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Nadav Sarid,1,2 Shir Mann,1 Yair Herishanu,1,2 Chava Perry,1,2 Yael C Cohen,1,2 Inna Passage,1 Miriam Neaman,1,2 Noam Benyamini,1,2 Maayan Jean,1 Irit Avivi1,2 1Departments of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelCorrespondence: Irit AviviDepartment of Hematology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv, 6423906, IsraelTel +972-3-6973576Fax +972-3-6974452Email iritavi@tlvmc.gov.ilObjective: Hemato-oncology patients are at high risk for morbidity and mortality from coronavirus disease (COVID-19). The resultant heightened anxiety among these patients may negatively affect adherence to therapy and treatment-related outcome. We aimed to assess whether the adoption of precautionary measures provided by the medical team led to a reduction in COVID-19-related anxiety and, consequently, to successful execution of treatment plans.Methods: All adult hemato-oncology patients actively treated or being followed-up at the outpatient service at Tel Aviv Sourasky Medical Center between March 25 and May 3, 2020, were invited to answer a questionnaire that focused on their anxiety and adherence to treatment following new measures to reduce risk of infection during the first COVID-19 outbreak.Results: One hundred and fifty patients (representing 24% of those being approached), average age 67 years, 52% male, and 57% undergoing antineoplastic therapy, responded to the survey. The introduction of precautionary measures resulted in a significant reduction in anxiety level in all patients, irrespective of age, sex, or treatment status. Attendance to scheduled visits in day care and outpatient clinics remained unchanged. Adherence to planned blood and imaging tests were 81% and 73%, respectively, and 93% of the patients were satisfied with their medical care. Thirty-two percent of patients used telemedicine. Satisfaction with telemedicine was highest among non-actively treated patients and those experiencing high anxiety levels.Conclusion: Reorganization of the hemato-oncology unit and provision of information to patients reduced COVID-19-related anxiety and enabled the same delivery of therapy as that prior to the pandemic.Keywords: anxiety, treatment adherence, COVID-19

Background: Talquetamab (anti-G protein-coupled receptor family C group 5 member D) and teclistamab (anti-B-cell maturation antigen) are bispecific antibodies that activate T cells by targeting CD3 and that have been approved for the treatment of triple-class-exposed relapsed or refractory multiple myeloma., Methods: We conducted a phase 1b-2 study of talquetamab plus teclistamab in patients with relapsed or refractory multiple myeloma. In phase 1, we investigated five dose levels in a dose-escalation study. Talquetamab at a dose of 0.8 mg per kilogram of body weight plus teclistamab at a dose of 3.0 mg per kilogram every other week was selected as the recommended phase 2 regimen. The primary objective was to evaluate adverse events and dose-limiting toxic effects., Results: A total of 94 patients received treatment, with the recommended phase 2 regimen used in 44. The median follow-up was 20.3 months. Three patients had dose-limiting toxic effects (including grade 4 thrombocytopenia in 1 patient with the recommended phase 2 regimen). Across all dose levels, the most common adverse events were cytokine release syndrome, neutropenia, taste changes, and nonrash skin events. Grade 3 or 4 adverse events, most commonly hematologic events, occurred in 96% of the patients. Grade 3 or 4 infections occurred in 64% of the patients. With the recommended phase 2 regimen, a response occurred in 80% of the patients (including in 61% of those with extramedullary disease); across all dose levels, a response occurred in 78%. The likelihood of patients continuing in response at 18 months was 86% with the recommended phase 2 regimen (82% among those with extramedullary disease) and 77% across all dose levels., Conclusions: The incidence of grade 3 or 4 infections with talquetamab plus teclistamab was higher than has been observed with either therapy alone. A response was observed in a high percentage of patients across all dose levels, with durable responses with the recommended phase 2 regimen. (Funded by Janssen Research and Development; RedirecTT-1 ClinicalTrials.gov number, NCT04586426.)., (Copyright © 2025 Massachusetts Medical Society.)

Early intervention of smoldering multiple myeloma (SMM) may delay progression to multiple myeloma. Here, we present the final analysis of the phase 2 CENTAURUS study (NCT02316106). In total, 123 patients with intermediate/high-risk SMM were randomized to intravenous daratumumab 16 mg/kg following a Long intense (n = 41), Intermediate (n = 41), or Short intense (n = 41) dosing schedule. At a combined median follow-up of 85.2 months, in the Long intense, Intermediate, and Short intense arms complete response or better rates were 4.9%, 9.8%, and 0%; overall response rates were 58.5%, 53.7%, and 37.5%; progressive disease/death rates were 0.096, 0.102, and 0.109 (P <0.0001 for all arms); and median progression-free survival was not reached, 84.4, and 74.1 months, respectively. Median overall survival was not reached in any arm. Thirty-six patients in the Long intense or Intermediate arms continued daratumumab in an optional extension phase after completing 20 cycles of per protocol treatment. Median (range) duration of study treatment was 44.0 (1.0-91.6), 35.2 (1.9-90.6), and 1.6 (0.1-1.9) months in the Long intense, Intermediate, and Short intense arms, respectively. No new safety signals were observed. With extended follow-up (median, ~7 years), these data highlight the tolerability of daratumumab and support ongoing trials investigating daratumumab as an early intervention for SMM. ClinicalTrials.gov Identifier: NCT02316106., (Copyright © 2024 American Society of Hematology.)

