Antiplasma cell antibodies: A new era of human leukocyte antigen antibody control in solid organ transplantation.

New therapies directed against plasma cells such as anti-CD38 antibodies and the bispecific anti-B cell maturation antigen antibodies, represent not only an important advance in the treatment of multiple myeloma but have the potential to change the treatment landscape of other antibody-mediated diseases. In solid organ transplantation, the therapeutic armamentarium targeting humoral alloimmune responses in desensitization of highly sensitized transplant candidates and posttransplant antibody-mediated rejection has lagged behind advances in preventing and treating T cell-mediated rejection. Intravenous immunoglobulin and plasmapheresis are used extensively but have limited efficacy. Currently available anti-CD20 antibodies are only partially effective in achieving B cell depletion and leaving mature plasma cells untouched. Although interleukin 6 plays an important role in the humoral alloimmune response and injury, the benefits of interleukin 6 inhibition have failed to be demonstrated in clinical trials. Even proteasome inhibitors developed specifically to target plasma cells have not fulfilled their promise, due to limited efficacy as single agents. This review focuses on the recent experience with, and potential applicability of, anti-CD38 antibodies in the field of organ transplantation and experimental data supporting their use and development for human leukocyte antigen desensitization and antibody-mediated rejection.

A CD38/CD3xCD28 trispecific T-cell engager as a potentially active agent in multiple myeloma patients relapsed and/or refractory to anti-CD38 monoclonal antibodies.

There is accumulating evidence of BCMA and GPRC5D loss after treatment with T-cell redirecting therapies in patients with relapsed/refractory multiple myeloma (RRMM). While complete CD38 loss is not observed upon relapses after treatment with anti-CD38 monoclonal antibodies (mAb), there is downregulation of surface CD38 expression and decreased number and function of NK cells, which renders these patients resistant to retreatment with anti-CD38 mAb. Here, we provide preclinical evidence that RRMM patients previously exposed to anti-CD38 mAb could benefit from T-cell-based immunotherapy that depend less on CD38 antigen density and NK-cell activity, such as the novel CD38/CD3xCD28 trispecific T-cell engager, SAR442257.

Prognostic value of the "dynamic" R2-ISS in patients with multiple myeloma undergoing anti-CD38 antibody-based triplet therapies.

To retrospectively analyze whether the second revision of the international staging system (R2-ISS) influenced prognosis at treatment initiation in patients with multiple myeloma (MM) receiving anti-CD38 antibody-based triplet treatments. High-risk chromosomal abnormalities were examined from diagnosis to treatment initiation and considered positive if detected once. R2-ISS was recalculated at the initiation of treatment and defined as "dynamic R2-ISS." Data from 150 patients who underwent the defined treatments were analyzed. The median progression-free survival (PFS) was 19.5 months, and the median overall survival (OS) was 36.5 months. Dynamic R2-ISS significantly stratified prognoses for both PFS and OS. The median PFS for patients with dynamic R2-ISS IV was 3.3 months, and the median OS was 11.7 months, indicating extremely poor outcomes. Although the Revised International Staging System (R-ISS) calculated at the initiation of treatment significantly stratified treatment outcomes, the patients classified as R-ISS could be further stratified by R2-ISS to provide better prognostic information. Dynamic R2-ISS showed potential as a prognostic tool in patients with MM who are treated with anti-CD38 antibody-based triplet therapies.

How do transfusion services manage patients taking therapies such as anti-CD38 and anti-CD47 known to interfere with red blood cell compatibility testing?

