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Autologous hematopoietic stem cell transplant (autoHCT) is a mainstay of treatment for multiple myeloma and non-Hodgkin lymphoma but is underutilized in older adults. We investigated the association of vulnerabilities identified by a geriatric assessment (GA)-guided multidisciplinary clinic (MDC) on the receipt of autoHCT and evaluated its ability to predict outcomes in older autoHCT candidates. Patients 50+ years received GA-informed optimization recommendations: 'decline' if unlikely to realize benefits of autoHCT, 'defer' if optimization necessary before autoHCT, and 'proceed' if autoHCT could proceed without delay. We compared characteristics and outcomes of autoHCT recipients (n = 62) to non-autoHCT patients (n = 29) and evaluated GA deficits on outcomes. 91 patients were evaluated; the MDC recommendation was 'decline' for 5 (6%), 'defer' for 25 (27%), and 'proceed' for 61 (67%). AutoHCT recipients had fewer GA-rated impairments relative to non-autoHCT patients, as did patients with a 'proceed' recommendation relative to 'defer'. Among autoHCT recipients, 1-year and 3-year non-relapse morality (NRM) was 0% and 5%, and there was no difference in length of hospitalization, readmission rate, or mortality after transplant by MDC recommendation. Frail grip strength and poor performance status were associated with inferior post-autoHCT progression-free survival and overall survival. Patients pursuing autoHCT after MDC-directed optimization achieved excellent outcomes, including patients deferred but ultimately receiving autoHCT. GA-identified functional deficits, especially frail grip strength, may improve risk stratification in older autoHCT candidates. Employing a GA earlier in the disease trajectory to inform early referral to an MDC may increase autoHCT safety and utilization in older patients. [ABSTRACT FROM AUTHOR]

Abstract: Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to its target. In July 2012, carfilzomib received accelerated approval in the United States for the treatment of relapsed and refractory multiple myeloma. Based on emerging preclinical data and clinical results, the total dose, infusion time, and administration schedule of carfilzomib have evolved during phase I and phase II clinical studies, with the aim of optimizing the risk-benefit profile of the agent. Based on in vitro and in vivo findings and encouraging phase I tolerability data, a consecutive-day, twice-weekly dosing schedule was implemented early in the development program. Other phase II studies have led to further refinements in the dosing schedule of carfilzomib, resulting in the current approved schedule for carfilzomib to be administered intravenously over 2–10min on 2 consecutive days each week for 3weeks of a 28-day cycle. Prolonged infusion over 30min has also been assessed in clinical studies to enable the use of higher carfilzomib doses with the aim of improving drug tolerability and efficacy. These data collectively informed the dosing and scheduling schemas for carfilzomib in ongoing trials, including phase I and II studies of combination regimens, and the randomized phase III trials ASPIRE, FOCUS, ENDEAVOR, and CLARION. Additional studies are underway to examine alternative dosing schedules (e.g., once-weekly dosing [CHAMPION-1]). [Copyright &y& Elsevier]

High risk multiple myeloma (HRMM) continues to portend worse outcomes despite the many advances in anti-myeloma therapeutics. The optimal approach to treatment is not clearly defined on account of the variable definitions of HRMM and the paucity of studies dedicated to the treatment of HRMM. In this review, we use a case-based approach to review the definitions of HRMM, and evaluate the evidence for induction, stem cell transplantation, and post-transplant therapy approaches for HRMM. • Definitions of high risk multiple myeloma (HRMM) are varied and overlapping. • HRMM requires extended multi-drug therapy for durable responses. • At least one autologous stem cell transplant should be pursued in HRMM. • HRMM should be treated with the intent to achieve (sustained) MRD-negativity. [ABSTRACT FROM AUTHOR]

