Banerjee, Rahul

Background: 24-hour urine (24HRU) assessments are a key component of International Myeloma Working Group (IMWG) response criteria for multiple myeloma (MM) and are requested longitudinally in clinical trials even if not routinely used in real-world practice. Several analyses have suggested a limited role for 24HRU if serum immunofixation or free light chain (LC) testing is abnormal (Dejoie Blood 2016, Lahuerta Blood 2023). Adopting urine-free response criteria (with 24HRU removal from every level of IMWG response) may change responses in <5% of patients (Natsuhara et al, Leuk Lymph 2023) but not have been studied in terms of progression-free survival (PFS) in a larger population. Methods: This was a secondary analysis of data from the Phase 3 BMT CTN 0702 (STaMINA) trial (Stadtmauer et al, JCO 2019) studying post-autologous stem cell transplantation (ASCT) strategies. Only patients evaluable for Day +56 response following ASCT were included, and patients with progressive disease (PD, n=8) at this timepoint were excluded. Post-ASCT responses relative to diagnosis were calculated by two sets of criteria. First, traditional responses were calculated per IMWG criteria (Kumar et al, Lancet Onc 2016) as stable disease (SD), partial response (PR), very good PR (VGPR), or complete response (CR, including stringent CR). Second, urine-free response assessments were calculated as follows: negative 24HRU immunofixation no longer required for CR, 24HRU M-protein < 100 milligrams (mg) per day no longer required for VGPR, and no 24HRU M-protein thresholds (e.g., < 200 mg per day or > 90% reduction) required for PR. PFS was estimated (using PD by traditional IMWG criteria or death as events) using proportional hazard models. Results: Of 636 evaluable patients (84% of all BMT CTN 0702 participants), LC-only disease was noted in 18.9% (n=120). Pre-enrollment 24HRU testing at diagnosis was done in 28.9% of patients (n=184). IMWG responses were as follows: CR, 29.4% (n=187) traditional vs 29.7% (n=189) urine-free; VGPR, 37.0% (n=235) traditional vs 36.6% (n=233) urine-free; PR, 30.7% (n=195) for both; SD, 3.0% (n=19) for both. A total of 4 responses (0.6%) changed with urine-free criteria. Three patients were ‘upgraded’ (VGPR to CR, n=2, PR to VGPR, n=1) because 24HRU requirements for CR/VGPR were no longer required. One patient without a measurable serum paraprotein was ‘downgraded’ from a traditional VGPR (with negative 24HRU immunofixation) to a urine-free PR based on LC-only criteria. Among the subset of 184 patients with 24HRU electrophoresis results at diagnosis, there were no differences between traditional and urine-free IMWG responses. Median PFS and 95% confidence intervals (CI) were the same at each depth of both traditional and urine-free criteria: 63.0 months (50.8 - 71.4 months) for CR, 49.6 months (42.6 - 55.1 months) for VGPR, 44.9 months (37.2-54.8 months) for PR, and 34.4 months (14.0-51.5 months) for SD. Urine-free IMWG criteria were highly prognostic for PFS (p = 0.006, 95% CI 1.05-1.36). The achievement of urine-free CR vs urine-free ≤CR was also prognostic (p = 0.005, 95% CI 0.54 - 0.89). Urine-free VGPR vs urine-free ≤VGPR was of borderline significance (p = 0.102, 95% CI 0.66 - 1.04), with median PFS 53.8 months (48.0 - 57.6 months) vs 44.6 months (36.3 - 54.7 months) respectively. Discussion: In this secondary analysis of a Phase 3 trial, omitting 24HRU assessments from IMWG criteria changed <1% of responses and had no impact on PFS prediction at any response depth. 24HRU assessments had been performed for less than a third of patients as standard of care prior to study entry, underscoring its infrequent use outside of trials. Urine-free IMWG assessments would reduce time toxicity and discomfort for patients, particularly for those with limited dexterity. If implemented in trials, they would also simplify study logistics and lower operational costs. Outside of situations such as AL amyloidosis where 24HRU assessments remain critical or for patients with urine as their only measurable MM biomarker, our results support the removal of 24HRU assessments from future iterations of IMWG response criteria. Funding: Grants #U10HL069294 and #U24HL138660 to the BMT CTN from the NHLBI and the NCI; contributions by Celgene Corporation and Millennium Pharmaceuticals, Inc.; funding by The Alliance for Clinical Trials in Oncology, the ECOG-ACRIN Cancer Research Group and SWOG.

