refractory [19]. regimens of twice-weekly KdD56 and once-weekly Previously, the phase 3 A.R.R.O.W. study demon- KdD70 have not been directly compared in a random- strated that once-weekly Kd (Kd70) was effective and ized trial. Therefore, we performed a robust cross- safe [20]; this regimen achieved regulatory approval study comparison that demonstrated similar efficacy for the treatment of relapsed and/or refractory mul- and safety, which was confirmed with sensitiv- tiple myeloma in the United States and elsewhere. ity analyses. QW KdD70 COMPARABLE TO BIW KdD56 361 Methods CANDOR KdD arm; 185 of the 312 patients in the CANDOR study receiving KdD met this requirement. Study design All these patients had at least one study treatment CANDOR is a phase 3, open-label, multicenter, dose and were included in the safety summaries. The randomized study in patients with relapsed and/or efficacy endpoints were derived based on the refractory multiple myeloma who received 1–3 prior response and disease progression from both studies lines of therapy (NCT03158688). Patients were random- assessed post hoc by the same blinded Independent ized 2:1 to receive KdD or Kd in 28-day cycles until Review Committee (IRC). The PFS endpoint was ana- disease progression (Figure S1A, Table S1). Treatment lyzed using Cox models, while the Kaplan-Meier meth- continued until confirmed disease progression, odology was used to summarize its distribution, unacceptable toxicity, consent withdrawal, or death including the point estimates and 95% confidence (whichever occurred first), and lasted up to 48 months. intervals (CIs) for medians [24]. ORRs were calculated The primary endpoint was PFS; secondary endpoints as the rate of responders who achieved a partial were ORR, MRD-negative CR rate at 12 months, overall response (PR) or better and associated 95% CIs were survival (OS), time to response, and safety. Data are estimated with the Clopper-Pearson method. Odds through July 14, 2019 (primary analysis date). ratios (ORs) were evaluated with logistic models, while EQUULEUS is a phase 1 b, multicenter, open-label, 95% CIs were constructed with robust vari- multiarm, non-randomized study of daratumumab in ance estimates. combination with other agents in patients with For efficacy comparisons, results were adjusted with relapsed and/or refractory multiple myeloma inverse probability of treatment weighting (IPTW). The (NCT01998971) (Figure S1B, Table S1). One cohort weights were calculated using the propensity score combined daratumumab with carfilzomib and dexa- that a patient received once-weekly KdD70 by balanc- methasone (i.e. KdD), which is the dataset described ing the baseline covariates that had been preselected here and elsewhere [19]. Patients received 1–3 prior as prognostic for multiple myeloma. Selection of these lines of therapy, including bortezomib and an IMiD. covariates was independent of prior knowledge of effi- Treatment continued until confirmed disease progres- cacy outcomes and was based on subject matter sion, unacceptable toxicity, withdrawal of consent, expert guidance and literature review. The covariates death, or end of study, which was approximately included baseline demographics (age), disease charac- 25 months after the last patient received the first dose teristics (prior treatment exposure/refractoriness and of daratumumab or when 38 PFS events were time from initial diagnosis to relapse), and other char- reached. The primary endpoints were safety and toler- acteristics (creatinine clearance, Eastern Cooperative ability. Secondary endpoints included ORR and OS; Oncology Group [ECOG] performance status), many of PFS was an exploratory endpoint. Data are through which have been evaluated in previous carfilzomib January 31, 2019 (final analysis date for this cohort). In analyses [25]. We did not include all components of the original report, the number of patients evaluable the revised International Staging System (R-ISS) as for response per study criteria was 82 of 85; all 85 data were not available for all patients for fluores- patients are included in our analyses. cence in situ hybridization (FISH) and as b2 microglo- bulin data were not collected in the EQUULEUS study. The appropriateness of the model was assessed by Statistical analysis boxplots and absolute standardized difference, evalu- This cross-study comparison was a prespecified meta- ating the balance reached between the two groups analysis exploring the similarity between the efficacy after weighting adjustment. Propensity score matching and safety outcomes for patients treated with the trip- was also used as a sensitivity analysis by sequentially let combination KdD in two different studies. The effi- matching patients based on greedy nearest neighbor cacy data were analyzed both unadjusted and with matching of the propensity scores derived for the propensity score adjustment, while safety data were IPTW method. Propensity score matching creates summarized in side-by-side tables. mutually exclusive sets of observations that have simi- In order to evaluate efficacy in comparable popula- lar propensity scores. Greedy nearest neighbor match- tions, as all patients from the EQUULEUS KdD cohort ing was used to sequentially match each patient in were required to have prior therapy with bortezomib the KdD70 cohort with one patient in the KdD56 and an IMiD, similar patients (i.e. those with prior bor- external control group if the difference in the logits of tezomib and IMiD exposure) were selected from the the propensity score for pairs of patients from the two 362 X. LELEU ET AL. Table 2. Baseline demographics and disease characteristics of adjusted BIW KdD56 and QW KdD70 groups after using propensity score. CANDOR, 20/56 mg/m2 KdD BIW, EQUULEUS Absolute Bortezomib and IMiD exposed 20/70 mg/m2 KdD QW Standard (N ¼ 89.3)a (N ¼ 85.0) Difference Age group, n (%) <65 years 34.2 (38.3%) 36.0 (42.4%) 65–74 years 45.8 (51.3%) 41.0 (48.2%) 0.06 75 years 9.3 (10.4%) 8.0 (9.4%) 0.03 ECOG performance status, %, 0 / 1–2 34.6% / 65.4% 37.6% / 62.4% 0.06 Time from initial diagnosis, months, mean (SD) 57.2 (21.8) 57.3 (29.8) <0.01 Creatinine clearance, n (%) <50 mL/min 16.0 (17.9%) 15.0 (17.6%) 50–79 mL/min 34.2 (38.3%) 28.0 (32.9%) 0.11 80 mL/min 39.1 (43.8%) 42.0 (49.4%) 0.11 Prior regimens, 1 / 2, % 28.0% / 72.0% 23.5% / 76.5% 0.10 Prior transplant, % 73.6% 72.9% 0.01 Refractory to last prior treatment, % 60.0% 62.4% 0.05 Time from last relapse, months, mean (SD) 2.81 (2.44) 2.72 (5.94) 0.02 Received lenalidomide, n (%) 85.3 (95.6%) 81.0 (95.3%) 0.01 Refractory to prior lenalidomide, n (%) 47.9 (53.6%) 50.0 (58.8%) 0.10 Refractory to prior bortezomib, n (%) 26.7 (29.9%) 27.0 (31.8%) 0.04 BIW: twice weekly; ECOG: Eastern Cooperative Oncology Group; IMiD: immunomodulatory imide drug; KdD: carfilzomib, dexamethasone, and daratumu- mab; QW: once weekly; SD: standard deviation. Absolute standard difference was a prespecified method used to quantify the balance for each covariate; an absolute standard difference of 0.1 signifies little or no imbalance between KdD BIW and KdD QW for that variable. a The N ¼ 89.3 is not a whole number as it represents a weighted sum of the 185 KdD56 CANDOR patients included in the analysis. Specifically, each patient of the KdD56 arm was weighted according to the inverse probability of treatment weighting (IPTW) based on the propensity score to have received KdD70, balancing for the baseline covariates included in this table. As these weights were not whole numbers, the sum of these weights was also not necessarily a whole number (in this case, the sum was 89.3). groups was less than or equal to 0.1 times the pooled considered prognostic were balanced for the two estimate of the standard deviation [26,27]. Efficacy groups (Table 2). endpoints derived based on unblinded evaluations by At the time of this analysis, 48% of CANDOR the investigators were included as a sensitivity ana- patients and 41% of EQUULEUS patients were continu- lysis. In addition, PFS and ORR were analyzed within ing treatment. Of patients who discontinued treat- prespecified subgroups, including by the number of ment, the most common reasons for discontinuation prior regimens, prior transplant, refractoriness to PIs