Background: Despite recent advances in therapeutic options, there remains an unmet need for treating patients with relapsed or refractory multiple myeloma, especially in those previously exposed or refractory to lenalidomide. This updated efficacy and safety analysis from the phase 3 CANDOR study compared carfilzomib, daratumumab, and dexamethasone (KdD) with carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma.Methods: In this updated analysis of the randomised, multicentre, open-label, phase 3 CANDOR study, patients (aged ≥18 years) with relapsed or refractory multiple myeloma, at least a partial response to between one and three previous therapies, and Eastern Cooperative Oncology Group performance status of 0-2, were recruited from 102 medical centres globally and randomly assigned (2:1) by interactive voice or web response software to receive KdD or Kd. Participants were stratified by disease stage, previous proteasome inhibitor or anti-CD38 antibody exposure, and number of previous therapies. All patients received intravenous infusions of carfilzomib twice per week at 56 mg/m2 (20 mg/m2 on days 1 and 2 during cycle 1) on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients >75 years old). This analysis was a preplanned interim analysis for overall survival; however, at the time of data cutoff, overall survival data were not mature. The primary endpoint was progression-free survival. Here, we provide updated progression-free survival data, assessed centrally by Onyx Response Computer Algorithm in the intention-to-treat population, with 11 months additional follow-up. Adverse events were assessed in the safety population, which included all participants who received at least one dose of trial treatment. CANDOR is registered with ClinicalTrials.gov, NCT03158688, and is active but not recruiting.Findings: Between June 13, 2017, and June 25, 2018, 466 patients were enrolled, of whom 312 received KdD and 154 received Kd. At data cutoff (June 15, 2020), median follow-up was 27·8 months (IQR 25·6-29·5) for KdD and 27·0 months (13·2-28·6) for Kd. Median progression-free survival was 28·6 months (95% CI 22·7-not estimable [NE]) in the KdD group and 15·2 months (11·1-19·9) in the Kd group (hazard ratio 0·59 [95% CI 0·45-0·78], log-rank p<0·0001). Treatment-emergent adverse events in the safety population were consistent with the primary analysis. Grade 3 or worse treatment-emergent adverse events occurred in 268 (87%) patients in the KdD group and 116 (76%) in the Kd group; most commonly thrombocytopenia (76 [25%] vs 25 [16%], respectively), hypertension (65 [21%] vs 23 [15%]), pneumonia (54 [18%] vs 14 [9%]), and anaemia (53 [17%] vs 23 [15%]). Serious adverse events occurred in 194 (63%) patients with KdD and 76 (50%) with Kd. Adverse events leading to death occurred in 27 (9%) patients in the KdD group and seven (5%) in the Kd group; most commonly septic shock (five [2%] vs one (1%]) and pneumonia (four [1%] vs none). No new treatment-related deaths have occurred since the primary analysis.Interpretation: A clear, maintained progression-free survival benefit of KdD over Kd with longer follow-up was confirmed, making KdD an emerging standard-of-care for patients with relapsed or refractory multiple myeloma.Funding: Amgen and Janssen. [ABSTRACT FROM AUTHOR]

Summary: Background: Multiple myeloma is the second most prevalent haematological malignancy and is incurable. Our aim was to assess the response and safety of the combination of temsirolimus (an mTOR inhibitor) and bortezomib in patients with relapsed or refractory multiple myeloma. Methods: We did an open-label, dose-escalation study in three centres in the USA. Patients were enrolled from June, 2007, to December, 2009. Eligible patients were aged 18 years or older with relapsed or relapsed and refractory multiple myeloma after one or more treatment (including lenalidomide, bortezomib, or thalidomide), with an Eastern Cooperative Oncology Group performance status of 0–2. Patients were assigned a dose level in the order of their entry into the study. Phase 1 was to assess the safety and establish the maximum tolerated dose (MTD) of the combination and phase 2 was to assess overall response rate at the MTD. Intravenous temsirolimus was given at 15 or 25 mg and intravenous bortezomib at 1·3 or 1·6 mg/m2 once a week, with dose escalation until dose-limiting adverse events were recorded in two of the three people in the dose cohort. Use of steroids were not permitted. The primary endpoint was the proportion of patients with a partial response or better. Analyses were done on an intention-to-treat basis, with all patients who had been enrolled included. The study is registered with ClinicalTrials.gov, number NCT00483262. Findings: 20 patients were enrolled into the phase 1 study and 43 into phase 2. All patients were heavily pretreated (median five lines in the phase 1 cohort, and four lines in the phase 2 cohort). The MTD was determined to be 1·6 mg/m2 bortezomib on days 1, 8, 15, and 22 in combination with 25 mg temsirolimus on days 1, 8, 15, 22, and 29, for a cycle of 35 days. In the phase 2 study, the proportion of patients with a partial response or better was 33% (14 of 43; 90% CI 21–47). Long-term follow-up of patients is ongoing. There were three deaths during treatment in the phase 1 and 2 studies: one patient died of septic shock in the phase 1 study; one patient died with H1N1 influenza infection and one died with cardiac amyloid and ventricular arrhythmia unrelated to treatment in the phase 2 study. In the phase 1 study, the most common treatment-related grade 3–4 adverse events were thrombocytopenia (13 patients), lymphopenia (ten), neutropenia (nine), leucopenia (seven), and anaemia (five). In the phase 2 study, the most common treatment-related grade 3–4 adverse events were thrombocytopenia (25 patients), lymphopenia (24), neutropenia (17), leucopenia (ten), anaemia (seven), and diarrhoea (five). Four patients in the phase 1 study had sensory peripheral neuropathy (grade 2 or less); in the phase 2 study, 11 had sensory peripheral neuropathy (all grade 2 or less) and seven motor peripheral neuropathy (one grade 3, six grade 2 or less). Interpretation: mTOR inhibitors could have a role in combination with weekly bortezomib for the treatment of patients with relapsed and refractory multiple myeloma without the addition of steroids. Funding: Millennium Inc, Pfizer Inc, Multiple Myeloma Research Foundation, and the Leukemia and Lymphoma Society. [Copyright &y& Elsevier]