Abstract Despite the widespread use of carfilzomib (K) in relapsed/refractory multiple myeloma (RRMM), there is no consensus on optimal K dose in milligrams per square meter (mg/m2) or dosing schedule. We assessed three modern K prescribing patterns in RRMM using a large United States electronic health record-derived database. Our final cohort (n = 486) included 136 patients (28.0%) who received K 56 mg/m2 once weekly (K56-1x), 86 (17.7%) who received 56 mg/m2 twice weekly (K56-2x), and 264 (54.3%) who received 70 mg/m2 once weekly (K70-1x). Between 2016 and 2023, once-weekly dosing became more common: K70-1x proportions changed from 21.1% in 2016 to 50.6% in 2023, K56-1x from 15.8% to 37.0%, and K56-2x from 63.2% to 12.3%. Median real-world progression-free survival was 13.0 months [95% confidence interval (CI) 11.2-20.7] for K56-1x, 13.2 months (95% CI 9.0-28.1 months) for K56-2x, and 10.9 months (95% CI 9.9-15.3 months) for K70-1x; these differences were not statistically significant (log-rank p = 0.46). The prevalence of heart failure was comparable (<5% in all cohorts). In summary, our findings do not support improved outcomes with twice-weekly carfilzomib in RRMM. K56-1x may provide the best balance of efficacy, safety, and avoidance of time toxicity from frequent infusions.

Abstract Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM), despite common toxicities, including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 mg once weekly was associated with lower mortality than higher doses. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM has not been fully characterized. We conducted a secondary pooled analysis of the SWOG 0777 and SWOG 1211 studies of NDMM, which used lenalidomide and dexamethasone (Rd) alone, with or without bortezomib, and with or without elotuzumab. The planned dexamethasone intensity was 40 to 60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for grade 3+ toxicities per both study protocols). Of the 541 evaluated patients, the LD-DEX group comprised 373 patients (69%). There were no differences in PFS or OS between the FD-DEX and LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in the multivariate models were treatment arm, age ≥70 years, and thrombocytopenia. FD-DEX did not significantly improve either outcome. Our study suggests that dexamethasone dose reductions are common in multiple myeloma, even within clinical trials. Given the many toxicities and unclear benefits of dexamethasone in the era of modern treatment regimens, dexamethasone dose reduction during NDMM induction warrants further prospective studies. These trials were registered at www.clinicaltrials.gov as #NCT00644228 and NCT01668719.

Summary Chimeric antigen receptor T‐cell (CAR‐T) therapy and bispecific T‐cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR‐T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo‐HCT). Thirty‐three MM patients with prior allo‐HCT received CAR‐T ( n = 24) or BsAb ( n = 9) therapy. CAR‐T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR‐T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR‐T and 78% of BsAb recipients, while immune effector cell‐associated neurotoxicity syndrome (ICANS) was observed in three CAR‐T patients. Infections of grade ≥3 were reported in 50% of CAR‐T and 44% of BsAb recipients. No exacerbation of graft‐versus‐host disease occurred except in one BsAb recipient. CAR‐T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo‐HCT.