BACKGROUND: Drugs such as daratumumab (Darzalex, anti-CD38) and Hu5F9-G4 (magrolimab, anti-CD47) may interfere with red blood cell compatibility testing as CD38 and CD47 are expressed on red blood cells. STUDY DESIGN AND METHODS: A survey of AABB member transfusion services was undertaken to understand their experiences of managing patients taking therapeutic monoclonal antibodies that are known to interfere with blood grouping and compatibility testing. RESULTS: The survey was distributed to the contact person at US-based AABB member transfusion services. The response rate was 27%. 172 of 240 (72%) indicated they had difficulties in performing compatibility testing in patients taking daratumumab and 66 of 91 (73%) reported difficulties in performing compatibility testing in patients taking magrolimab. Actions taken to provide compatible blood for these patients included referral of all samples to a reference center, blood group pheno/genotyping the patient in advance of starting the drug, treating reagent cells with 0.2 M dithiothreitol and using K-negative red cell units for patients taking daratumumab, and Gamma-clone (Immucor) anti-IgG for indirect antiglobulin testing for patients taking magrolimab. Lack of communication from clinical services about drug treatment was identified as a concern. CONCLUSION: The results of the survey demonstrate that transfusion services are having challenges with the transfusion management of patients taking therapeutic monoclonal antibodies, and further education is needed.

An open-label, first-in-human, single agent, dose escalation study for the evaluation of safety and efficacy of SAR442085 in patients with relapsed or refractory multiple myeloma.

OBJECTIVES: Cluster of differentiation 38 (CD38) is a key target on multiple myeloma (MM) cells. This multi-centre, Phase 1, single-agent study (NCT04000282) investigated SAR442085, a novel fragment crystallisable (Fc)-modified anti-CD38 monoclonal antibody (mAb), with enhanced affinity towards Fc-gamma receptor on effector cells in patients with relapsed and/or refractory (RR) MM. METHODS: This study comprised two parts: Part-A (dose-escalation involving anti-CD38 mAb pre-treated and naïve patients) and Part-B (dose expansion). Primary endpoints were maximum tolerated dose and recommended Phase 2 dose (RP2D). RESULTS: Thirty-seven heavily pre-treated patients were treated in Part A. Part-B (dose-expansion) was not studied. Seven dose-limiting toxicities were reported at DL3, DL5, DL6, and DL7. RP2D was determined to be 5-7·5 mg/kg. Most common treatment-emergent adverse events were infusion-related reactions in 70·3% (26/37) patients. Grade ≥3 thrombocytopenia was reported in 48·6% (18/37). Overall response rate was 70% in anti-CD38 mAb naïve and 4% in anti-CD38 pre-treated patients, with a median progression-free survival of 7·62 (95%CI: 2·858; not calculable) months and 2·79 (95%CI: 1·150; 4·172) months and, respectively. CONCLUSIONS: The efficacy of SAR442085 was promising in anti-CD38 mAb naïve patients but did not extend to the larger cohort of anti-CD38 mAb pre-treated patients. This observation, along with transient high-grade thrombocytopenia, could potentially limit its clinical use.

Immune responses to COVID-19 booster vaccinations in intensively anti-CD38 antibody treated patients with ultra-high-risk multiple myeloma: results from the Myeloma UK (MUK) nine OPTIMUM trial.

Multiple myeloma (MM) and anti-MM therapy cause profound immunosuppression, leaving patients vulnerable to coronavirus disease 2019 (COVID-19) and other infections. We investigated anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies longitudinally in ultra-high-risk patients with MM receiving risk-adapted, intensive anti-CD38 combined therapy in the Myeloma UK (MUK) nine trial. Despite continuous intensive therapy, seroconversion was achieved in all patients, but required a greater number of vaccinations compared to healthy individuals, highlighting the importance of booster vaccinations in this population. Reassuringly, high antibody cross-reactivity was found with current variants of concern, prior to Omicron subvariant adapted boostering. Multiple booster vaccine doses can provide effective protection from COVID-19, even with intensive anti-CD38 therapy for high-risk MM.

Daratumumab Use Prior to Kidney Transplant and T Cell-Mediated Rejection: A Case Report.