Background: Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved., Methods: In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria., Results: Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified., Conclusions: Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Preclinical studies suggest that combining nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, with pomalidomide/dexamethasone (Pd) with or without elotuzumab, an antisignaling lymphocytic activation molecule F7 monoclonal antibody, may improve multiple myeloma (MM) treatment efficacy., Patients and Methods: The phase 3 CheckMate 602 study (NCT02726581) assessed the efficacy and safety of nivolumab plus pomalidomide/dexamethasone (NPd) and NPd plus elotuzumab (NE-Pd). Eligible patients (aged ≥ 18 years) had measurable MM after ≥ 2 prior lines of therapy, that included an immunomodulatory drug (IMiD) and proteasome inhibitor (PI), each for ≥ 2 consecutive cycles, alone or combined, and were refractory to their last line of therapy. Patients were randomized 3:3:1 to receive NPd, Pd, or NE-Pd. The primary endpoint was progression-free survival (PFS); overall response rate (ORR) was a key secondary endpoint., Results: At a median follow-up of 16.8 months, PFS was similar between treatment arms (Pd, 7.3 months [95% CI, 6.5-8.4]; NPd, 8.4 months [95% CI, 5.8-12.1]; NE-Pd, 6.3 months [95% CI, 2.4-11.1]). ORR was similar in the Pd (55%), NPd (48%), and NE-Pd (42%) arms. Nivolumab-containing arms were associated with a less favorable safety profile versus Pd, including a higher rate of thrombocytopenia (NPd, 25.0%; NE-Pd, 16.7%; Pd, 15.7%), any-grade immune-mediated adverse events (NPd, 13.9%; NE-Pd, 16.7%; Pd, 2.9%), and adverse events leading to discontinuation (NPd, 25.0%; NE-Pd, 33.3%; Pd, 18.6%). No new safety signals were identified., Conclusion: CheckMate 602 did not demonstrate clinical benefit of nivolumab (+/- elotuzumab) plus Pd versus Pd for patients with relapsed/refractory MM (RRMM)., Competing Interests: Disclosure AO: honoraria from and data safety monitoring or advisory boards for Bristol Myers Squibb, GlaxoSmithKline, Janssen, and Sanofi. RH: grants (to institution) from Amgen, Bristol Myers Squibb, Celgene, Janssen, Novartis, and Takeda; consulting for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, Novartis, PharmaMar, and Takeda; honoraria from Amgen, Bristol Myers Squibb, Celgene, Janssen, PharmaMar, and Takeda; travel expenses from Amgen, Celgene, Janssen, and Takeda; and data safety monitoring or advisory boards for Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, and Takeda. I Spicka: consulting fees and honoraria from, and data safety monitoring or advisory boards for Amgen, Bristol Myers Squibb, Celgene, Janssen-Cilag, Novartis, Sanofi, and Takeda; travel expenses from Amgen, Bristol Myers Squibb, Celgene, and Janssen-Cilag. I Sandhu: consulting fees from Amgen, Bristol Myers Squibb/Celgene, Janssen, Kite/Gilead, Pfizer, Sanofi, and Takeda. YCC: grants from Amgen and Takeda; consulting fees from Janssen; honoraria from Amgen, GlaxoSmithKline, and Takeda; travel expenses from Janssen; and data safety monitoring or advisory boards for Janssen. MC: honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Roche, Sanofi, and Takeda. JB: grants (to institution) from 2seventybio, AbbVie, Acetylon, Amgen, Bluebird bio, C4 Therapeutics, CARsgen, Cartesian Therapeutics, Celgene, Celularity, CRISPR Therapeutics, EMD Serono, Fate Therapeutics, Genentech, GlaxoSmithKline, Ichnos Sciences, Incyte, Janssen, Karyopharm, Lilly, Novartis, Poseida, Sanofi, Takeda, Teva, and Zentalis; and consulting fees (to institution) from Bluebird bio, Bristol Myers Squibb, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, Secura Bio, and Takeda. KJ, PD, and YW: employees of Bristol Myers Squibb. MB: employee of, has stock in, and received travel support from Bristol Myers Squibb. RLM-M: employee of and has stock in Bristol Myers Squibb and stock in MacroGenics. DP: employee of and has stock in Bristol Myers Squibb. LJC: grants (to institution) from Amgen, Genentech, Ionis, and Janssen; consulting fees from Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Janssen, and Sanofi; and honoraria from Adaptive Biotechnologies, Janssen, and Sanofi., (Copyright © 2024. Published by Elsevier Inc.)

Background: Data on the outcome of octogenarian multiple myeloma (MM) patients (pts), especially if treated outside clinical studies, are scanty. Aims and Methods : MM pts ≥ 80 years, treated at TASMC with first-line therapy between 2010 and 2023, were reviewed. Characteristics and outcomes were analyzed. Results: A total number of 101 pts, of whom 54 were males with a median age of 84 years (80-98), were included. Among them, 67.4% had a Charlson comorbidity index of ≥5, 37% had ISS-3 (International staging system) and 20% had Revised-ISS-3. In our study, 44.5% received doublets and 50.5% received triplets/quadruplets. A bortezomib-based regimen was applied in 87%, and IMiDs were used in 27.7%. Despite an upfront employment of a low lenalidomide dose, dose reductions were required in 48%. Grade ≥ 3 adverse events (AEs) (mainly infections) were documented in 36.6% of patients, including grade 5 events in 9%, all attributed to infections. The overall response rate was 69%, including 31% ≥ VGPRs (Very good partial response). Sixty-seven percent (67%) received second-line therapy, administered within a median period of 12 months (1-84). Within a median follow-up period of 36 m (1-141), the median overall survival (OS) approached 42 m (range: 1-141); being shorter in pts > 84 years (HR = 1.7, p = 0.03), pts with lung disease (HR = 1.8, p = 0.044) and pts with ISS = 3 and R-ISS = 3 (HR = 1.65, p = 0.0016 and HR = 2.45, p = 0.006, respectively); Conclusions : Octogenarians treated outside clinical studies often have a lower tolerance to treatment. Nevertheless, upfront administration of low doses of anti-MM agents provided a response in the majority of patients, translated into impressive OS. Nevertheless, mortality due to AEs was high, emphasizing the need for new, "octogenarian-oriented" treatment protocols.

Not available.

The clinical significance of an abnormal free light chain (FLC) test, performed due to unspecific complains in the absence of a known plasma cell dyscrasia (PCD) or lymphoproliferative disease (LPD), is not fully elucidated. We investigated the importance of an abnormal FLC ratio (FLC-R) in this setting. Patients registered in the Maccabi Healthcare Services database, tested for FLC during 2007-2023 without previously documented PCD/LPD or increased total protein (TP) level, were reviewed. Demographics, co-morbidities, and laboratory tests were recorded. FLC-R was defined as normal (0.26-1.65) or slightly (slAb 0.1-0.26/1.65-4), moderately (mAbn 0.1-0.05/4-8) and significantly abnormal (sigAb- < 0.05 or > 8). Factors associated with PCD/LPD and overall survival were identified. In total, 8,661 patients, 2,215 (25.6%) with abnormal FLC-R [2,090 (24.1%)-slAb, 65 (0.75%)-mAbn and 60 (0.7%)-sigAb], were analyzed. Almost none had anemia nor acute renal failure. 14% had concomitant increased immunoglobulins. Within a median follow-up of 52 months, 943 were diagnosed with PCD (816-MGUS, 127-MM/Amyloidosis/plasmacytoma) and 48 with LPD. Median time to PCD and LPD were 19 and 28 months. Multivariate analysis found slAb (HR = 1.8, CI95%:1.53-2.12, p < 0.001), mAbn (HR = 6.3, CI95%:4.16-9.53, p < 0.001), and sigAb FLC (HR = 10.4, CI95%:7.0-15.35, p < 0.001), to be associated with PCD/LPD diagnosis. Decreased IgG, increased IgA, and concomitant comorbidities predicted PCD, whereas increased IgM predicted LPD. Older age, male gender, anemia, decreased albumin, increased IgG and concomitant comorbidities, predicted shorter survival. Our large study emphasizes the independent clinical significance of abnormal FLC-R as a predictor of PCD/LPD diagnosis even in patients with normal TP level, promoting early detection of PCD/LPD., (© 2024. The Author(s).)