Introduction: Most induction regimens for multiple myeloma (MM) contain bortezomib. In most clinical trials, bortezomib has been prescribed either intravenously or subcutaneously twice per week in 21-day or 28-day cycles. However, several retrospective single-center studies have shown that once-weekly bortezomib has comparable efficacy and less peripheral neuropathy compared to twice-weekly bortezomib ( Sidana et al, PLoS One 2017; Cook et al, AJH 2021). These findings have also been confirmed by a secondary analysis of data from three prospective Phase 3 randomized studies ( Mateos et al, Haematologica 2014). As such, many clinicians have adopted once-weekly bortezomib regimens in routine care in the past decade. However, the real-world (RW) prevalence and efficacy of once-weekly vs twice-weekly bortezomib regimens in a larger population have not yet been characterized. Methods: This study used US nationwide longitudinal Flatiron Health electronic health record-derived de-identified data. We included patients aged 18-70 years with newly diagnosed MM between 2017-2022 with ≥ 6 months of follow-up and ≥ 2 clinical visits who were treated with a first-line (1L) bortezomib-containing regimen. Patients aged &gt;70 were excluded a priori given the likelihood of altered practice patterns and more frequent comorbidities. Twice-weekly bortezomib was defined as patients for whom the most frequent interval between two doses of 1L bortezomib within a cycle was 3.0-4.9 days, while once-weekly bortezomib was defined as a corresponding interval of 5.0-9.9 days. We used multivariable logistic regression to assess demographic and clinical factors associated with once-weekly vs twice-weekly (reference) bortezomib. RW progression free survival (rwPFS) and RW overall survival (rwOS) from 1L treatment initiation were estimated using the Kaplan-Meier method. Outcomes were compared using Cox proportional hazards model including transplant as a time-varying covariate and adjustment for other demographic and clinical factors. Results: Of 2,522 patients included, 927 (36.8%) received twice-weekly while 1,522 (63.2%) received once-weekly bortezomib. Approximately half of patients (50.3%) were non-Latinx White, 21.7% non-Latinx Black, and 8.0% Latinx. Most patients were treated in the community setting (78.8%). Rates of once-weekly bortezomib administration were 66.2% and 62.1% among patients treated at academic and community practices, respectively. The frequency of weekly bortezomib use increased over time, from 58.0% between 2017-2019 to 68.8% between 2020-2022. In multivariate analysis, ECOG PS ≥ 2 (odds ratio [OR] 1.50; [95% CI 1.14 to 1.99] vs ECOG PS 0), and more recent year of diagnosis (OR 1.14; [95% CI 1.08 to 1.20] per year) were associated with higher odds of receiving once-weekly bortezomib. Conversely, Latinx patients vs non-Latinx White (OR 0.60 [95% CI 0.44 to 0.82]) and patients with ≥ 2 high-risk cytogenetic abnormalities (HRCA) vs 0 HRCA (OR 0.66 [95% CI 0.48 to 0.91]) had lower odds of receiving once-weekly bortezomib administration. No significant associations were found between gender, ISS stage, practice setting, insurance category, or baseline creatinine. There was no statistically significant difference in rwPFS among patients receiving once-weekly (median 37.3 months, 95% CI 33.8 to 42.5) vs twice-weekly bortezomib (median 39.2 months, 95% CI 32.9 to 42.8) (HR 0.87 [95% CI 0.77 to 1.00]) (Figure 1A). Similarly, there was no statistically significant difference in rwOS with median 25.5 months follow-up (Figure 1B). Median rwOS was not reached in either group (hazard ratio 0.89 [95% CI 0.75 to 1.07]). Discussion: We evaluated US bortezomib prescribing patterns for the first time in the modern era using a large nationwide RW-study. Whereas prescribing patterns have shifted towards once-weekly bortezomib over time, over 30% of patients diagnosed in the last three years received twice-weekly bortezomib. Importantly, once-weekly and twice-weekly bortezomib performed comparably with regard to rwPFS and rwOS. While our study did not analyze neuropathy or patient quality of life, once-weekly bortezomib is known to be associated with less neuropathy and less time in clinic. These data further support the conclusion that once-weekly bortezomib should be considered the standard of care for newly diagnosed patients with MM.