There is growing interest in daratumumab in the solid organ transplant realm owing to the potential immunomodulatory effects on CD38-expressing cells, primarily plasma cells, as they have a key role in antibody production. In particular there is interest in use of daratumumab for desensitization and potential treatment for antibody-mediated rejection. However, ongoing investigation with daratumumab has shown potential immunologic concerns in vitro, with a significant increase in populations of CD4-positive cytotoxic T cells and CD8-positive helper T cells in both peripheral blood and bone marrow that could lead to acute T cell-mediated rejection in the solid organ transplant patient. To date, there are no published reports of an association with daratumumab use and T cell-mediated rejection in vivo. In this case report we present what is to our knowledge the first documented case of an early severe T cell-mediated rejection in a low-immunologic-risk living-donor kidney transplant recipient who received daratumumab for multiple myeloma maintenance prior to transplant.

Steady-state versus chemotherapy-based hematopoietic cell mobilization after anti-CD38-based induction therapy in newly diagnosed multiple myeloma.

BACKGROUND: The incorporation of anti-CD38 monoclonal antibodies (mAb) in induction regimens of newly diagnosed transplant-eligible multiple myeloma (MM) patients has been established as a new standard. However, the optimal strategy of stem cell mobilization in this context is not yet clear. STUDY DESIGN AND METHODS: From May 2020 till September 2022, we retrospectively reviewed patients receiving anti-CD38 mAb-based induction therapy followed by stem cell mobilization either in a steady-state protocol (SSM) using 10 µg/kg granulocyte colony-stimulating factor (G-CSF) for 5 days or in a chemotherapy-based protocol (CM) using 1-4 g/m2 cyclophosphamide and G-CSF. RESULTS: Overall, 85 patients (median age 61 years) were included in the analysis. In total, 90 mobilization attempts were performed, 42 with SSM and 48 with CM. There was no significant difference in the median concentration of CD34+ cells in peripheral blood (PB) prior to apheresis between SSM and CM (61/µL vs. 55.4/µL; p = .60). Cumulative CD34+ yields did not differ between the groups with median of 6.68 and 6.75 × 106 /kg body weight, respectively (p = .35). The target yield (≥4 × 106 CD34+ cells/kg body weight) was reached in 88% (CM) and 86% (SSM), with a high proportion even after a single apheresis session (76% vs. 75%). Plerixafor was found to be more frequently used in SSM (52%) than in CM (23%; p < .01). A total of 83 patients underwent autologous transplantation and all were engrafted. CONCLUSIONS: Stem cell collection in patients undergoing anti-CD38-based induction therapy is feasible with either CM or SSM, although SSM more frequently requires plerixafor.

Mitigation of therapeutic anti-CD38 antibody interference with fab fragments: How well does it perform?

BACKGROUND: Administration of anti-CD38 antibodies is a state-of-the-art therapy for patients diagnosed with multiple myeloma (MM). However, this treatment frequently leads to pan-agglutination of red blood cells (RBCs) in patients' serological testing making accurate blood typing and timely transfusion of compatible blood a challenging effort. The antigen masking indirect antiglobulin test (AMIAT) is an approach to address this diagnostic challenge. STUDY DESIGN AND METHODS: A new reagent, called DaraEx plus, uses anti-CD38 Fab fragments to mitigate the anti-CD38 antibody interference in serological assays by masking CD38 on the cell surface. Its performance is extensively examined with commercial sera as well as with patient samples, and compared to the current standard method using dithiothreitol (DTT), which denatures the CD38 antigens on test panel erythrocytes. RESULTS: In the Bio-Rad ID System, DaraEx plus effectively mitigated the interference caused by anti-CD38 antibodies in 86% of patient samples tested while DTT was successful in only 68%. Moreover, there was no negative influence on DTT-sensitive blood group systems such as KEL upon DaraEx plus treatment. The agglutination reactions of all tested anti-CD38 antibodies (Daratumumab, Felzartamab, and Isatuximab) were inhibited by DaraEx plus. The treatment was successful only if DaraEx plus was added to the test cells before the sample. Some of the other gel card systems tested showed background reactions with DaraEx plus-treated cells. CONCLUSION: DaraEx plus treatment is straightforward and quick to perform. In the Bio-Rad ID System, it is superior to DTT treatment in the prevention of anti-CD38 antibody interference.