Introduction High dose melphalan with autologous stem cell transplantation (ASCT) is a therapy mainstay in multiple myeloma (MM). However, the median PFS after ASCT is under 5 years even with contemporary agents. This may be due to immune dysfunction after ASCT. Regulatory T cells (Tregs, CD4+CD25+FoxP3+) reconstitute rapidly after ASCT, can inhibit antitumor immune responses, and are a target for non-cross-resistant therapy in the MRD-positive state. Methods We conducted a randomized pilot study to evaluate 2 methods of Treg depletion in MM patients undergoing ASCT. No Treg depletion was performed in the control ASCT arm. An anti-CD25 mAb (basiliximab 20 mg IV) was given day +1 post-ASCT in the in vivo Treg depletion (IVTRD) arm. In the ex vivo Treg depletion (EVTRD) arm, CD4+CD25+ Tregs were depleted from ASC grafts with anti-CD25 microbeads and CliniMACS device (Miltenyi). Primary endpoints were: 1) evaluate efficiency of Treg depletion, 2) measure kinetics of Treg depletion and recovery and 3) determine toxicities with the two methods of Treg depletion. Secondary endpoints were engraftment rates and disease response. Results Fifteen patients were enrolled, 5 in each arm. One patient in the IVTRD arm was removed from study due to mobilization failure. ASC were collected following filgrastim/plerixafor. The conditioning regimen consisted of melphalan 200 mg/m2. All patients engrafted; median times to neutrophil/platelet engraftment were similar between arms. 4/5 patients in the EVTRD arm had neutropenic fever (vs 2/5 in control ASCT arm and 2/4 in IVTRD arm). Engraftment syndrome occurred in 1 patient in the EVTRD arm. Conclusion Median ex vivo depletion of CD4+CD25+ Tregs from 5 ASC grafts was 93% (figure 1). Baseline frequencies of peripheral blood (PB) CD4+FoxP3+ Tregs were similar between all arms (p=NS). A reduction in Treg frequency was seen in the EVTRD arm compared to controls at day +14 (p=0.0001) and +21 (p=0.025, figure 2). The IVTRD arm had lower Treg frequency at day +28 compared to controls (p=0.053). These data suggest that in vivo and ex vivo Treg depletion are feasible and result in significant reduction and delay in Treg recovery post-ASCT for MM. These methods could serve as a platform for using post-transplant immunotherapies to improve post-ASCT outcomes. [ABSTRACT FROM AUTHOR]

AutoHCT recipients age 70+ who attended a GA-guided MDC had favorable outcomes with 0% 1-yr non-relapse mortality (NRM). We now examine vulnerabilities and outcomes in all older autoHCT candidates undergoing MDC, including HCT utilization rates. An HCT MD, advanced practice provider, dietician, PT/OT, social worker, ID MD, and geriatric MD comprised the MDC. All pts received GA-informed optimization. Pts were classified by MDC recommendation: 'Decline' if unlikely to realize benefits of HCT, 'Defer' if significant optimization necessary before HCT, and 'Proceed' if autoHCT could proceed without delay. We compared autoHCT recipients (AR, n=62) to non-autoHCT recipients (non-AR, n=29). Differences by 'Defer' (n=25) vs 'Proceed' (n=61) included more impairments (median HCT-CI 3 vs 2, p = 0.01; more frail 4-meter walk times, 48% v 14%, p = 0.001) and more lymphoma (52% vs 30%, p = 0.01). AutoHCT occurred in 49/61 (80%) 'Proceed', 13/25 (52%) 'Defer', and 0/5 'Decline'. AutoHCT recipients (AR) vs non-AR did not differ by age but had fewer impairments as shown in table 1. AR vs non-AR was enriched for plasma cell dyscrasia (PCD, 77% vs 48%, p = 0.008). AR had longer OS compared to non-AR (HR 0.26, 95% CI 0.11-0.57, p = 0.0012). No AR pts experienced NRM. Within AR, MDC 'Defer' pts had a longer time from MDC to HCT compared to 'Proceed' pts (median 41 vs 20 days, p = 0.001). Although 'Defer' AR pts at DC had more frail 4-meter walk times (38% vs 10%, p = 0.03) and worse Mental Health Index-5 (p = 0.03), length of hospitalization, readmission rate, skilled nursing facility admission, and mortality did not differ relative to the 'Proceed' AR group (see figure). 1-yr OS for 'Defer' AR (n=13) vs 'Defer' Non-AR (n=12) was 92% vs 60% (p = 0.07); 3-yr OS 55% vs 48% (p = 0.8). A GA guided MDC deferred around 27% of older autoHCT candidates likely due to significant impairments, and half went on to receive HCT. Pts pursuing autoHCT after MDC achieved excellent outcomes, even among those initially deferred. Employing GA earlier in the disease trajectory to inform early referral to a GA-guided MDC should be tested to increase utilization and improve outcomes in older autoHCT candidates. [ABSTRACT FROM AUTHOR]