Background: Bortezomib (Velcade), a mainstay of treatment regimens for newly diagnosed multiple myeloma (MM), is often dosed twice-weekly in trials (i.e., Days 1, 4, 8, 11 in 21-day cycles). However, several analyses have shown that once-weekly bortezomib performs comparably and is associated with less peripheral neuropathy (Sidana PLoS One 2017, Mateos L&L 2020, Cook AJH 2021). Many centers thus use once-weekly bortezomib in MM induction regimens regardless of transplant eligibility, e.g. modified VRd or Dara-VRd in 28-day cycles with once-weekly subcutaneous (SC) bortezomib 1.3 mg/m 2 (McCaughan BJH 2022). Physician attitudes and perceptions regarding how bortezomib should be dosed, an important step toward establishing a global standard of care in MM, have not been investigated. Methods: We conducted a global online survey of hematologists/oncologists who had treated ≥1 patient with MM in the past 12 months. The survey was distributed via social media platforms as well as targeted emails to MM physicians, IMWG members, and outreach through professional societies. The survey comprised 14 questions including usage of once- vs twice-weekly bortezomib, usage of SC vs IV bortezomib, attitudinal questions about potential benefits/disadvantages of each approach, and perceived barriers to using once-weekly bortezomib. Statistics were analyzed descriptively with Wilcoxon rank-sum and signed-rank tests. Results: Of 317 webpage visits, 205 responses were recorded (65% completion rate).Most respondents were from US academic practices (25%, n=52), US community practices (22%, n=46), or Australian academic practices (6%, n=13); however, responses were recorded from 38 countries including 22 low- or middle-income countries (LMICs: 29% of responses, n=60).Over a third of respondents (37%, n=76) practiced in community settings, and most respondents (58%, n=119) reported &gt;20 patients with MM under their personal care . 93 respondents (45%) had previously helped write institutional or societal guidelines, including 21 IMWG members.Respondents reported using once-weekly bortezomib most of the time (median 95% of patients, IQR 80%-100%) and almost always used SC bortezomib (IQR 100%-100%).There were no significant differences in bortezomib frequency or route based on academic vs community practice, experience with MM, US vs non-US, or LMIC vs non-LMIC. Large majorities of respondents (Table 1) felt that once-weekly bortezomib is preferred by patients (94%), associated with comparable durations of response (79%), and associated with less peripheral neuropathy (89%). Conversely, 61% of respondents felt that twice-weekly bortezomib in superior in newly diagnosed MM with acute cast nephropathy.Physician estimates of the incidence of any-grade peripheral neuropathy were significantly lower with once-weekly bortezomib (median 30%, IQR 20-43%) vs twice-weekly bortezomib (median 50%, IQR 40-73%). Similarly, Grade 3+ neuropathy estimates were significantly lower with once-weekly (median 10%, IQR 5-17%) vs twice-weekly bortezomib (median 25%, IQR 15-38%), with p&lt;0.001 in all cases . The most common cited barriers to ordering once-weekly bortezomib (Table 2) were perceived lack of prospective data (31%), difficulty modifying treatment orders (24%), and resistance from pharmacist colleagues who prefer adhering to trial-studied regimens (13%). Discussion: In our survey of over 200 MM-treating physicians from 38 countries (including 22 LMICs), once-weekly subcutaneous bortezomib was overwhelmingly preferred regardless of practice setting or country. The only exception was acute cast nephropathy, where twice-weekly bortezomib may expedite renal recovery and is reasonable to use initially. Neuropathy estimates were similar to published incidences (32% with once-weekly bortezomib vs 47% with twice-weekly bortezomib) from prospective data collected from the ALCYONE, GIMEMA-QW, and VISTA randomized trials (Mateos L&L 2020). Our findings highlight the widening mismatch between what physicians routinely prescribe to patients versus what registrational trials typically require. Given that &gt;90% of physicians personally prefer once-weekly bortezomib and that &gt;90% report that their patients feel similarly, once-weekly bortezomib appears to have become the global standard of care. This consensus should be taken into consideration for clinical trial design in the future.

