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Renal impairment is common during multiple myeloma and persistent reduction in kidney function strongly affects prognosis. Cast nephropathy, by monoclonal free light chains precipitation with uromodulin in renal tubules, is the main cause of acute kidney injury in multiple myeloma. Kidney biopsy, although not necessary for diagnosis, allows assessment of renal prognosis according to the extent of cast formation, tubular atrophy and interstitial fibrosis. Prevention and early diagnosis of acute kidney injury are essential to optimize management and avoid progression to chronic kidney disease. Rehydration, interruption of nephrotoxic treatments, correction of precipitating factors, anti-plasma cell chemotherapy can rapidly reduce the free light chains nephrotoxicity. The association of the proteasome inhibitor Bortezomib and high dose Dexamethasone is the reference treatment in newly diagnosed patients with renal impairment. Adding Cyclophosphamide or the immunomodulator Lenalidomide may improve the hematological response, but with a poorer tolerance. Use of anti-CD38 monoclonal antibodies is being evaluated in this population. Hemodialysis with high-flux or high-cut-off membranes, combined to chemotherapy, may improve renal function recovery. Management of multiple myeloma have to be adapted in patients with chronic kidney disease, dialysis or kidney transplantation. Because of improvement in global survival, kidney transplantation remains an option to consider in selected patients. Collaboration between hematologists and nephrologists is essential throughout the course of the disease., (Copyright © 2023 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Bispecific antibodies (BsAbs) are an effective treatment used in relapsed or refractory multiple myeloma. Despite a well-tolerated safety profile, infectious events appear to be frequent in clinical trials. Real-world data on epidemiology, characteristics, risk factors, and outcomes of infections in patients treated with BsAb are still needed., Methods: A retrospective, multicentre study in BsAb-treated patients with multiple myeloma was performed in 14 French centres from December 2020 to February 2023. The primary objective was to describe the incidence of infections that required hospitalization, specific treatment, or adaptation in BsAb administration., Results: Among 229 patients with multiple myeloma treated with BsAb, 153 (67%) received teclistamab, 47 (20%) received elranatamab, and 29 (13%) talquetamab. We reported a total of 234 infections, including 123 (53%) of grade of ≥3. Predominant infections affected the respiratory tract (n = 116, 50%) followed by bacteraemias (n = 36, 15%). The hospitalization rate was 56% (n = 131), and 20 (9%) infections resulted in death. Global cumulative incidence of the first infection was 70% in all patients, 73% in patients treated with B-cell maturation antigen-targeting, and 51% with GPRC5D-targeting BsAb. In univariate analyses, corticosteroids for cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with a higher risk of first infection (HR = 2.13; 95% CI, 1.38-3.28), whereas GPRC5D-targeting BsAb and anti-bacterial prophylaxis were associated with a lower risk (HR = 0.53; 95% CI, 0.3-0.94 and HR = 0.65; 95% CI, 0.46-0.9). Fine and Gray multivariate model found that only corticosteroids for CRS/ICANS were correlated with a higher risk of first infection (HR = 2.01; 95% CI, 1.27-3.19)., Discussions: The implementation of preventive measures that aim to mitigate the risk of infection under BsAb is pivotal, notably in patients who received corticosteroids for CRS/ICANS., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hyperviscosity syndrome (HVS) is a rare complication of newly diagnosed multiple myeloma (NDMM) related to high tumour burden. Studies about the prognosis of HVS in modern-era therapy for NDMM are missing. We investigated a retrospective cohort study of NDMM with HVS between 2011-2021. Thirty-nine NDMM patients with HVS were included. HVS presentation was heterogeneous, with asymptomatic, mild, and neurological forms in 23%, 59%, and 18% of cases, respectively. No thrombosis or major bleeding was observed. Therapeutic plasma exchanges were used in 92% of patients, which were effective and well tolerated. No rebound effect was observed. All patients except one had at least one CRAB criterion. Most of the patients received bortezomib and high-dose steroids (95%) associated with an immunomodulatory drug (43%) or alkylating agents (42%). HVS in NDMM patients had dismal overall survival matched to multiple myeloma patient controls (without HVS) in our center (median: 3.6 vs. 7.7 years, p=0.01), as confirmed by multivariate analysis. Early deaths (in the first two months) occurred in 21% of older patients (>65 years). HVS in NDMM patients is a rare but life-threatening complication associated with high lethality in older patients and be a potential dismal prognosis factor in the modern treatment era., Competing Interests: AB received support from OCTAPHARMA for attending a meeting. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Debureaux, Harel, Parquet, Lemiale, Siguret, Goubeau, Morin, Royer, Cuccuini, Elessa, Theves, Brignier, Azoulay, Arnulf and Talbot.)