In hemato-oncological patients, COVID-19 can present as a persistent infection with ongoing symptoms and viral replication over a prolonged period of time. Data are scarce on the preferred treatment options for these patients. We describe our experience with a five-day course of dual anti-viral treatment with remdesivir and nirmatrelvir/ritonavir for hemato-oncological immunocompromised patients with persistent COVID-19. Fifteen patients with a history of lymphoma, CLL, and MM were included. Eight were male, median age was 74. All patients had an immediate clinical and virological response. In 73 % of patients, PCR for SARS-CoV-2 became negative at the end of treatment and the rest had an increase in PCR cycle threshold (CT) values, with a median increase of 6 cycles. After a follow-up of three months, 60 % of patients remained in full clinical and virological remission. None required invasive mechanical ventilation or died. The side effects we observed, neutropenia, lactatemia and elevated transaminases, were mild and almost all transient in nature. We conclude that dual anti-viral treatment appears to be a valid treatment option for persistent COVID-19., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Objectives: To evaluate whether low-dose belantamab mafodotin (B-MAF) dosing results in lower toxicity and better overall outcome., Methods: We retrospectively evaluated nine consecutive patients treated with low-dose (1.9 mg/kg) B-MAF., Results: The median age was 70 years. Most patients were penta-refractory. Ocular toxicity was observed in 77.7%. Adverse events resulting in treatment delays were recorded in 9 out of 124 cycles being given. Overall response rate was 66% (6/9), and all responding patients achieved very good partial response or better. Within a median follow-up of 12 (range 0.5-13.8) months, median progression-free survival and overall survival were 14 (CI95% 6-22) and 20 (95%CI 0-41) months, respectively., Conclusion: Low-dose B-MAF regimen showed high-efficacy and low-toxicity profile., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Treatment options for multiple myeloma (MM) at 1st relapse are expanding. The current study compared common 2nd line regimens administered in a real-world setting. MM patients registered in Maccabi health care services and treated with second line therapy during 2014-2020 were evaluated, analyzing factors affecting time to third line therapy (TT3T). The study included 500 MM patients, previously treated with proteasome inhibitor (PI)-based induction. Median age at second line treatment was 68.5 years (IQR: 61.6-76.4). Most patients received a triplet based induction composed of PI (n = 471, 94.2%), with (n = 71) or without IMID (n = 400), followed by second line treatment composed of lenalidomide-dexamethasone (RD) (n = 225, 45%) or lenalidomide-dexamethasone-daratumumab (RD-Dara (n = 104, 20.8%)). Multivariable analysis confirmed treatment type (RD-Dara vs. IMID) to be associated with a lower risk to progress to third line therapy; (HR = 0.5, 95% CI 0.3-0.86, p = 0.012). Within a median follow-up period of 22.5 months (intraquartile range 11.1-39.4 m), median TT3T was not reached in patients receiving RD-Dara vs. 32.4 months (95% CI 18.0-46.8 m) with IMID, 18 months (95% CI 10.4-25.6 m) with IMID-PI and 12.1 months (95% CI 5.6-18.7 m) with PI-based regimen. In contrast, PI vs. IMID-based therapy and increased body weight were associated with a higher likelihood of progression (HR = 2.56 (95% CI 1.49-4.42); HR = 1.43, (95% CI 0.96-2.14), p = 0.08). To conclude, second line therapy with RD-Dara was associated with a significantly longer TT3T compared with IMID-based regimen, longer than obtained with PI-IMID and PI-based regimens, in patients treated outside clinical studies and previously exposed to bortezomib., Competing Interests: Declarations. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Competing interests: Prof. Gabriel Chodick, Naama Yekutiel, Clara Weil, Prof. Yael C. Cohen, and Dr. Tamir Shragai do not have any conflict of interest. Prof. Irit Avivi was a consultant to abbvie and received research funding. Dr. Moshe Grunspan, Dr. Noa Rivlin, Dr. Neta Frankel, and Dr. Raanan Cohen are employees of AbbVie and own AbbVie stock., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease., Methods: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival., Results: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%)., Conclusions: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.)., (Copyright © 2023 Massachusetts Medical Society.)

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Patient-specific autonomous finite element analyses of femurs, based on clinical computed tomography scans may be used to monitor the progression of bone-related diseases. Some CT scan protocols provide lower resolution (slice thickness of 3 mm) that affects the accuracy. To investigate the impact of low-resolution scans on the CT-based finite element analyses results, identical CT raw data were reconstructed twice to generate a 1 mm ("gold standard") and a 3 mm slice thickness scans., Methods: CT-based finite element analyses of twenty-four femurs (twelve patients) under stance and sideways fall loads were performed based on 1 and 3 mm slice thickness scans. Bone volume, load direction, and strains were extracted at different locations along the femurs and differences were evaluated., Findings: Average differences in bone volume were 1.0 ± 1.5%. The largest average difference in strains in stance position was in the neck region (11.0 ± 13.4%), whereas in other regions these were much smaller. For sidewise fall loading, the average differences were at most 9.2 ± 16.0%., Interpretation: Whole-body low dose CT scans (3 mm-slice thickness) are suboptimal for monitoring strain changes in patient's femurs but may allow longitudinal studies if larger than 5% in all areas and larger than 12% in the upper neck. CT-based finite element analyses with slice thickness of 3 mm may be used in clinical practice for patients with smoldering myeloma to associate changes in strains with progression to active myeloma if above ∼10%., Competing Interests: Declaration of Competing Interest None of the authors have any conflict of interest to declare that could bias the presented work. ZY has financial interest in PerSimiO Ltd., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

B-cell maturation antigen (BCMA)-targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and noncellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10-5. Overall, 20 patients were treated (13 ADC exposed; 7 BsAb exposed; 1 in the ADC group also had prior BsAb exposure). Sixteen (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7 of 20 (35%) patients were MRD negative (7 of 10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% confidence interval [CI]) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9-not estimable) and 9.1 (1.5-not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1-2); 4 had immune effector cell-associated neurotoxicity syndrome (2 had grade 3-4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who had exhausted other therapies. This trial was registered at www.clinicaltrials.gov as NCT04133636., (© 2023 by The American Society of Hematology.)

Belantamab mafodotin, an immuno-conjugate targeting B-cell maturation antigen, showed single-agent activity in phase 1 and 2 studies, and was recently approved for heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. Real-world data and long-term follow-up are scarce. We conducted a multisite retrospective study aimed to assess safety and efficacy of belantamab mafodotin monotherapy administered via the GSK expanded access compassionate care programme. One-hundred and six RRMM patients were treated with belantamab mafodotin between July 2019 and March 2021. The median age was 69.4 years. Patients were heavily pretreated with a median of six (range 2-11) prior therapy lines. Major adverse effects included ocular toxicity (keratopathy 68.4%, grade ≥3: 40.5%; blurred vision 36.8%, grade ≥3: 6.3%), thrombocytopenia (27.4%, grade ≥3: 17.9%) and infections (11.3%, grade ≥3: 7.5%). Median follow-up time was 11.9 [95% confidence interval (CI) 10.0-13.8] months. Overall response rate was 45.5%. Median progression-free survival was 4.7 (95% CI 3.5-5.9) months in the entire cohort and 8.8 (95% CI 6.6-10.9) months among responders. Median overall survival was 14.5 (95% CI 9.5-19.6) months, and not reached for responders. To conclude, in a real-world setting, belantamab mafodotin monotherapy showed efficacy comparable with the prospective clinical trials, with a tolerable toxicity profile., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: AL amyloidosis (AL) treatments are generally based on those employed for multiple myeloma. Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CART)-cell therapy, already approved for multiple myeloma, might be too toxic for patients with AL., Experimental Design: Here we describe the ex vivo applicability of a novel in-house, academic anti-BCMA CAR construct on AL primary cells, as well as the safety and efficacy in 4 patients with relapsed/refractory (RR) primary AL, treated in a phase I clinical trial (NCT04720313)., Results: Three had MAYO stage IIIa cardiac involvement at enrollment. The treatment proved relatively safe, with a short and manageable grade 3 cytokine release syndrome evident in 2 patients and no neurotoxicity in any. Cardiac decompensations, observed in 2 patients, were also short and manageable. The overall hematologic response and complete response rates were observed in all patients with an organ response evident in all four. Within a median follow-up period of 5.2 (2.5-9.5) months, all 4 patients maintained their responses., Conclusions: BCMA-CART cells provide a first proof-of-concept that this therapy is safe enough and highly efficacious for the treatment of patients with advanced, RR AL., (©2022 American Association for Cancer Research.)

Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia. In this retrospective multicenter study, 68 SP patients were included. Compared to solitary extramedullary plasmacytoma (SEP), patients with solitary bone plasmacytoma (SBP) were younger (57.3 vs. 70.9 years, p  = 0.031), had larger plasmacytoma (median: 5.4 vs. 3 cm, p  = 0.007) and higher median involved free light chain level (61 vs. 25.8 mg/L, p  = 0.056). 92.6% of patients were treated by radiotherapy and 11.8% received systemic anti-myeloma treatment. With a median follow-up of 42 months, 45.6% of patients progressed (8.8% - recurrent SP, 36.8% - active myeloma). The median PFS was 58 months and the median OS has not been reached (10-year OS: 84.8%). Patients who received also anti-myeloma treatment had longer PFS compared to those who did not (median not reached vs. 48 months, p  = 0.056). In conclusion, SBP and SEP appear to be different diseases. Radiotherapy is the cornerstone in the SP treatment. A large prospective trial is needed to evaluate the impact of adding systemic anti-myeloma treatment to local radiotherapy.

Patients with lymphoproliferative diseases are at high risk for SARS-CoV-2-related complications and mortality. The role of casirivimab and imdevimab (REGEN-COV), a neutralizing antibody cocktail, to treat immunocompromised hemato-oncological patients with SARS-CoV-2 disease 2019 (Covid-19) remains unknown. Here, we present our clinical experience on the outcome of 15 hematological patients treated with REGEN-COV for SARS-CoV-2 infection. Most patients failed to respond or achieved low antibody titer after 2-3 doses of BNT162b2 mRNA vaccine. All patients experienced clinical improvement with no mortality within a median follow-up of 70 days. In conclusion, early administration of REGEN-COV to high-risk hematological patients may prevent clinical deterioration and mortality from SARS-CoV-2 infection. The effectiveness of neutralizing antibodies may vary depending on the virus variants and in particular with the omicron variant (B.1.1.529)., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

About 20% of MM patients have T2DM. We assessed the impact of T2DM/pre-T2DM on MM progression and OS. We collected retrospective data of newly diagnosed MM patients in Maccabi health services, Israel, between 2012 and 2016. The study included 503 MM patients, median age 67.2 years (IQR: 33.5-91.2). Median follow-up was 32 months (IQR 19.4-47). T2DM and pre-T2DM were recorded in 24.1% and 51% patients, respectively. Median TT2T and OS in the cohort were 17.5 months (95% confidence interval (CI) 15-20) and unreached, respectively. T2DM patients had shorter TT2T (HR = 1.31, 95%CI 1.0-1.72, p =.047), particularly transplanted patients; 20.2 vs. 40 months (HR = 2.09, 95%CI 1.18-3.71, p =.012). In a multivariable model, T2DM had a borderline significant risk of all-cause mortality, adjusted HR 1.38 ( p =.09). Pre-diabetes had no impact on TT2T or OS. T2DM predicted a shorter TT2T, particularly in transplanted patients, and tended to be associated with shorter survival.

Multiple myeloma (MM) patients are at excess risk for clinically significant COVID19 infection. BNT162b2 mRNA COVID19 (BNT162b2) vaccine provides effective protection against COVID19 for the general population, yet its effect in MM patients may be compromised due to disease and therapy-related factors and was not yet evaluated. This single-centre prospective study included MM patients tested for serological response 14-21 days post second vaccine. Vaccinated healthy volunteers served as controls. In all, 171 MM patients, median age 70 (38-94) were included; 159 active MM and 12 smouldering myeloma (SMM). Seropositive response rate (median titer) was 76% (91 U/ml) in active MM patients vs 98% (992 U/ml) in the 64 controls (P < 0·0001), and 100% (822 U/ml) in SMM patients. Multivariate analysis revealed older age (P = 0·009), exposure to ≥4 novel anti-myeloma drugs (P = 0·02) and hypogammaglobulinaemia (P = 0·002) were associated with lower response rates. None of the novel agents significantly decreased response rate, whereas daratumumab trended towards reduced response (P = 0·08). Adverse events occurred in 53% and 55% of the MM patients and controls, respectively, all transient grade 1-2. In conclusion, BNT162b2 vaccine was safe and provided a high seropositivity rate in MM patients, independent of treatment type. Older, hypogammaglobulinaemic and heavily pretreated patients had lower response rates., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Vaccine-associated hypermetabolic lymphadenopathy (VAHL) is frequently observed on [ 18 F]FDG PET-CT following BNT162b2 administration. Recent data suggest a prominent B cell germinal-center (GC) response elicited by mRNA vaccines in draining lymph nodes. Thus, in this study we aimed to explore the correlation between VAHL and humoral immunity as reflected by post-vaccination serologic testing and by comparing the incidence of VAHL between lymphoma patients treated recently with B cell depleting therapy and those that were not., Methods: A total of 137 patients with hematologic malignancy that had post-vaccination [ 18 F]FDG PET-CT were included (All-PET group), 86 received both vaccine doses before imaging (PET-2 group). Their VAHL status and grade on imaging were recorded. Among 102 lymphoma patients, 34 (33.3%) were treated during the year prior vaccination with anti-CD20 antibody containing therapy. A subgroup of 54 patients also underwent serologic testing 2-3 weeks after the booster dose, and their anti-spike titers were recorded and graded as well., Results: The overall incidence of VAHL in patients with hematologic malignancy was 31.4%. The 34 lymphoma patients treated during the year prior vaccination with anti-CD20 antibody containing therapy had significantly lower rates of VAHL comparted with all other lymphoma patients (8.8 versus 41.2% in all-PET patients, Pv < 0.01). VAHL rates were 10% in patients with negative serology, 31.3% in patients with low anti-spike titers, and 72.2% in patients with high anti-spike titers. The positive predictive values of VAHL were 90 and 93.3% in all-PET and PET-2 patients, respectively. A positive statistically significant correlation was found between VAHL and serology ranks in All-PET patients (r s  = 0.530, Pv < 0.001), and stronger correlation was found in PET-2 patients (r s  = 0.642, Pv < 0.001)., Conclusion: VAHL on [ 18 F]FDG PET-CT of patients with hematologic malignancy may reflect GC B cell proliferation and an effective humoral response elicited by BNT162b2 vaccine., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Patients diagnosed with B-cell non-Hodgkin lymphoma (B-NHL), particularly if recently treated with anti-CD20 antibodies, are at risk of severe COVID-19 disease. Because studies evaluating humoral response to COVID-19 vaccine in these patients are lacking, recommendations regarding vaccination strategy remain unclear. The humoral immune response to BNT162b2 messenger RNA (mRNA) COVID-19 vaccine was evaluated in patients with B-NHL who received 2 vaccine doses 21 days apart and compared with the response in healthy controls. Antibody titer, measured by the Elecsys Anti-SARS-CoV-2S assay, was evaluated 2 to 3 weeks after the second vaccine dose. Patients with B-NHL (n = 149), aggressive B-NHL (a-B-NHL; 47%), or indolent B-NHL (i-B-NHL; 53%) were evaluated. Twenty-eight (19%) were treatment naïve, 37% were actively treated with a rituximab/obinutuzumab (R/Obi)-based induction regimen or R/Obi maintenance, and 44% had last been treated with R/Obi >6 months before vaccination. A seropositive response was achieved in 89%, 7.3%, and 66.7%, respectively, with response rates of 49% in patients with B-NHL vs 98.5% in 65 healthy controls (P < .001). Multivariate analysis revealed that longer time since exposure to R/Obi and absolute lymphocyte count ≥0.9 × 103/μL predicted a positive serological response. Median time to achieve positive serology among anti-CD20 antibody-treated patients was longer in i-B-NHL vs a-B-NHL. The humoral response to BNT162b2 mRNA COVID-19 vaccine is impaired in patients with B-NHL who are undergoing R/Obi treatment. Longer time since exposure to R/Obi is associated with improved response rates to the COVID-19 vaccine. This study is registered at www.clinicaltrials.gov as #NCT04746092., (© 2021 by The American Society of Hematology.)