Background: Dex is a key component of induction regimens for NDMM despite common toxicities including insomnia and anxiety. The E4A03 randomized trial (Rajkumar, Lancet Oncol 2010) demonstrated that dex dosed at 40 mg weekly outperformed higher-intensity dex and established this regimen as the standard of care for NDMM. In standard practice as well as clinical trials, however, dex doses are often reduced to 20 mg weekly or lower (if not stopped entirely) among older patients or among patients experiencing toxicities. As a first step toward establishing the equipoise of planned dex dose reductions in NDMM, we investigated outcomes with patients from two previous SWOG trials to understand the impact of dex dose reductions on post-induction outcomes. Methods: This was a secondary analysis of data from two completed NDMM studies, S0777 (comparing VRd vs Rd) and S1211 (comparing Elo-VRd vs VRd). For this secondary analysis, we analyzed the subset of patients who completed all eight 3-week cycles of induction (or six 4-week cycles in the S0777 Rd arm). As shown in Figure 1A, we defined DEX fullDose as patients for whom the starting dex dose (either 40 mg once per week or 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of 21-day cycles) did not change during induction. In contrast, DEX lowered was defined as patients for whom the end-of-induction dex dose and/or frequency were lower than their starting values. As an exploratory analysis, we also compared PFS and OS between the DEX fullDose (no changes to dex strength during induction) and DEX veryLow (dex dosing reduced ≥50% during induction) subgroups. All analyses were landmarked from the end of induction, defined as 24 weeks from registration, to account for the time-dependent nature of dex treatment received. Survival curves were based on the Kaplan-Meier method and comparisons were made using the log-rank test. Results: Of 541 evaluable patients ( n = 441 from S0777, n = 100 from S1211), dex was reduced during induction in 76% ( n = 410). Compared to DEX fullDose patients, DEX lowered patients were more likely to be anemic (37% vs 26%, p = 0.02) but had similar distributions of age ≥70 (24% of DEX lowered vs 26% of DEX fullDose), Performance Status &gt; 1 (15% vs 12%), ISS stage 3 disease (33% vs 27%), ≥ 60% bone marrow plasma cell burden (37% vs 31%), M-spike &gt; 3 g/dL (48% vs 48%) platelets &lt; 150,000 cells/mm 3 (18% vs 14%), baseline LDH ≥ 190 U/L (36% vs 41%), and baseline CRP ≥ 8 mg/L (27% vs 30%). PFS (Figure 1B) was comparable between DEX lowered (median 36 months, 95% CI 29 to 39 months) and DEX fullDose (median 33 months, 95% CI 24 to 48 months) with p = 0.90. Similarly, OS (Figure 1C) was comparable between DEX lowered [median 77 months, 95% CI 68 months to not reached (NR)] and DEX fullDose (median 92 months, 95% CI 65 months to NR) with p = 0.93. In the DEX veryLow subgroup with ≥50% reduction in dex dosing during induction, median PFS was 39 months (95% CI 34 to 50 months) and median OS was NR (95% CI NR to NR). As shown in Figure 1D and Figure 1E, PFS and OS were comparable between these patients and DEX fullDose patients. Discussion: To our knowledge, this is the first analysis of dex dosing strength in NDMM since E4A03. In two separate randomized trials, over half of patients required dex reductions below a starting dose of ~40 mg weekly. Dex dose reductions during induction had no impact on post-induction PFS and OS, even in the subset of patients who required significant dose reductions. Limitations of our post hoc analysis include heterogeneity between dex dosing schedules and lack of cytogenetic data for all patients. We could not discern specifically why dex was lowered, and it is possible that dex might have been lowered disproportionately commonly in patients who had achieved early responses and thus independently did better. Regardless, these results strongly suggest that maintaining dex 40 mg weekly for the entirety of NDMM induction may be unnecessary in the modern era. Cooperative efforts to study a planned dex de-escalation protocol (i.e., once no longer needed for symptom management or as a pre-medication) alongside patient-reported outcome assessments of symptom burden are being planned. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180821, U10CA180820; and in part by Millennium Pharmaceuticals, Inc. (now part of Takeda Pharmaceutical Company), and by Celgene.

Abstract The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P &lt; .001 and HR 5.01, P &lt; .001, respectively) and OS (HR 3.85, P &lt; .001 and HR 8.13, P &lt; .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post–auto-HSCT.