Real-world clinical outcomes in patients with relapsed and refractory multiple myeloma receiving VTD-PACE treatment in the era of monoclonal antibodies.

Bortezomib (Velcade), thalidomide, dexamethasone, platinum (cisplatin), adriamycin (doxorubicin), cyclophosphamide, and etoposide (VTD-PACE) are commonly used as salvage treatment for patients with relapsed/refractory multiple myeloma (RRMM). However, its outcomes in the era of monoclonal antibodies remain unclear. Therefore, this retrospective cohort study assessed the clinical outcomes of 60 patients with RRMM (median four prior treatment lines) administered VTD-PACE. The median follow-up period was 11.1 months, during which they received a median of two cycles of VTD-PACE. The overall response rate (ORR) was 66.7%; ORRs of 53.1 and 82.1% were noted in patients with ≥ 4 and ≤ 3 prior lines (P = 0.027), respectively. The median overall survival (OS) was 17 months, with a median progression-free survival (PFS) of 9.8 months. Using the 3-month time point after VTD-PACE treatment as a landmark, 54 patients were still alive. Landmark analysis was conducted for PFS and OS of patients who received or did not receive HSCT or CART after VTD-PACE treatment. Patients who underwent subsequent hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell therapy (CART) following VTD-PACE showed a trend of longer PFS and OS than those who did not undergo subsequent HSCT or CART. The median OS in patients with and without renal dysfunction was 10.7 months and 21.5 months, respectively (P = 0.0091). Therefore, VTD-PACE is useful as a bridging therapy for HSCT or CART, as a response can be expected regardless of organ damage, disease risk, or history of anti-CD38 antibody use.

Efficacy of isatuximab in combination with steroids for the treatment of relapsed/refractory multiple myeloma patients exhibiting only biochemical progression-A single center retrospective study.

OBJECTIVES: Isatuximab is approved for treatment of relapsed/refractory multiple myeloma (RRMM) with dexamethasone and carfilzomib or pomalidomide. Patients receiving these three-drug regimens have exhibited more Grade ≥ 3 adverse events (AEs) compared to the two-drug class combination of isatuximab and steroids alone. Thus, this single-center retrospective study investigated the efficacy of isatuximab with dexamethasone and methylprednisolone (ISAdm) for RRMM patients showing only biochemical progression (BP) of their disease. METHODS: Twenty-four RRMM patients exhibiting only BP were administered isatuximab at 10 mg/kg with dexamethasone once weekly for cycle 1 of a 28-day cycle, followed by every other week for each cycle thereafter. Starting in cycle 2, oral methylprednisolone was added every other day stopping 48 h before and starting 48 h after each dexamethasone infusion. RESULTS: Overall response rate and clinical benefit rate were 63% and 79%, respectively. Progression free survival was 12.9 months. There were only 5 AEs of Grade ≥ 3 which included lymphocytopenia (13%), leukopenia (4%), and neutropenia (4%). No Grade ≥ 3 AE related to respiratory infection, anemia, or thrombocytopenia were reported. CONCLUSION: This study shows that the two-drug class combination of ISAdm is an effective and well tolerated treatment option for RRMM patients exhibiting only BP.

Transient Daratumumab-Induced Refractive Shift in Multidrug-Resistant Multiple Myeloma: Case Report and Literature Review.

Daratumumab, an anti-CD38 monoclonal antibody, is worldwide approved for treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM) patients and is available as intravenous or subcutaneous formulations. Intravenous daratumumab is associated with frequent infusion-related reactions, while eye complications, especially refractive shifts, are very rare, with only previously reported cases. Here, we described a rare case of multi-refractory MM who developed transient myopic shift during intravenous daratumumab infusion successfully treated only with cycloplegic collyrium not requiring infusion rate lowering or drug discontinuation. This conservative therapeutic approach allowed termination of induction therapy and autologous hematopoietic stem-cell transplantation resulting in durable complete remission.

Better resolving of anti-CD38 antibody interference with blood compatibility testing by using manual polybrene method compared with dithiothreitol-pretreatment indirect antiglobulin test.