Background: Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial., Methods: Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pretreatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 µm 2 /ms) or low (<1.24 µm 2 /ms) ADC L , the mean value of the lower peak of the ADC histogram, within the contrast enhancing tumor., Results: Baseline tumor volume ( P = .3460) and ADC L ( P = .2143) did not differ between treatment arms. Univariate analysis showed patients with high ADC L had a significant survival advantage in all patients ( P = .0006), as well as BV ( P = .0159) and BV+VB-111 individually ( P = .0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume, and ADC L identified continuous measures of tumor volume ( P < .0001; HR = 1.0212) and ADC L phenotypes ( P = .0012; HR = 0.5574) as independent predictors of OS., Conclusion: Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.

Objectives: Patients with relapsed/refractory AL amyloidosis (RRAL) have poor prognosis, but emerging data shows promising results with the use daratumumab. We evaluated daratumumab treatment in RRAL in real-world setting., Methods: A retrospective multisite study of RRAL patients treated with daratumumab alone and in combinations., Results: Forty-nine patients, diagnosed between 1.1.2008 and 1.2.2018 were included; 27% also had multiple myeloma (MM). Revised Mayo score was ≥ 3 in 67%. Hematologic overall response rate was 81%, 64% achieved very good partial response (VGPR) or better. Concurrent active MM was associated with lower rates of VGPR (OR 0.19, 95% CI 0.04-0.81; P = .03) in a multi-variate analysis. Cardiac and renal responses were 74% and 73%, respectively. Median progression-free survival (PFS) was 28.4 months and median overall survival (OS) was not reached; 2-year PFS and OS were 68.6 ± 7.5% and 90.4 ± 4.6%, respectively. Hematologic response correlated with prolonged PFS and OS. Daratumumab was safe and well tolerated, no patients discontinued therapy due to toxicity. Our data was aligned with outcomes from a systematic literature review, which identified 10 case series (n = 517) and 2 clinical trials (n = 62) meeting prespecified criteria., Conclusions: Our data support favorable safety tolerability and efficacy of daratumumab among non-selective RRAL patients in a real-world setting., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Multiple myeloma (MM) patients presenting with anaemia as their sole clinical manifestation are rare and not fully defined., Methods: Retrospective multi-site study comparing the characteristics and outcome of MM patients with anaemia only with matched patients, presenting with multi-organ disease., Results: Anaemia-only patients had a higher percentage of bone marrow monoclonal plasma cells group (median 60% [IQR 42-80%] vs. 37% [IQR 17-65%], respectively; p < 0.001), and a lower responsiveness to treatment (≥VGPR rates were 54% vs 74%, p = 0.049). Median survival in anaemia only patients was 65.9 ± 6.9 vs 83.4 ± 8.8 months in matched control patients (P = n.s)., Conclusions: MM patients presenting with anaemia only represents a unique, potentially less favorable population., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Daratumumab is approved for relapsed or refractory multiple myeloma (RRMM) as monotherapy or in combination regimens. We evaluated daratumumab plus cetrelimab, a programmed death receptor-1 inhibitor, in RRMM., Patients and Methods: This open-label, multiphase study enrolled adults with RRMM with ≥ 3 prior lines of therapy. Part 1 was a safety run-in phase examining dose-limiting toxicities of daratumumab (16 mg/kg intravenously weekly for cycles 1-2, biweekly for cycles 3-6, and monthly thereafter) plus cetrelimab (240 mg intravenously biweekly, all cycles). In Parts 2 and 3, patients were to be randomized to daratumumab with or without cetrelimab (same schedule as Part 1). Endpoints included safety, overall response rate, pharmacokinetics, and biomarker analyses., Results: Nine patients received daratumumab plus cetrelimab in the safety run-in, and 1 received daratumumab in Part 2 before administrative study termination following a data monitoring committee's global recommendation to stop any trial including daratumumab combined with inhibitors of programmed death receptor-1 or its ligand (programmed death-ligand 1). The median follow-up times were 6.7 months (safety run-in) and 0.3 months (Part 2). No dose-limiting toxicities occurred. All 10 patients had ≥ 1 treatment-emergent adverse event; 7 patients had grade 3 to 4 treatment-emergent adverse events, and none led to treatment discontinuation or death. In the safety run-in, 7 (77.7%) patients had ≥ 1 infusion-related reaction (most grade 1-2), and 1 had a grade 2 immune-mediated reaction. Among safety run-in patients, the overall response rate was 44.4%., Conclusions: No new safety concerns were identified for daratumumab plus cetrelimab in RRMM. The short study duration and small population limit complete analysis of this combination., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Lenalidomide and ixazomib maintenance improve long-term outcomes in newly diagnosed multiple myeloma (NDMM) patients. However, there is less evidence to support bortezomib (BTZ) maintenance therapy, and real-life data on maintenance are scarce. We investigated the efficacy and safety of BTZ maintenance therapy in NDMM., Patients and Methods: A retrospective multisite study was performed in 6 medical centers in Israel. All consecutive patients with NDMM diagnosed between January 1, 2010, and July 3, 2019, who received a BTZ-based induction, with or without an autologous transplantation, followed by BTZ maintenance therapy, were identified. Maintenance therapy was defined as BTZ (1.3 mg/m 2 ) once every 2 weeks, administered subcutaneously alone or with dexamethasone, or weekly BTZ monotherapy., Results: A total of 105 patients were identified, 58 of whom had received a transplant (transplant eligible) and 47 who had not (not transplant eligible). During BTZ maintenance therapy, 96% had one or more adverse event, 11.5% had grade 3 or higher adverse events, and 11.5% discontinued treatment due to toxicity. Median progression-free survival (PFS) and overall survival were 45 and 91.5 months, respectively; 4-year survival was 88%. Adverse cytogenetics was associated with worse PFS (24 vs. 46 months, P = .001). In subgroup analysis, adverse cytogenetics were associated with worse PFS (P < .001) and OS (P < .001) among transplant-ineligible but not transplant-eligible patients., Conclusion: Analysis of multisite real-life data showed that BTZ maintenance therapy is safe, well tolerated, and effective. Median PFS was similar to that reported with alternative maintenance strategies. Our findings further support its use among patients with adverse cytogenetics, it may also be relevant for patients with lenalidomide-intolerant disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules. At the prespecified primary analysis (15.8-month median follow-up), the complete response (CR) rates (co-primary endpoint) were 2.4%, 4.9%, and 0% for intense, intermediate, and short dosing, respectively; the co-primary endpoint of CR rate >15% was not met. Progressive disease (PD)/death rates (number of patients who progressed or died divided by total duration of progression-free survival [PFS] in patient-years; co-primary endpoint) for intense, intermediate, and short dosing were 0.055 (80% confidence interval [CI], 0.014-0.096), 0.102 (80% CI, 0.044-0.160), and 0.206 (80% CI, 0.118-0.295), respectively, translating to a median PFS ≥24 months in all arms (P < 0.0001, <0.0001, and =0.0213, respectively). With longer follow-up (median follow-up, 25.9 months), CR rates were 4.9%, 9.8%, and 0% for intense, intermediate, and short dosing, respectively. PD/death rates for intense, intermediate, and short dosing were 0.059 (80% CI, 0.025-0.092), 0.107 (80% CI, 0.058-0.155), and 0.150 (80% CI, 0.089-0.211), respectively, again translating to a median PFS ≥ 24 months in all arms (P < 0.0001 for all arms). Twenty-four-month PFS rates were 89.9% (90% CI, 78.5-95.4%), 82.0% (90% CI, 69.0-89.9%), and 75.3% (90% CI, 61.1-85.0%) for intense, intermediate, and short dosing, respectively. Pharmacokinetic analyses indicated that intense dosing maintained target-saturating trough concentrations in most patients throughout weekly, every-2-week, and every-4-week dosing periods. No new safety signals were observed. These data provide the basis for an ongoing phase 3 study of daratumumab in SMM.

