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Carfilzomib (K), a widely used proteasome inhibitor in multiple myeloma (MM), is generally dosed at 20 mg/m2 during the first week of therapy. However, there is no consensus on its dosing thereafter. Over 30 K-containing trials (Table S1) have been conducted in newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM), with a wide range in schedules (Figure 1) in terms of target doses (from 27 to 70 mg/m2) and frequencies (once-weekly [QW, e.g. Days 1, 8 and 15] vs. twice-weekly [BIW, e.g. Days 1, 2, 8, 9, 15 and 16]). While three randomized trials of K dosing schedules have been conducted (Table S1), their results are difficult to interpret collectively given heterogeneity in regimen types and statistical designs.1-3 BIW dosing increases time in clinic and infusion costs,4, 5 but the equivalency of QW versus BIW administration of the same carfilzomib dose has not been investigated in a randomized trial. Given the unmet need to describe how physicians optimize K dosing in their standard-of-care (SOC) practice, we conducted an international survey of haematologists and oncologists. Study details (including Institutional Review Board approval) are provided in Table S2. In brief, we disseminated an anonymous survey from February to September 2024 with questions about K dosing preferences and supportive care (including venous thromboembolism [VTE] prophylaxis when combining K with an immunomodulatory drug [IMiD]). As done previously for international MM-related analyses with expected intra-country heterogeneity,6, 7 physician consensus was defined using a threshold of ≥70%. We analysed responses among all physicians and also three subgroups of interest: physicians based in the United States given unique reimbursement mechanisms, physicians practicing in academic settings and physicians with high MM volume (defined as >100 patients with MM annually). Of 240 webpage visits, 154 responses (64% response rate) were recorded. The majority of respondents resided in the United States (45%, n = 69), India (8%, n = 13) or Australia (7%, n = 11) (Table S3). However, six continents and 29 countries were represented altogether (Figure S1); this included 37 respondents (24%) from one of 12 low- or middle-income countries (LMICs). Two-thirds of respondents had at least 5 years of experience, including 13% (n = 20) with over 20 years of experience. While 65% (n = 100) practiced in academic settings, 19% (n = 29) practiced in large community settings and 9% (n = 14) in private practice. Finally, 29% (n = 44) reported seeing >100 patients with MM annually and were defined as having high-volume myeloma practices. Preferred K target doses varied based on the number of drugs within a given regimen (Figure 2). Respondents reported prescribing once-weekly K 70 mg/m2 (K70-QW) 43% of the time when using doublets, 31% of the time with triplets and 10% of the time with quadruplets. For once-weekly K 56 mg/m2 (K56-QW), corresponding proportions were 28% with doublets, 45% with triplets and 45% with quadruplets. Twice-weekly K 56 mg/m2 (K56-BIW) or twice-weekly K ≤36 mg/m2 were each never used by more than 10% of physicians. No individual dosing schedule met our 70% threshold for consensus; however, QW administration (pooling K56-QW and K70-QW) surpassed this threshold for doublets (71%) and triplets (75%). The corresponding proportion for quadruplets (56%) did not, in part because 20% of respondents (22% of LMIC respondents) reported lacking SOC access to K-containing quadruplets. Among US-based physicians (n = 69), however, this threshold was met with 71% of respondents using K56-QW for quadruplets (Table S4). Response distributions with regard to preferred K target doses were comparable in terms of practice setting and MM volume (Table S4). Questions about dosing considerations (Table S5) demonstrated broad consensus that low left ventricular ejection fraction influenced physician decision-making regarding the choice of K, even in the absence of cardiac symptoms. In contrast, no disease-related or therapy-related factors reached our threshold for consensus among all respondents. With K+IMiD regimens, preferred VTE prophylaxis strategies were aspirin 81 mg daily for 56%, direct anticoagulants (DOAC) for 23%, aspirin ≥162 mg daily for 10% and low-molecular-weight heparin (LMWH) for 7%. Routine cardiac testing practices before carfilzomib initiation varied widely (Table S6). While 15% (n = 23) always ordered four tests (electrocardiogram, echocardiogram, serum troponin and B-natriuretic peptide) routinely before prescribing carfilzomib for any patient, 18% (n = 27) never routinely ordered any of those tests. Optional comments were provided by 30 physicians and generally fell into four themes (Table S7). First, some physicians periodically ordered other workup during K treatment: for example, lactate dehydrogenase to screen for thrombotic microangiopathies. Second, some physicians modulated VTE prophylaxis or routine intravenous (IV) fluid usage based on individual clinical circumstances. Third, some physicians modulated target K doses based on specific partner drugs: for example, K70-QW with a monoclonal antibody but K56-QW with an IMiD. Fourth, many physicians described barriers to SOC K access, particularly in NDMM and/or as part of a quadruplet. Two LMIC-based physicians reported flat-dosing K (e.g. 30–60 mg depending on patient weight) to reduce drug wastage and financial costs. In summary, our global survey of over 150 haematologists/oncologists from 29 countries including 12 LMICs reflected the same heterogeneity of K dosing as seen in trials. Over 40% of respondents preferred K70-QW for doublets, K56-QW for triplets and K56-QW for quadruplets; however, no individual dosing schedule met our 70% threshold for consensus across all respondents. The