BACKGROUND: It is advised to pretreat the reagent erythrocytes with Dithiothreitol (DTT) to denature the surface CD38 to prevent anti-CD38 monoclonal antibodies (MoAb) from interfering with the blood compatibility test. Anti-CD38 has little impact on the Polybrene test, but it is still unknown how sensitive it is to detect irregular antibodies and how effective it is when compared to the standard DTT-based method. METHODS: Twenty-one patients receiving daratumumab (N = 13) and isatuximab (N = 8) had their serum collected. Standard anti-sera (anti-c, D, E, Fyb , Jka , M, Mia ) with serial dilution were added to patients' serum. Antibody screening tests were performed simultaneously using the manual polybrene method (MP) and DTT-pretreated, automatic indirect antiglobulin test (DTT-IAT) to compare the detection sensitivity. These two methods' operating times and costs were also analyzed. RESULTS: Both MP and DTT-IAT can overcome the interference caused by anti-CD38 MoAb. However, MP is more sensitive in detecting anti-M and anti-Mia and is comparable to DTT-IAT in detecting other antibodies. In terms of cost and operating time, MP is also far superior to DTT-IAT. CONCLUSION: MP is a cost-effective alternative to DTT-IAT in resolving anti-CD38 interference and is especially suitable for populations with a high prevalence of anti-M and anti-Mia . However, both methods have a well-known drawback of low detection sensitivity for anti-K, and K-units should be provided to patients to prevent hemolytic transfusion reactions.

Pharmacy considerations: Use of anti-CD38 monoclonal antibodies in relapsed and/or refractory multiple myeloma.

OBJECTIVE: This article reviews current evidence for the approved anti-CD38 monoclonal antibodies, isatuximab and daratumumab, for the treatment of patients with relapsed and/or refractory multiple myeloma (RRMM) and the implications for pharmacists. DATA SOURCES: We conducted a literature search on PubMed/Medline and other sources using the drug names and the terms CD38, multiple myeloma, and pharmacists. DATA SUMMARY: Monoclonal antibodies targeting the CD38 transmembrane glycoprotein offer a promising treatment approach for patients with RRMM. Isatuximab and daratumumab bind to different epitopes on CD38. In this review, we describe the similarities and differences in their mechanism of action, regulatory labeling, and the current guidelines for isatuximab and daratumumab use in RRMM. We review the current evidence for the efficacy and safety of these agents in combination with pomalidomide or carfilzomib and dexamethasone from the landmark phase 3 clinical trials that led to their approval. We discuss key differences in the eligibility criteria between the clinical trials, and differences in dosing, administration, available formulations, and pre- and post-infusion medications for the two agents. We outline recent data from pharmacoeconomic analyses comparing the cost-effectiveness of isatuximab-based regimens with that of daratumumab-based regimens. A brief overview of other anti-CD38 agents in the pipeline for the treatment of patients with RRMM is presented. CONCLUSIONS: Given that pharmacists play an integral role in driving cost-effective use of drugs without compromising efficacy and safety for the end user, educating pharmacists on the key differences between isatuximab and daratumumab can guide the selection of the appropriate anti-CD38 antibody.

Novel therapies for immune thrombocytopenia.

Current therapies for immune thrombocytopenia (ITP) are successful in providing a haemostatic platelet count in over two-thirds of patients. Still, some patients have an inadequate response and there is a need for other therapies. A number of novel therapies for ITP are currently being developed based upon the current pathophysiology of ITP. Many therapies are targetted at reducing platelet destruction by decreasing anti-platelet antibody production by immunosuppression with monoclonal antibodies targetted against CD40, CD38 and the immunoproteasome or physically reducing the anti-platelet antibody concentration by inhibition of the neonatal Fc receptor. Others target the phagocytic system by inhibiting FcγR function with staphylococcal protein A, hypersialylated IgG, polymeric Fc fragments, or Bruton kinase. With a recognition that platelet destruction is also mediated by complement, inhibitors of C1s are also being tested. Inhibition of platelet desialylation may also play a role. Other novel therapies promote platelet production with new oral thrombopoietin receptor agonists or the use of low-level laser light to improve mitochondrial activity and prevent megakaryocyte apoptosis. This review will focus on these novel mechanisms for treating ITP and assess the status of treatments currently under development. Successful new treatments for ITP might also provide a pathway to treat other autoimmune disorders.