Objectives: We aimed to determine the impact of washout period in patients with multiple myeloma between bortezomib-based induction regimens and the collection of stem cells., Methods: This was a single-center historical prospective study, including all sequential newly diagnosed patients with myeloma between 2012 and 2017 that were given a first-line bortezomib-based induction therapy (≤6 cycles) followed by stem cell collection (n = 75)., Results: We found a statistically significant correlation between the days from last dose of bortezomib and both CD34 + cells/kg yield on the first collection day and the overall collected CD34 + cells/kg (r = .466, P < .001, and r = .341, P = .03, respectively). The optimal receiver operating curve's cutoff point was 8.5 days (79% sensitivity and 71% specificity, P = .001). On multivariate analysis, timing of last dose of bortezomib remained statistically significant (P = .01). Based on this, we developed a model to predict the total collected CD34 + cells/kg = 11.76 + 0.13 (timing in days of last dose of bortezomib) -0.1 (age) -1.39 (if female) -0.01 (≥PR) -1.35 (if prior radiation)., Conclusions: Timing of last dose of bortezomib may predict a successful collection. A washout period of 9 days is associated with a better collection yield. A prospective validation of this novel finding is required., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Report final results of a phase I/II study of VB-111, a targeted anti-cancer gene therapy with a dual mechanism: anti angiogenic/vascular disruption and induction of an anti-tumor directed immune response, in combination with paclitaxel in patients with platinum-resistant ovarian cancer., Methods: Study NCT01711970 was a prospective, open label, dose escalation study assessing combination treatment of VB-111 and weekly paclitaxel. In the Phase I part of the study, patients were treated with escalating doses of intravenous VB-111 and paclitaxel. In Phase 2, patients were treated with therapeutic doses of VB-111 and paclitaxel 80 mg/m 2 . Assessments included safety, overall survival (OS), progression free survival (PFS), and tumor response (CA-125 and RECIST)., Results: 21 patients with recurrent platinum-resistant ovarian cancer were enrolled. 17/21 received the therapeutic dose. Patients had a median of 3 prior lines of therapy. Half of the subjects were platinum refractory, and half were previously treated with antiangiogenics. No DLTs were observed. VB-111 was well tolerated and associated with mild flu-like symptoms. In the therapeutic dose cohort, a 58% CA-125 GCIG response rate was seen in evaluable patients. The median OS was 16.6 months in patients treated with therapeutic dose compared to 5.8 months in sub-therapeutic dose (p = 0.028). Tumor specimens taken after treatment demonstrated tumor infiltrated with cytotoxic CD8 T-cells in regions of apoptotic cancer cells., Conclusions: Treatment with VB-111 in combination with paclitaxel was safe and well tolerated. Favorable tumor responses and overall survival outcomes were associated with induction of an immunotherapeutic effect., Competing Interests: Declaration of competing interest HB, SB, SC, MF, and JW have no conflicts of interest to disclose. RA has financial activities with CLOVIS, TESARO, AstraZeneca and VBL Therapeutics. MB is on the Data Safety and Monitoring Board for VBL Therapeutics. YC and TRM report personal fees during the conduct of the study and have a patent Methods of Anti-Tumor Therapy pending. RP reported grants and personal fees from VBL during the conduct of the study. DH is CEO of VBL., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Secretion of monoclonal immunoglobulins (MIg) detected in the serum and/or urine is one of the typical features of multiple myeloma (MM). However, some patients secrete MIg in quantities below "measurable" (termed oligosecretory MM) and others have no detectable MIgs by standard serum and urine immunofixation (termed non-secretory MM). In a cohort of 852 consecutive patients with active myeloma, we identified 100 (11.7%) patients with oligo/non-secretory MM, including 20 (2.3%) with non-secretory MM. Compared to patients with secretory MM, these were younger, less anemic, and had less often renal dysfunction and less extensive bone marrow infiltration. Presence and extent of bone disease were similar, however, hypercalcemia was less common and more often is ISS (International Staging System)-1 and, in those with available FISH (Fluoresense In Situ Hybridization) , high-risk cytogenetics were less common. FLCs (Free Light Chains) were available in 17 patients with non-secretory MM: only 3 had normal FLC ratio; the others had abnormal ratio and 9/14 had involved FLC ≥ 100 mg/L. The 4-year OS for patients with oligo/non-secretory disease was 64% vs 58% for secretory MM. In multivariate analysis, oligo/non-secretory disease was not an independent prognostic factor per se. Thus, 12% of MM patients present with oligo/non-secretory disease at diagnosis and have different biologic characteristics but similar outcome to other MM patients.