general choice of once-weekly K administration did meet this threshold globally as well as within key subgroups (e.g. for physicians with high-volume practices). This level of consensus among physicians bolsters recent real-world evidence suggesting comparable outcomes with QW and BIW carfilzomib, with rising adoption of K56-KW over the last decade in the United States.8 Given the added time toxicity of BIW K administration and the increasing implementation of K56-QW in trials for both NDMM and RRMM,4, 9-11 we suspect that K56-QW will gradually emerge as a dominant dosing schedule. However, as our data highlight, global levels of consensus currently remain modest. Furthermore, access to carfilzomib-containing quadruplets remains a challenge for many physicians due to lack of regulatory approvals and/or reimbursement frameworks in their countries for such regimens. Decision-making must thus be personalized to each patient's unique situation, both clinically and logistically. In terms of supportive care and monitoring, our study demonstrated wide variability in physician practices. While we did not specifically inquire about pre- and post-carfilzomib IV hydration, some physicians added in their comments that they generally stop such hydration after the first cycle to avoid volume overload. The fact that over half of physicians used aspirin prophylaxis with K+IMiD regimens was notable given the higher breakthrough VTE risk with this approach.12, 13 Emerging retrospective data suggest that DOAC prophylaxis can mitigate this thrombotic risk with K+IMiD approaches.13 The ongoing Phase III MIDAS trial of carfilzomib/lenalidomide/dexamethasone (KRd) plus isatuximab mandates either LMWH or DOAC prophylaxis with this risk in mind,10 a practice that we endorse for any K+IMiD regimen. However, we are unable to identify whether VTE risk stratification models or DOAC-related financial constraints may have factored into how our respondents answered this question. Our study has important limitations, including selection bias from our online survey of English-speaking physicians. We endeavoured to reach as many MM-treating physicians as possible, including survey links at an international MM meeting (Table S2); however, our results still are unlikely to have captured the full breadth of MM treatment patterns around the globe. Levels of consensus regarding carfilzomib were generally much lower than with a similar physician survey regarding bortezomib. In a previous survey-based study, 95% of physicians had endorsed QW bortezomib for SOC practice despite the persistence of BIW bortezomib in trials.14 This difference between bortezomib and carfilzomib may reflect the heterogeneity of specific trial-studied K doses across QW and BIW schedules. Alternatively, given that carfilzomib is primarily used in RRMM, physician decision-making may reflect patient preferences wherein increased toxicities are sometimes considered acceptable if efficacy is perceived to be superior.15 As a final limitation, our indirect evidence in favour of K56-QW must be tempered by the recently published A.R.R.O.W.2 trial.3 This trial technically did not demonstrate non-inferiority with K56-QW versus K27-BIW (twice-weekly 27 mg/m2) within KRd in terms of the study's primary end-point of overall response rates (82.5% vs. 86.3%). However, the authors concluded that the clinical efficacy of K56-QW in their trial was virtually identical to K27-BIW by every metric; for example, 12-month progression-free survival estimates were 80.7% vs. 79.7% while prespecified restricted mean survival time analyses showed a PFS difference of only 3 days between arms.3 The A.R.R.O.W.2 authors overall concluded that KRd using K56-QW was an effective and patient-friendly regimen for RRMM, a statement with which we agree. In conclusion, our global analysis of physician preferences supports once-weekly K as an established schedule for use in SOC practice and clinical trials. K56-QW is the most commonly used SOC regimen for triplets and quadruplets. However, supportive care considerations such as VTE prophylaxis with K+IMiD regimens warrant further investigation and standardization. Improving access to K around the world, particularly in NDMM and within quadruplet regimens, is an important unmet need for the field. R.B., S.V.R. and G.K. conceived the research question. R.B., S.D. and G.K. contributed to survey development and analysis. All authors contributed to survey operationalization and provided critical feedback on the manuscript. All authors approved the final manuscript. The authors wish to acknowledge the physicians who completed the survey. The use of REDCap was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1 TR002319. The authors have nothing to report. R.B. reports consulting: Abbvie, Adaptive Biotech, Arcellx, BMS, Caribou Biosciences, Genentech, Gilead/Kite, GSK, Janssen, Karyopharm, Legend Biotech, Pfizer, Poseida Therapeutics, Sanofi, SparkCures; Research: Abbvie, BMS, Gilead/Kite, Janssen, Karyopharm, Novartis, Pack Health, Prothena, Sanofi. G.M. reports honoraria: Pfizer, Janssen and research funding: Antengene. A.J.C. reports consulting: Abbvie, Adaptive, BMS, HopeAI, Janssen, Sebia, Sanofi; Research: Abbvie, Adaptive Biotechnologies, Caelum, Harpoon, Nektar, BMS, Janssen, Sanofi, OpnaBio, IgM Biosciences, Regeneron. L.D.A. reports consulting: Janssen, Celgene, BMS, Amgen, GSK, AbbVie, Beigene, Cellectar, Sanofi, Karyopharm, Pfizer, Prothena. Research: BMS, Celgene, GSK, Janssen, Abbvie. G.K. reports consulting: BMS, Prothena, Sanofi, Kite Pharma, Janssen, and Arcellx. The remaining authors have no disclosures. This study was reviewed and declared exempt by the University of Washington Institutional Review Board. Data are available from the corresponding author via reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.