Depletion of CD38-positive regulatory T cells by anti-CD38 monoclonal antibodies induces a durable response to SARS-CoV-2 vaccination in patients with plasma cell dyscrasia.

This study reports the relationship between CD38+ regulatory T cells (Tregs) and messenger RNA coronavirus disease 2019 (mRNA-COVID-19) vaccination in 60 patients with plasma cell dyscrasia. Patients treated with anti-CD38 monoclonal antibodies (mAbs) had significantly lower CD38+ Tregs than those not treated (0.9 vs. 13.2/µl). Late-responders, whose antibody titres increased from weeks 4-12 after the second vaccination, had significantly lower CD38+ Treg counts than non-late-responders (2.5 vs. 10.3/µl). Antibody titres in patients with lower CD38+ Treg levels were maintained from weeks 4-12 but decreased in those with higher CD38+ Treg levels. Therefore, depletion of CD38+ Tregs by anti-CD38 mAbs may induce a durable response to mRNA-COVID-19 vaccination.

Practice patterns and outcomes for triple-class exposed patients with relapsed/refractory multiple myeloma in Japan.

Aim: Treatment options for triple-class exposed (TCE) patients with multiple myeloma (MM) in Japan are limited. Materials & methods: Retrospective observational study using the Medical Data Vision database (April 2008-April 2021). Eligible adults with MM received a new post-TCE treatment. Treatments, healthcare resource utilization (HCRU) and costs (per patient per month [PPPM]) were analyzed with subgroup analyses by prior stem cell transplantation (SCT vs No SCT). Results: Of 459 TCE patients, 216 (47%) had post-TCE treatment of whom 194 (90%) had no prior SCT. Median duration of the first post-TCE line of therapy (LOT) was 2 months; 49% of No SCT patients received a subsequent LOT. Total healthcare costs were comparable between No SCT and SCT groups (¥1.3 million PPPM each; US$12,328 and $12,391, respectively), driven by treatment costs. Median post-index overall survival (n = 216) was 15.8 months (95% CI: 10.5, 22.3). Conclusion: New treatments with better effectiveness are needed for patients with TCE MM in Japan.

Treatment options are limited for patients with multiple myeloma (MM) in Japan who have received the 3 classes of drugs known as immunomodulatory drugs, proteasome inhibitors and anti-CD38 monoclonal antibodies, and are considered to be 'triple-class exposed' (TCE). The objective of this study was to understand the characteristics of this patient population and the treatments they received after becoming TCE. The study evaluated healthcare resources and costs and considered whether patients had received stem cell transplant as their first treatment, where cells that may differentiate into blood cells are administered. This study analyzed a database of anonymous patients' medical records collected from April 2008 through April 2021 in Japan. A total of 216 patients were included, of whom 194 never received stem cell transplantation. Patients who received treatment after being considered TCE received that first treatment for a median of 2 months. All patients who received treatment after TCE had a median overall survival of 15.8 months meaning half the patients were still alive after receiving treatment at 15.8 months. Patients who did not have a stem cell transplant after diagnosis had a median overall survival of 17.4 months. Healthcare resources were similar between groups, except those who did not have stem cell transplantation after diagnosis needed more medications. Both groups had total healthcare costs of ¥1.3 million per patient per month. These findings support the need for new treatments and future studies to understand how new treatments would help TCE relapsed or refractory multiple myeloma patients in Japan.

Innovative Anti-CD38 and Anti-BCMA Targeted Therapies in Multiple Myeloma: Mechanisms of Action and Resistance.