Ixazomib, the first oral proteasome inhibitor (PI), has been approved for the treatment of relapsed refractory multiple myeloma (RRMM) in combination with lenalidomide and dexamethasone, based on the TOURMALINE-MM1 phase 3 trial, which demonstrated the efficacy and safety of this all-oral triplet, compared with lenalidomide-dexamethasone. However, clinical trial outcomes do not always translate into real-world outcomes. The aim of this study was to assess the outcomes of ixazomib-based combination for treatment of patients with RRMM in a real-world setting. All consecutive RRMM patients who received at least one cycle of ixazomib-based treatment combination between June 2013 and June 2018 were identified. Data was extracted from medical charts focusing on demographics, disease characteristics, prior treatment, and responses. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), safety, and tolerability. A total of 78 patients across 7 sites were retrospectively included. Median follow-up was 22 months. Median age was 68 (range 38-90). Sixty-four percent received ixazomib in 2nd line, 19% in 3rd line. Overall, 89% of patients had been exposed to PIs (bortezomib 87%) prior to IRd, 41% to IMiDs. Twenty-nine (48%, of 60 available) had high (t(4:14), t(14:16), del17p) or intermediate (+1q21) risk aberrations. Most patients (82%) received ixazomib in combination with lenalidomide and dexamethasone. An exploratory assessment for disease aggressiveness at diagnosis was classified by a treating physician as indolent (rapid control to protect from target organ damage not required) vs aggressive (imminent target organ damage) in 63% vs 37%, respectively. Treatment was well tolerated, with a low discontinuation rate (11%). Median PFS on ixazomib therapy was 24 months (95% CI 17-30). PFS was 77% and 47% at 12 and 24 months, respectively. Median OS was not reached; OS was 91% and 80% at 12 and 24 months, respectively. Higher LDH, older age, and worse clinical aggressiveness were associated with worse PFS, whereas a deeper response to ixazomib (≥ VGPR) and a longer response to first-line bortezomib (≥ 24 m) were associated with an improved PFS on ixazomib. No effect on PFS was found for cytogenetic risk by FISH, ISS/rISS, and prior anti-myeloma treatment. Ixazomib-based combinations are efficacious and safe regimens in RRMM patients in the real-world setting, regardless to cytogenetic risk, with a PFS of 24 months comparable with clinical trial data. This regimen had most favorable outcomes among patients who remained progression-free more than 24 months after a bortezomib induction and for those who have a more indolent disease phenotype.

Background: Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab., Methods: This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS)., Results: Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91-1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3-5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction., Conclusions: In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results., Clinical Trials Registration: NCT02511405., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: VB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor-specific immune response. This phase I/II study evaluated the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM)., Methods: Patients with rGBM (n = 72) received VB-111 in 4 treatment groups: subtherapeutic (VB-111 dose escalation), limited exposure (LE; VB-111 monotherapy until progression), primed combination (VB-111 monotherapy continued upon progression with combination of bevacizumab), and unprimed combination (upfront combination of VB-111 and bevacizumab). The primary endpoint was median overall survival (OS). Secondary endpoints were safety, overall response rate, and progression-free survival (PFS)., Results: VB-111 was well tolerated. The most common adverse event was transient mild-moderate fever. Median OS time was significantly longer in the primed combination group compared with both LE (414 vs 223 days; hazard ratio [HR], 0.48; P = 0.043) and unprimed combination (414 vs 141.5 days; HR, 0.24; P = 0.0056). Patients in the combination phase of the primed combination group had a median PFS time of 90 days compared with 60 in the LE group (HR, 0.36; P = 0.032), and 63 in the unprimed combination group (P = 0.72). Radiographic responders to VB-111 exhibited characteristic, expansive areas of necrosis in the areas of initial enhancing disease., Conclusions: Patients with rGBM who were primed with VB-111 monotherapy that continued after progression with the addition of bevacizumab showed significant survival and PFS advantage, as well as specific imaging characteristics related to VB-111 mechanism of action. These results warrant further assessment in a randomized controlled study., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

We investigated incidence, characteristics and outcome of patients with macrofocal multiple myeloma (MFMM) treated mainly with novel therapies. Based on definition (BMPCs <20% and lytic lesions/plasmacytomas, without anemia, renal insufficiency or hypercalcemia) we identified 140 patients with MFMM, among 4650 myeloma patients (3%). Twice the number of patients with typical myeloma were used as controls; 60% were <65 years and 70% had advanced bone disease. Plasmacytomas were more frequent in MFMM compared with standard myeloma (68% vs 15%, P < .05). Adverse prognostic parameters (high lactate dehydrogenase, advanced stage, high risk cytogenetics, immunoparesis) were less common in patients with MFMM compared with controls (P < .05); 90% received novel agents and 47% underwent autologous transplantation upfront; 90% achieved an objective response; 70% had at least very good partial response which was significantly higher compared with controls (P < .05). After a median follow-up of 52 months, 33 patients have died. Early death (<12 months) was infrequent in MFMM. Median progression-free survival and overall survival (OS) were 46 and 129 months respectively, both significantly longer compared with controls (P < .001). Proteasome inhibitor (PI)-based therapy was the only independent predictor for OS in the multivariate analysis (HR: 3.9; P < .001). In conclusion, MFMM is a distinct entity presented in young and elderly subjects, characterized by limited bone marrow infiltration, advanced bone disease and frequent presence of plasmacytomas; MFMM patients have less often adverse prognostic features and achieve excellent responses and prolonged OS especially when treated with PI-based therapies. Novel imaging will help in a more accurate classification of this entity., (© 2020 Wiley Periodicals, Inc.)