Multiple myeloma (MM) is rare in young patients, especially before age 40 years at diagnosis, representing <2% of all patients with MM. Little is known about the disease characteristics and prognosis of these patients. In this study, we examined 214 patients diagnosed with MM at age ≤40 years over 15 years, in the era of modern treatments. Among them, 189 patients had symptomatic MM. Disease characteristics were similar to older patients: 35% had anemia, 17% had renal impairment, and 13% had hypercalcemia. The staging was ISS-1 in 52.4%, ISS-2 in 27.5%, and ISS-3 in 20.1%. Overall, 18% of patients had high-risk cytogenetics [del 17p and/or t(4;14)]. Ninety percent of patients received intensive chemotherapy followed by autologous stem cell transplant, and 25% of patients had allogeneic stem cell transplant predominantly at time of relapse. The median follow-up was 76 months, the estimated median overall survival was 14.5 years, and the median progression free-survival was 41 months. In multivariate analysis, bone lesions (hazard ratio [HR], 3.95; P = .01), high ISS score (HR, 2.14; P = .03), and high-risk cytogenetics (HR, 4.54; P < .0001) were significant risk factors for poor outcomes. Among predefined time-dependent covariables, onset of progression (HR, 13.2; P < .0001) significantly shortened overall survival. At 5 years, relative survival compared with same age- and sex-matched individuals was 83.5%, and estimated standardized mortality ratio was 69.9 (95% confidence interval, 52.7-91.1), confirming that MM dramatically shortens the survival of young patients despite an extended survival after diagnosis., (© 2021 by The American Society of Hematology.)

Multiple myeloma has extremely heterogeneous outcomes. Among prognostic factors, t(4;14) and del(17p) are rare oncogenic events associated with very poor prognosis. In an exploratory case-control study, we compared the combination of Busulfan-Melphalan or TBI-Melphalan with high dose Melphalan as a conditioning regimen in a series of 48 patients with del(17p) or t(4;14). These regimens were preceded by a Bortezomib-containing induction. Progression-free survival (PFS) was the primary endpoint whereas overall survival (OS) and complete response (CR) rate were the secondary endpoints. Twenty consecutive cases of high-risk myeloma received a reinforced conditioning regimen of Busulfan 0.8 mg/kg x4/j IV from day-6 to day-3 pre- graft (BuMel) or total body irradiation (TBI) 12 Gy (TbiMel), having received Melphalan 140 mg/m 2 at day-2 pre-graft. These cases were matched to 28 controls treated with Melphalan 200 mg/m 2 at day-2 (Mel200). After intensification ± consolidation, with a median follow-up of 6.3 years, the CR rate was higher in the BuMel/TbiMel group (65% vs 50%, P = .006). No differences were observed between both groups in terms of PFS and OS (P = .96). PFS in patients with a del(17p) mutation tended to be superior in the BuMel/TbiMel group. Our exploratory study shows that reinforcing the intensification regimen with Busulfan or TBI does not seem to improve the prognosis associated to t(4;14) and del(17p) abnormalities., (© 2020 John Wiley & Sons Ltd.)

Rationale: Crystal sorting histiocytosis (CSH) is a rare disorder that is morphologically characterized by the accumulation of monoclonal immunoglobulin crystals, predominantly of a kappa light chain type, within lysosomes of macrophages. CSH may result in a variety of clinical manifestations depending on the involved organs. In this case report, we aim to describe a patient with ophthalmic manifestations which lead to the diagnosis of multiple myeloma with crystal-storing histiocytosis, crystalline podocytopathy, and light chain proximal tubulopathy., Patient Concerns: A 60-year-old male patient presented with progressive bilateral decreased vision for 2 years., Diagnosis: Ophthalmic explorations showed bilateral macular and papillary edema, and multiple crystalline deposits in the anterior stromal cornea and in the retina. Laboratory tests showed nephrotic syndrome and renal dysfunction. Further work-up revealed IgG kappa multiple myeloma, with biopsy-proven combined crystalline podocytopathy and tubulopathy., Interventions: The patient received chemotherapy (bortezomib, cyclophosphamide, and dexamethasone for 3 cycles, then bortezomib, lenalidomide, and dexamethasone)., Outcomes: Despite partial hematologic response and improvement of the papilledema and macular edema, the patient developed dialysis-dependent end-stage renal failure., Lessons: This report, highlighting the protean presentation of paraprotein-mediated injuries, provides additional information on the ocular anomalies not previously described that may be associated with crystal-storing histiocytosis.

Hyperviscosity syndrome (HVS) is a rare complication of newly diagnosed multiple myeloma (NDMM) related to high tumour burden. Studies about the prognosis of HVS in modern-era therapy for NDMM are missing. We investigated a retrospective cohort study of NDMM with HVS between 2011-2021. Thirty-nine NDMM patients with HVS were included. HVS presentation was heterogeneous, with asymptomatic, mild, and neurological forms in 23%, 59%, and 18% of cases, respectively. No thrombosis or major bleeding was observed. Therapeutic plasma exchanges were used in 92% of patients, which were effective and well tolerated. No rebound effect was observed. All patients except one had at least one CRAB criterion. Most of the patients received bortezomib and high-dose steroids (95%) associated with an immunomodulatory drug (43%) or alkylating agents (42%). HVS in NDMM patients had dismal overall survival matched to multiple myeloma patient controls (without HVS) in our center (median: 3.6 vs. 7.7 years, p=0.01), as confirmed by multivariate analysis. Early deaths (in the first two months) occurred in 21% of older patients (>65 years). HVS in NDMM patients is a rare but life-threatening complication associated with high lethality in older patients and be a potential dismal prognosis factor in the modern treatment era.