CD38 and B-cell maturation antigens (BCMAs) are prevalently expressed on neoplastic plasma cells in multiple myeloma (MM), making them ideal therapeutic targets. Anti-CD38 monoclonal antibodies, such as approved daratumumab and isatuximab, are currently the milestone in MM treatment because they induce plasma cell apoptosis and kill through several mechanisms, including antibody-dependent cellular cytotoxicity or phagocytosis. BCMA is considered an excellent target in MM, and three different therapeutic strategies are either already available in clinical practice or under investigation: antibody-drug conjugates, such as belantamab-mafodotin; bispecific T cell engagers; and chimeric antigen receptor-modified T cell therapies. Despite the impressive clinical efficacy of these new strategies in the treatment of newly diagnosed or multi-refractory MM patients, several mechanisms of resistance have already been described, including antigen downregulation, the impairment of antibody-dependent cell cytotoxicity and phagocytosis, T- and natural killer cell senescence, and exhaustion. In this review, we summarize the current knowledge on the mechanisms of action and resistance of anti-CD38 and anti-BCMA agents and their clinical efficacy and safety.

EMA Review of Isatuximab in Combination with Pomalidomide and Dexamethasone for the Treatment of Adult Patients with Relapsed and Refractory Multiple Myeloma.

Isatuximab is a monoclonal antibody that binds to the human CD38 antigen. On May 30, 2020, a marketing authorization valid through the European Union (EU) was issued for isatuximab in combination with pomalidomide and dexamethasone (IsaPd) for the treatment of adult patients with relapsed and refractory (RR) multiple myeloma (MM). The recommended dose of isatuximab was 10 mg/kg, administered intravenously weekly at cycle 1 and then biweekly in subsequent 28-day cycles. Isatuximab was evaluated in a phase III, open-label, multicenter, randomized trial that randomly allocated IsaPd versus pomalidomide plus dexamethasone (Pd) to adult patients with RR MM. The primary endpoint of the trial was progression-free survival, as assessed by an independent review committee, which was superior for the IsaPd arm (hazard ratio, 0.596; 95% confidence interval, 0.436-0.814; p = .001) compared with the Pd arm. Treatment with IsaPd led to higher incidences of treatment-related adverse events (AEs), grade ≥ 3 AEs, and serious AEs compared with Pd treatment. Most frequently observed AEs that occurred more often in the IsaPd arm were infusion-related reactions, infections, respiratory AEs, neutropenia (including neutropenic complications), and thrombocytopenia. The aim of this article is to summarize the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Isatuximab was approved in the European Union, in combination with pomalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have already received therapy but whose disease did not respond or relapsed afterward. The addition of isatuximab resulted in a clinically meaningful and significant prolongation of the time from treatment initiation to further disease relapse or patient's death. The safety profile was considered acceptable, and the benefit-risk ratio was determined to be positive.

Infection risks in multiple myeloma: a systematic review and meta-analysis of randomized trials from 2015 to 2019.

BACKGROUND: Patients with multiple myeloma (MM) remain at an increased risk of infection due to the disease process, as well as the ensuing treatments. METHODS: We performed a systematic review to evaluate the monthly risk of grade III/IV infection, pneumonia, and neutropenia in patients with myeloma enrolled in randomized clinical trials (RCTs). RESULTS: The risk of grade III or higher infection, pneumonia, and neutropenia persists among all phases of treatment. There was no statistical difference in grade III or higher infection, pneumonia, and neutropenia between frontline and relapsed/refractory setting. In the maintenance setting, the complications of infection, pneumonia, and neutropenia were low, but not negligible. Three-drug regimens were no more likely than two-drug regimens to have an increased risk of Grade III or higher infection. CONCLUSIONS: This is the first study to quantify the monthly risk of grade III or higher infection, pneumonia, and neutropenia across different treatment regimens in the frontline, maintenance, and relapsed/refractory settings. The results of our systematic review demonstrate a significant risk for severe infection, pneumonia, and neutropenia in patients with MM. Further studies are needed to determine the value of antibiotic prophylaxis in a broader myeloma patient population, as well as other approaches that will further mitigate the morbidity and mortality related to infection in this vulnerable patient population.