or were disease progression (CANDOR: 27%, EQUULEUS: IMiDs, age, ECOG performance status, and baseline 42%), adverse events (AEs, 10%, 6%), and per patient creatinine clearance. The hazard ratios (HRs; with 95% request (7%, 7%) (Table S2). CIs) for PFS and ORs (with 95% CIs) for ORR between treatment groups within each subgroup were esti- mated using the same methodology as for the over- all analysis. Efficacy In a side-by-side comparison, after a median follow-up Results of 16.8 months, median PFS for the KdD56 group was not reached (not estimable [NE]; 95% CI, 18.4–NE), Demographic and baseline characteristics whereas for the KdD70 cohort, median PFS was Baseline demographic and disease characteristics were 25.8 months (95% CI, 19.4–NE, median follow-up of generally comparable between the two groups in this 23.5 months) (Table 3, Figure 1(A)). PFS event-free analysis: twice-weekly KdD56 CANDOR arm (i.e. rates at 12 months were 64.9% (95% CI: 57.3%–71.4%) CANDOR subset with prior bortezomib and IMiD for KdD56 and 75.2% (95% CI: 64.2%–83.2%) for exposure) and once-weekly KdD70 EQUULEUS cohort. KdD70 (graph in Figure 1(D,E)). ORR was 83.2% (95% However, some baseline characteristics were imbal- CI, 77.1%–88.3%) for KdD56 and 81.2% (95% CI, anced across the studies (Table 1). Specifically, in the 71.2%–88.8%) for KdD70. After IPTW adjustment, the KdD70 cohort, more patients had a higher ECOG per- 95% CI for the HR for PFS and the OR for ORR formance status, at least two prior treatments, and included 1, showing similar efficacy for the KdD56 and prior exposure to lenalidomide, and disease duration KdD70 groups (median PFS, NE and 25.8 months, was longer than in the KdD56 arm. Following IPTW respectively [HR, 0.80; 95% CI, 0.49–1.32]; ORR, 79.6% adjustment, baseline and disease characteristics and 81.2%, respectively [OR, 1.11; 95% CI, 0.50–2.45]). QW KdD70 COMPARABLE TO BIW KdD56 363 Table 3. Unadjusted and adjusted ORR and PFS. not duration-adjusted), the unadjusted frequency of Unadjusted analysis Adjusted analysis grade 3 TEAEs was similar in the KdD56 and KdD70 CANDOR EQUULEUS CANDOR EQUULEUS groups (84.3% and 82.4%, respectively), while the inci- BIW KdD56 QW KdD70 BIW KdD56 QW KdD70 dence of serious (58.9% and 48.2%) and fatal (10.8% (n ¼ 185) (n ¼ 85) (n ¼ 89.3)a (n ¼ 85) ORR, % 83.2 81.2 79.6 81.2 and 3.5%) TEAEs was higher in the KdD56 group. For (95% CI) (77.1–88.3) (71.2–88.8) (71.2–87.9) (72.9–89.5) fatal AEs, of the 20 in the KdD56 group, 10 were due OR (QW/BIW) – 1.11 to infections (five septic shock, four pneumonia, one (95% CI) (0.50–2.45) Median PFS, months NE 25.8 NE 25.8 respiratory tract infection), whereas for the three fatal (95% CI) (18.4–NE) (19.4–NE) (12.0–NE) (19.4–NE) AEs in the KdD70 cohort, two were due to general HR (QW/BIW) – 0.80 (95% CI) (0.49–1.32) physical health and one due to multiple organ dys- BIW: twice weekly; CI: confidence interval; HR: hazard ratio; KdD: carfilzo- function. The proportions of patients with AEs leading mib, dexamethasone, and daratumumab; NE: not estimable; OR: odds to carfilzomib discontinuation (21.1% for KdD56 and ratio; ORR: overall response rate; PFS: progression-free survival; QW: once weekly. 18.8% for KdD70) and daratumumab discontinuation a The N ¼ 89.3 is not a whole number as it represents a weighted sum of (8.1% and 8.2%) were comparable between the two the 185 KdD56 CANDOR patients included in the analysis. Specifically, each patient of the KdD56 arm was weighted according to the inverse treatment groups. For AEs of interest, the rates of probability of treatment weighting (IPTW) based on the propensity score grade 3 AEs in the KdD56 and KdD70 groups, to have received KdD70, balancing for the baseline covariates included in this table. As these weights were not whole numbers, the sum of respectively, were 1.1% and 2.4% for cardiac failure, these weights was also not necessarily a whole number (in this case, the 0.5% and 3.5% for acute renal failure, 18.4% and sum was 89.3). 