The current study assesses the characteristics and outcomes of multiple myeloma (MM) patients, treated with novel agents for hematogenous extramedullary (HEMM) relapse. Consecutive patients diagnosed with HEMM between 2010-2018 were included. Patients' characteristics at diagnosis and at HEMM presentation, response to treatment, survival and factors predicting survival were recorded and analyzed. A group of 127 patients, all diagnosed with HEMM by imaging (87.3%) and/or biopsy (79%), were included. Of those, 44% were initially diagnosed with ISS3, 57% presented with plasmacytomas, and 30% had high-risk cytogenetics. Median time to HEMM was 32 months. In multivariate analysis, ISS3 and bone plasmacytoma predicted shorter time to HEMM (P = .005 and P = .008, respectively). Upfront autograft was associated with longer time to HEMM (P = .002). At HEMM, 32% of patients had no BM plasmacytosis, 20% had non-secretory disease and 43% had light-chain disease. Multiple HEMM sites were reported in 52% of patients, mostly involving soft tissue, skin (29%), and pleura/lung (25%). First treatment for HEMM included proteasome inhibitors (50%), immunomodulatory drugs (IMiDs) (39%), monoclonal antibodies (10%), and chemotherapy (53%). Overall response rate (ORR) was 57%. IMiDs were associated with higher ORR (HR 2.2, 95% CI 1.02-4.7, P = .04). Median survival from HEMM was 6 months (CI 95% 4.8-7.2). Failure to achieve ≥VGPR was the only significant factor for worse OS in multivariate analyses (HR = 9.87, CI 95% 2.35 - 39, P = .001). In conclusion, HEMM occurs within 3 years of initial myeloma diagnosis and is associated with dismal outcome. The IMiDs might provide a higher response rate, and achievement of ≥VGPR predicts longer survival., (© 2019 Wiley Periodicals, Inc.)

OPA1 related disorders include: classic autosomal dominant optic atrophy syndrome (ADOA), ADOA plus syndrome and a bi-allelic OPA1 complex neurological disorder. We describe metabolic stroke in a patient with bi-allelic OPA1 mutations. A twelve-year old girl presented with a complex neurological disorder that includes: early onset optic atrophy at one year of age, progressive gait ataxia, dysarthria, tremor and learning impairment. A metabolic stroke occurred at the age of 12 years. The patient was found to harbor a de novo heterozygous frame shift mutation c.1963&#95;1964dupAT; p.Lys656fs (NM&#95;015560.2) and a missense mutation c.1146A > G; Ile382Met (NM&#95;015560.2) inherited from her mother. The mother, aunt, and grandmother are heterozygous for the Ile382Met mutation and are asymptomatic. The co-occurrence of bi-allelic mutations can explain the severity and the early onset of her disease. This case adds to a growing number of patients recently discovered with bi-allelic OPA1 mutations presenting with a complex and early onset neurological disorder resembling Behr syndrome. To the best of our knowledge metabolic stroke has not been described before as an OPA1 related manifestation. It is important to be aware of this clinical feature for a prompt diagnosis and consideration of available treatment.

Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients.

Umbilical cord blood (UCB) transplantation has a high early mortality rate primarily related to transplanted stem cell dose. To decrease early mortality and enhance engraftment, a portion of selected cord blood units (20% to 50%) was expanded with cytokines and the copper chelator tetraethylenepentamine (carlecortemcel-L) and transplanted with the unmanipulated fraction after myeloablative conditioning. The primary endpoint was 100-day survival, which was compared with a contemporaneous double-unit cord blood transplantation (DUCBT) group. We enrolled 101 patients at 25 sites; the DUCBT comparison (n = 295) was selected from international registries using study eligibility criteria. Baseline carlecortemcel-L study group unit nucleated cell (NC) and CD34 + were 3.06 × 10 7 cell dose/kg and 1.64 × 10 5 cell dose/kg. Median NC and CD34 + fold expansion were 400 and 77, with a mean total CD34 infused of 9.7 × 10 5 /kg. The 100-day survival was 84.2% for the carlecortemcel-L study group versus 74.6% for the DUCBT group (odds ratio, .50; 95% CI, .26 to .95; P = .035). Survival at day 180 was similar for the 2 groups; the major cause of death after day 100 was opportunistic infections. Faster median neutrophil (21 days versus 28 days; P < .0001), and platelet (54 days versus 105 days; P = .008) engraftment was seen in the carlecortemcel-L study group; acute and chronic graft-versus-host disease rates were similar. In this multinational comparative study, transplanting expanded CD34 + stem cells from a portion of a single UCB unit, with the remaining unmanipulated fraction improved 100-day survival compared with DUCBT control patients while facilitating myeloid and platelet engraftment. This trial was registered at www.clinicaltrials.gov as #NCT00469729., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Del17p is a genomic imbalance occurring in ∼7%-10% of myeloma at diagnosis newly diagnosed myeloma patients (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008 and 1/2016 proven to carry 17p deletion by means of fluorescence in situ hybridization (FISH) were identified. Most received a bortezomib-based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance. Overall response rate (ORR) after induction was 85%; 94% for transplant eligible (TE); and 75% for transplant ineligible (NTE), and declined in subsequent treatment lines, 64% achieved ≥ VGPR. Median overall survival (OS) was 43 months; median progression free survival (PFS) was 11 months, 19 months for TE and 7 for NTE. In multivariate analysis: higher M-Spike, presence of extramedullary disease, and >50% of cells baring del17p were associated with adverse PFS; Autologous HCT and higher hemoglobin were associated with longer PFS; OS was 59 months for patients with early access to newer agents. Older age and higher M-Spike levels were associated with adverse OS, Autologous HCT was associated with favorable OS, 59.7 vs 28.7 months for NTE patients. Despite the improvement achieved with autologous HCT and new novel agents, the prognosis of patients with 17p deletion is still inferior, emphasizing the need for novel approaches., (© 2018 Wiley Periodicals, Inc.)

Multiple myeloma (MM) is a multi-subclonal malignancy with relatively high heterogeneity. Patients who initially presented with both monoclonal-protein (MP) and free light chain (FLC) secretion but then relapsed with a light chain escape pattern have been shown to reflect disease clonal evolution and to bare a worse prognosis. We hypothesized that a discordant MP/FLC pattern at diagnosis may reflect a similar clonal evolution that had occurred prior to diagnosis of active myeloma, conferring a worse outcome. We analyzed 255 consecutive newly diagnosed MM patients who received first line bortezomib-based therapy between 2007 and 2014, hypothesizing that their MP/FLC fingerprint at diagnosis reflects clonal heterogeneity and, therefore, affects outcome. An involved FLC level ≥ 700 mg/L and MP ≥ 2.5 g/L were used as cutoffs for low vs high FLC and MP levels, respectively. Patients were divided into 4 subgroups according to their involved FLC and MP blood levels at diagnosis: HiLC and HiMP for patients with either a predominant FLC or a predominant MP, respectively, and HiLC-MP and LoLC-MP when both FLC and MP were increased or decreased, respectively. There were 68 (27%) patients with HiLC, which presented more often with International Staging System-3 stage (P < .0001). Multivariate analysis showed that HiLC was associated with a 5.1-fold risk for mortality in a multivariate model (95% confidence interval [CI], 1.34-19.68). Both HiLC and HiLC-MP phenotypes were associated with shorter progression-free survival (hazard ratio of 2.66 [95% CI, 1.33-5.32] and 2.82 [95% CI, 1.37-5.83], respectively), independently of other prognostic factors, including the use of autograft. Thus, we identified an LC predominant secretory fingerprint (HiLC phenotype) at diagnosis as a potential independent risk factor that may affect disease control and survival in newly diagnosed MM patients treated with bortezomib-based induction therapy; this may represent increased subclonal heterogeneity., (Copyright © 2016 John Wiley & Sons, Ltd.)