Hyperviscosity syndrome (HVS) is a rare complication of newly diagnosed multiple myeloma (NDMM) related to high tumour burden. Studies about the prognosis of HVS in modern-era therapy for NDMM are missing. We investigated a retrospective cohort study of NDMM with HVS between 2011- 2021. Thirty-nine NDMM patients with HVS were included. HVS presentation was heterogeneous, with asymptomatic, mild, and neurological forms in 23%, 59%, and 18% of cases, respectively. No thrombosis or major bleeding was observed. Therapeutic plasma exchanges were used in 92% of patients, which were effective and well tolerated. No rebound effect was observed. All patients except one had at least one CRAB criterion. Most of the patients received bortezomib and high-dose steroids (95%) associated with an immunomodulatory drug (43%) or alkylating agents (42%). HVS in NDMM patients had dismal overall survival matched to multiple myeloma patient controls (without HVS) in our center (median: 3.6 vs. 7.7 years, p=0.01), as confirmed by multivariate analysis. Early deaths (in the first two months) occurred in 21% of older patients (>65 years). HVS in NDMM patients is a rare but life-threatening complication associated with high lethality in older patients and be a potential dismal prognosis factor in the modern treatment era. [ABSTRACT FROM AUTHOR]

Background: CAR-T cell (chimeric antigen receptor T) therapy has emerged as an effective treatment of refractory hematological malignancies. Intensive care management is intrinsic to CAR-T cell therapy. We aim to describe and to assess outcomes in critically ill CAR-T cell recipients. Study design and methods: Hospital-wide retrospective study. Consecutive CAR-T cell recipients requiring ICU admission from July 2017 and December 2020 were included. Results: 71 patients (median age 60 years [37–68]) were admitted to the ICU 6 days [4–7] after CAR-T cell infusion. Underlying malignancies included diffuse large B cell lymphoma (n = 53, 75%), acute lymphoblastic leukemia (17 patients, 24%) and multiple myeloma (n = 1, 1.45%). Performance status (PS) was 1 [1–2]. Shock was the main reason for ICU admission (n = 40, 48%). Isolated cytokine release syndrome (CRS) was the most common complication (n = 33, 46%), while 21 patients (30%) had microbiologically documented bacterial infection (chiefly catheter-related infection). Immune effector cell-associated neurotoxicity syndrome was reported in 26 (37%) patients. At ICU admission, vasopressors were required in 18 patients (25%) and invasive mechanical ventilation in two. Overall, 49 (69%) and 40 patients (56%) received tocilizumab or steroids, respectively. Determinant of mortality were the reason for ICU admission (disease progression vs. sepsis or CRS (HR 4.02 [95%CI 1.10–14.65]), Performance status (HR 1.97/point [95%CI 1.14–3.41]) and SOFA score (HR 1.16/point [95%CI 1.01–1.33]). Conclusions: Meaningful survival could be achieved in up to half the CAR-T cell recipients. The severity of organ dysfunction is a major determinant of death, especially in patients with altered performance status or disease progression. [ABSTRACT FROM AUTHOR]

Immunoglobulin G (IgG) metabolism has received much attention in the literature for two reasons: (i) IgG homeostasis is regulated by the neonatal Fc receptor (FcRn), by a pH-dependent and saturable recycling process, which presents an interesting biological system; (ii) the IgG-FcRn interaction may be exploitable as a means for extending the plasma half-life of therapeutic monoclonal antibodies, which are primarily IgG-based. A less-studied problem is the importance of endogenous IgG metabolism in IgG multiple myeloma. In multiple myeloma, quantification of serum monoclonal immunoglobulin plays an important role in diagnosis, monitoring and response assessment. In order to investigate the dynamics of IgG in this setting, a mathematical model characterizing the metabolism of endogenous IgG in humans is required. A number of authors have proposed a two-compartment nonlinear model of IgG metabolism in which saturable recycling is described using Michaelis-Menten kinetics; however it may be difficult to estimate the model parameters from the limited experimental data that are available. The purpose of this study is to analyse the model alongside the available data from experiments in humans and estimate the model parameters. In order to achieve this aim we linearize the model and use several methods of model and parameter validation: stability analysis, structural identifiability analysis, and sensitivity analysis based on traditional sensitivity functions and generalized sensitivity functions.We find that allmodel parameters are identifiable, structurally and taking into account parameter correlations, when several types of model output are used for parameter estimation. Based on these analyses we estimate parameter values from the limited available data and compare them with previously published parameter values. Finally we show how the model can be applied in future studies of treatment effectiveness in IgG multiple myeloma with simulations of serum monoclonal IgG responses during treatment. [ABSTRACT FROM AUTHOR]

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