20.0% for hypertension, and 2.7% and 0.0% for respiratory tract infections. For the category of grade Additional sensitivity analyses were performed to 3 infections/infestations, the rate was higher with support the robustness of the main comparison results. One sensitivity analysis for efficacy results KdD56 than with KdD70 (36.8% and 21.2%, respect- adjusted for IPTW using an extended list of covariates, ively). These same general trends were seen in expos- specifically laboratory values for albumin, hemoglobin, ure-adjusted rates of AEs; however, conclusions are lactate dehydrogenase (LDH), and platelet count, and limited as there were relatively few events for several the presence of plasmacytoma, in addition to the AEs of interest in both studies. covariates included in the main analysis, yielded con- sistent results. Efficacy results adjusted by propensity Discussion score matching showed similar results as well. In another sensitivity analysis, the adjusted and The KdD regimen is recommended by the National unadjusted comparisons performed on investigator- Comprehensive Cancer Network (NCCN 2020, version assessed ORR and PFS yielded similar findings to those 3) guidelines for patients with previously treated mul- performed on IRC-assessed ORR and PFS (Figure tiple myeloma [4]. As weekly carfilzomib dosing can 1(B,C), Tables SIII, SIV). Prespecified subgroup analyses be more convenient and improve the quality of life (e.g. number of prior regimens, prior transplant, refrac- [21,22], we undertook rigorous efficacy analyses in this toriness to PIs or IMiDs, age, ECOG performance status, cross-study comparison to support the comparability baseline creatinine levels) were consistent with the of twice-weekly KdD56 to once-weekly KdD70. We results from the main analysis for PFS and ORR out- found that the corresponding groups of the CANDOR comes, including in the lenalidomide-refractory sub- and EQUULEUS studies showed similar efficacy in group and by prior transplant status (Table 4). terms of ORR and PFS, both before and after IPTW adjustment, including in patients who were refractory to lenalidomide and independent of past stem cell Exposure and safety transplant status. We also examined safety in side-by- The median duration of carfilzomib treatment was side unadjusted analyses and found that the safety shorter for the twice-weekly KdD56 group (54.3 weeks) profiles of KdD56 and KdD70 were generally consist- than for the once-weekly KdD70 cohort (66.0 weeks) ent with the known safety profiles of the individual and the median relative dose intensity was similar for agents. The proportions of patients with grade 3 AEs both groups at approximately 90%. Safety analyses were similar in the KdD56 and KdD70 groups and the were performed side-by-side for all patients with no incidences of grade 3 cardiac AEs, renal failure, adjustment. All-grade treatment-emergent adverse hypertension, and respiratory tract infections did not events (TEAEs) occurred in 100% of patients in both differ appreciably. However, there were more grade groups (Table 5). Over the course of the studies (i.e. 3 infectious AEs and fatal infections with KdD56 364 X. LELEU ET AL. Table 4. Efficacy results for selected subgroups. Unadjusted Adjusted (IPTW-IRC) (QW/BIW KdD) (QW/BIW KdD) Overall response rate odds ratio (95% CI) All patients in analysis 0.87 (0.45–1.69) 1.11 (0.50–2.45) Refractory to lenalidomide Yes 0.72 (0.32–1.62) 0.64 (0.28–1.46) No 1.62 (0.43–6.13) 3.18 (0.67–15.11) Prior stem cell transplanta Yes 0.77 (0.35–1.69) 1.17 (0.45–3.02) No 1.16 (0.33–4.11) 0.93 (0.24–3.53) Progression-free survival hazard ratio (95% CI) All patients in analysis 0.87 (0.57–1.32) 0.80 (0.49–1.32) Refractory to lenalidomide Yes 1.22 (0.70–2.10) 1.25 (0.71–2.20) No 0.54 (0.27–1.05) 0.43 (0.19–1.00) Prior stem cell transplant Yes 0.82 (0.51–1.34) 0.77 (0.42–1.40) No 0.94 (0.42–2.14) 0.87 (0.36–2.11) BIW: twice weekly; CI: confidence interval; IPTW: inverse probability of treatment weighting; IRC: Independent Review Committee; KdD: carfilzomib, dexamethasone, and daratumumab; QW: once weekly. a For CANDOR patients, prior transplant includes autologous and allogeneic transplant; for EQUULEUS patients, prior transplant includes autologous transplant only. Table 5. Safety. CANDOR Subset Bortezomib and IMiD Exposure EQUULEUS KdD 20/56 mg/m2 BIW KdD 20/70 mg/m2 QW (N ¼ 185) (N ¼ 85) # per 100 # per 100 patient-years patient-years n (%) (95% CI) n (%) (95% CI) All treatment-emergent adverse events 185 (100.0) NC 85 (100.0) NC Grade 3 156 (84.3) 229 (196–268) 70 (82.4) 173 (137–219) Serious adverse events 109 (58.9) 85 (70–102) 41 (48.2) 46 (34–62) Leading to D/C carfilzomib 39 (21.1) 22 (16–30) 16 (18.8) 15.1 (9.3–24.6) Leading to D/C daratumumab 15 (8.1) 8.2 (4.9–13.5) 7 (8.2) 6.1 (2.9–12.8) Fatal adverse events 20 (10.8) 10.6 (6.8–16.4) 3 (3.5) 2.6 (0.8–7.9) Adverse events of interest, grade 3 Cardiac failure 2 (1.1) 1.1 (0.3, 4.3) 2 (2.4) 1.8 (0.4, 7.0) Acute renal failure 1 (0.5) 0.5 (0.1, 3.8) 3 (3.5) 2.6 (0.8, 8.0) Hypertension 34 (18.4) 20.8 (14.8, 29.1) 17 (20.0) 17.6 (11.0, 28.3) Respiratory tract infections 5 (2.7) 2.7 (1.1, 6.5) 0 (0.0) 0.00 (NA, NA) Infections / infestationsa 68 (36.8) 44.5 (35.1, 56.4) 18 (21.2) 18.3 (11.5, 29.0) BIW: twice weekly; CI: confidence interval; D/C: discontinuation of; KdD: carfilzomib, dexamethasone, and daratumumab; NA: not applicable; QW: once weekly. NC indicates that exposure-adjusted adverse event rates were not calculated as collection of adverse events can vary across studies, making interpretation of rates of all adverse events across studies infeasible. Safety data were compared side-by-side without any propensity score adjustment. a By system organ class category; other adverse events are preferred terms. than with KdD70. Although the benefit-risk profile was method was used to balance prespecified baseline similar for both regimens, the once-weekly carfilzomib covariates selected to be prognostic for multiple mye- regimen may be more convenient for patients and loma, with the goals of controlling for potential con- healthcare providers. The more convenient regimen founding factors of cross-trial comparison and may improve adherence to the on-label carfilzomib minimizing selection bias. The IPTW/propensity score dosing and frequency, and thus optimize carfilzomib approach is a well-established method intended to dose intensity and outcomes in the real-world setting, mirror the effects of randomization [34,35]. Specifically, as suboptimal carfilzomib dose intensity has been adjustment for selection bias was done by weighting shown to be associated with poorer outcomes [28]. the data based on the propensity score that a patient Direct comparisons across studies can be con- received once-weekly KdD70. As IPTW is based on founded by differences in study design, including eli- covariates selected as prognostic for multiple mye- gibility criteria that result in patient populations with loma outcomes, the methodology was applied to effi- different characteristics, such as prior treatment his- cacy data, but not to safety events. Other studies tory, leading to biased estimates of treatment effects evaluating treatment outcomes among patients with [29–33]. To account for this, the propensity score hematologic malignancies have also used propensity QW KdD70 COMPARABLE TO BIW KdD56 365 score analysis to compare two distinct study popula- encourage adherence and potentially lead to tions and achieve balance in baseline factors [36,37]. improved outcomes for patients. Besides possible confounding due to the nature of cross-study comparisons, another limitation of this Acknowledgments analysis was that baseline covariates in this analysis did not include R-ISS as b2 microglobulin data were Amgen conducted the CANDOR study; Janssen conducted the EQUULEUS study. Amgen funded the analyses for this not collected in the EQUULEUS study and as FISH data publication. Medical writing assistance was provided by were not available for many patients in both studies. Susanna Mac and Jacqueline Sayyah, both of Amgen. However, LDH and albumin levels, two components of R-ISS, were used as additional variables, along with platelet count, hemoglobin, and plasmacytoma pres- Author contributions ence, in a sensitivity analysis. In this sensitivity ana- Monica Khurana, Mihaela Obreja, and Jianqi Zhang contrib- lysis, there appears to be a larger effect size uted to the conception and design of the analyses. All authors had a role in collection of data, analyzing and inter- associated with KdD70 versus KdD56 for both ORR preting data, and reviewing the manuscript. and PFS. This sensitivity analysis may have reduced residual confounding; however, the 95% CIs still included 1. Disclosure statement Previously, once-weekly carfilzomib dosing with  Xavier Leleu reports honoraria from Janssen, Celgene, Kd70 was shown to have improved patients’ quality of Amgen, Takeda, Merck, GlaxoSmithKline, Sanofi, CARsgen, life with improved clinical outcomes relative to twice- AbbVie, Incyte, and Novartis. weekly carfilzomib dosing [21–23]. In line with these  Meral Beksac reports consulting/advising for Celgene, Takeda, Amgen, Sanofi, and Janssen, and being a speaker results for the once-weekly Kd70 doublet regimen, we for Celgene, Amgen, Sanofi, and Janssen. expect that the once-weekly KdD70 triplet regimen  Takaaki Chou reports receiving honoraria from Janssen, will provide patients a more convenient lenalidomide- Takeda, Celgene, and Ono, and consulting for Takeda free treatment option, thus fostering adherence to the and Ono. treatment schedule, dose, and treatment duration.  Meletios Dimopoulos reports consulting fees, lecture fees, and honoraria from Janssen, Amgen, Celgene, and Future analyses could confirm whether a weekly regi- Takeda; research funding from Janssen, Amgen, Takeda, men is associated with better adherence and and Genesis Pharma; and consulting fees from Bristol- improved responses and survival. In addition, in the Myers Squibb. era of COVID-19, guidelines have recommended  Sung-Soo Yoon reports consulting/advising for Janssen, switching patients from twice-weekly to weekly carfil- Takeda, Amgen, Celgene, and Novartis, and receiving zomib at an appropriate dose [38,39], thus decreasing research funding from Kyowa Kirin and Roche-Genentech. patients’ potential exposure to coronavirus as well as  Henry Miles Prince reports honoraria from Amgen, enabling adherence and reducing strain on the health- Novartis, and Takeda; consulting for Takeda; and research care system during a time when non-emergent visits funding from Allergan. to healthcare facilities should be limited. As the  Ludek Pour and Tatiana Shelekhova report no recently approved subcutaneous daratumumab [40] disclosures.  Ajai Chari reports research funding from Amgen, becomes more widely available, the treatment option Celgene, Janssen, Millennium/Takeda, Novartis, of weekly KdD may result in further improvements in Pharmacyclics, and Seattle Genetics; has served in an patient satisfaction, since use of subcutaneous daratu- advisory role for Amgen, Celgene, Janssen, Karyopharm, mumab has been associated with higher patient satis- Novartis, Oncopeptides, Sanofi, and Seattle Genetics; and faction versus intravenous daratumumab [41], as consulting fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millennium/Takeda, and Novartis. would be expected with reduced infusion chair time  Monica Khurana, Jianqi Zhang, and Mihaela Obreja are and decreased infusion-related reactions. employees and stockholders of Amgen. In conclusion, this cross-study analysis showed that  Ming Qi reports being an employee and stockholder of once-weekly KdD70 in the EQUULEUS study is compar- Janssen R&D LLC. able to the twice-weekly KdD56 regimen used in the  Albert Oriol reports consulting fees from Celgene and Janssen, and has been a speaker for Celgene pivotal phase 3 CANDOR trial in terms of efficacy and and Amgen. safety. The weekly KdD70 dosing option addresses an  David Siegel reports honoraria and speakers’ bureau fees important need for patients by providing a more con- from Amgen, Celgene, Takeda, Novartis, Bristol-Myers venient lenalidomide-free regimen that may Squibb, and Janssen, and honoraria from Karyopharm. 366 X. LELEU ET AL. ORCID [13] Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory mul- Xavier Leleu http://orcid.org/0000-0002-9822-4170 tiple myeloma. N Engl J Med. 2015;373(7):621–631. 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