Multiple Myeloma Therapy Research Articles

Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma

AbstractB-cell maturation antigen (BCMA)–targeting therapeutics have dramatically improved outcomes in relapsed/refractory multiple myeloma (RRMM). However, whether the mechanisms of resistance between these therapies are shared and how the identification of such mechanisms before therapy initiation could refine clinical decision-making remains undefined. We analyzed outcomes for 72 RRMM patients treated with teclistamab, a CD3 × BCMA bispecific antibody, 42% (30/72) of whom had prior BCMA-directed therapy exposure. Malignant plasma cell BCMA expression was present in all BCMA therapy–naïve patients. Prior therapy–mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and 1 of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from 1 patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA–directed treatments, underscoring the importance of verifying the presence of a target antigen.

Beyond BCMA: the next wave of CAR T cell therapy in multiple myeloma.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape of relapsed/refractory multiple myeloma. The current Food and Drug Administration approved CAR T cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel both target B cell maturation antigen (BCMA), which is expressed on the surface of malignant plasma cells. Despite deep initial responses in most patients, relapse after anti-BCMA CAR T cell therapy is common. Investigations of acquired resistance to anti-BCMA CAR T cell therapy are underway. Meanwhile, other viable antigenic targets are being pursued, including G protein-coupled receptor class C group 5 member D (GPRC5D), signaling lymphocytic activation molecule family member 7 (SLAMF7), and CD38, among others. CAR T cells targeting these antigens, alone or in combination with anti-BCMA approaches, appear to be highly promising as they move from preclinical studies to early phase clinical trials. This review summarizes the current data with novel CAR T cell targets beyond BCMA that have the potential to enter the treatment landscape in the near future.

A research center’s experience of T-cell–redirecting therapies in triple-class refractory multiple myeloma

AbstractThe efficacies of chimeric antigen receptor T cells (CAR-Ts) and bispecific monoclonal antibodies (BiAbs) for triple-class refractory (TCR) myeloma have not previously been compared, and clinical data on how to rescue patients after relapse from these immunotherapies are limited. A retrospective study of 73 TCR patients included in trials was conducted: 36 received CAR-Ts and 37 received BiAbs. CAR-Ts produced a higher overall response rate (ORR) than BiAbs (97.1% vs 56.8%, P = .002). After a median of follow-up of 18.7 months, no significant difference in progression-free survival (PFS) was observed between the CAR-T and BiAbs groups (16.6 vs 10.8 months; P = .090), whereas overall survival (OS) was significantly longer in the CAR-T than in the BiAbs group (49.2 vs 22.6 months; P = .021). BiAbs after CAR-Ts yielded a higher ORR and longer PFS2 than did nonredirecting T-cell therapies after CAR-Ts (ORR: 87.5% vs 50.0%; PFS2: 22.9 vs 12.4 months). By contrast, BiAbs after BiAbs resulted in an ORR of 33% and PFS2 of 8.4 months, which was similar to that produced by the nonredirecting T-cell therapies (ORR: 28.6%; PFS2: 8.1 months). Although this is a pooled analysis of different trials with different products and the patient profile is different for CAR-Ts and BiAbs, both were effective therapies for TCR myeloma. However, in our experience, although the PFS was similar with the 2 approaches, CAR-T therapy resulted in better OS, mainly because of the efficacy of BiAbs as rescue therapy. Our results highlight the importance of treatment sequence in real-word experience.

Mass spectrometry–based assessment of M protein in peripheral blood during maintenance therapy in multiple myeloma

AbstractMass spectrometry (MS) can detect multiple myeloma–derived monoclonal proteins in the peripheral blood (PB) with high sensitivity, potentially serving as a PB assay for measurable residual disease (MRD). This study evaluated the significance of PB MS MRD negativity during posttransplant therapy in patients with newly diagnosed multiple myeloma. Serum samples from 138 patients treated in the phase 3 ATLAS trial of posttransplant maintenance with either carfilzomib, lenalidomide, and dexamethasone, or with lenalidomide alone were analyzed using EXENT MS methodology. We established feasibility of measuring MRD by MS in the PB in the posttransplant setting, despite unavailability of pretreatment calibration samples. There was high agreement between MRD by MS in the PB and paired bone marrow (BM) MRD results at the 10–5 threshold, assessed by either next-generation sequencing (NGS) or multiparameter flow cytometry (MFC) (70% and 67%, respectively). Agreement between PB MS and both BM MRD methods was lowest early after transplant and increased with time. MS negativity was associated with improved progression-free survival (PFS), which, in landmark analysis, reached statistical significance after 18 cycles after transplant. Combined PB/BM MRD negativity by MFC or NGS was associated with superior PFS compared with MRD negativity by only 1 modality. Sustained MS negativity carried similar prognostic performance to sustained BM MRD negativity at the 10–5 threshold. Overall, posttransplant MS assessment was feasible and provided additional prognostic information to BM MRD negativity. Further studies are needed to confirm the role and optimal timing of MS in disease evaluation algorithms. The ATLAS trial is registered at www.clinicaltrials.gov as #NCT02659293.

MYC Inhibition Potentiates CD8+ T Cells Against Multiple Myeloma and Overcomes Immunomodulatory Drug Resistance.

Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, are a cornerstone of multiple myeloma (MM) therapies, yet the disease inevitably becomes refractory. IMiDs exert cytotoxicity by inducing cereblon-dependent proteasomal degradation of IKZF1 and IKZF3, resulting in downregulation of the oncogenic transcription factors IRF4 and MYC. To date, clinical IMiD resistance independent of cereblon or IKZF1/3 has not been well explored. Here, we investigated the roles of IRF4 and MYC in this context. Using bone marrow aspirates from patients with IMiD-naïve or refractory MM, we examined IKZF1/3 protein levels and IRF4/MYC gene expression following ex vivo pomalidomide treatment via flow cytometry and qPCR. We also assessed exvivo sensitivity to the MYC inhibitor MYCi975 using flow cytometry. We discovered that although pomalidomide frequently led to IKZF1/3 degradation in MM cells, it did not affect MYC gene expression in most IMiD-refractory samples. We subsequently demonstrated that MYCi975 exerted strong anti-MM effects in both IMiD-naïve and -refractory samples. Unexpectedly, we identified a cluster of differentiation 8+ (CD8+ T) cells from patients with MM as crucial effectors of MYCi975-induced cytotoxicity in primary MM samples, and we discovered that MYCi975 enhanced the cytotoxic functions of memory CD8+ T cells. We lastly observed synergy between MYCi975 and pomalidomide in IMiD-refractory samples, suggesting that restoring MYC downregulation can re-sensitize refractory MM to IMiDs. Our study supports the concept that MYC represents an Achilles' heel in MM across disease states and that MYCi975 may be a promising therapeutic for patients with MM, particularly in combination with IMiDs.

Evaluation of serum cystatin C levels in multiple myeloma: diagnostic significance and clinical implications

Cystatin C (CysC) levels in patients with multiple myeloma (MM) have been linked to tumour load and outcomes’ prediction. This study aimed at assessing the diagnostic utility of CysC in distinguishing MM patients from controls and advanced stages of MM. In total, 98 MM patients and 57 healthy controls participated in this cross-sectional case-control study. Demographic, clinical, and biochemical data were assessed. The study groups exhibited significantly diverse measures of urea, creatinine, CysC, β2-microglobulin, and lactate dehydrogenase activity. β2-Microglobulin was found to be a reliable predictor for both the MM staging and its diagnosis, but CysC was found to only possess a partial capacity of predicting advanced MM stages. Our results highlight the significance of taking into account many biomarkers in the therapy of MM, so as to achieve effective clinical evaluation. More research is required in order to clarify the CysC implication in the prognosis and management of MM.

Clinical and economic implications of using daratumubab with lenalidomide in the 1st and 2nd lines of therapy for multiple myeloma patients

Objective: to assess clinical and economic implications of adding daratumumab (Dara) to the “lenalidomide + dexamethasone” (Rd) treatment program in early lines of therapy for patients with multiple myeloma (MM) ineligible for high-dose chemotherapy (HDCT) with subsequent autologous hematopoietic stem cell transplantation (autoHPSCT).Material and methods. Partitioned survival model was developed to compare overall survival in the treatment programs of MM patients in the 1st to 3rd lines of therapy. The following treatment options were included in the analysis: 1st line – Dara+Rd; 2nd line – “carfilzomib + lenalidomide” (K+Rd) or “ixazomib + lenalidomide” (Ixa+Rd) triplets; 3rd line – pomalidomide (Pom+dex) and Rd+(Dara+Rd)+(Pom+dex) versus Rd+(K/Ixa+Rd)+(Pom+dex/Dara). Probabilities of transition between health states (progression-free, progressed disease, and death) were based on published clinical data. Lifetime direct healthcare costs and incremental cost-effectiveness ratios (ICERs) per 1 life year gained were calculated from a Russian health care perspective. The indicator of the difference in costs between current and expected practice was used in budget impact analysis.Results. Dara+Rd combination increased life expectancy by 1.04 years (+16.05%) and 0.95 years (+14.57%) per patient, and in the target population (n=955) by 995.48 and 903.40 years for (Dara+Rd)+(K+Rd)+(Pom+dex) and (Dara+Rd)+(Ixa+Rd)+(Pom+dex) treatment programs, respectively, compared to Rd use in the 1st line. The ICER per 1 life year gained for Dara+Rd in 1st line therapy was 8.95 mln rubles for (Dara+Rd)+(K+Rd)+(Pom+dex) and 8.41 mln rubles for (Dara+Rd)+(Ixa+Rd)+(Pom+dex). It's lower than the median ICER of 13.64 million per 1 life year gained for antitumor drugs used to treat cancer of lymphatic and hematopoietic tissues (reference ICER). Dara+Rd triplet is used in 2nd line therapy after Rd, the number of life years gained in the target population due to greater efficacy is higher by 291.50 years compared with K+Rd and by 203.93 years compared with Ixa+Rd. The ICER per 1 life year gained for Dara+Rd is also lower than the ICER reference value: 9.25 mln rubles versus 13.64 mln rubles. The budget impact analysis showed that using Dara in early stages of MM therapy does not increase drug provision costs in the target population.Conclusion. The obtained results allowed to conclude that it is economically feasible to add Dara to the 1st and 2nd lines of therapy in lenalidomide treatment programs for MM patients who are not candidates for HDCT with autoHPSCT.

Influence of lithium ion doping and mitoxantrone hydrochloride loading on the structure and in vitro biological properties of mesoporous bioactive glass microspheres in the treatment of multiple myeloma

Multiple myeloma (MM) is an incurable plasma cell hematologic tumor in which bone pain is a typical symptom. The current main treatment methods not only easily cause multidrug resistance but also cause bacterial infections. Therefore, improving multidrug resistance and bacterial infection during MM therapy and repairing bone defects caused by bone pain are necessary. In this work, we propose a drug delivery platform of lithium-doped bioactive glass microspheres (7Li-MBGs) with a mesoporous structure (2–5 nm) and a high specific surface area (636 m2/g) to achieve these functions. Interestingly, lithium ions are network modifier doped into the silicon-oxygen network. This in turn affects the dissolution and release behavior of silicon ions in the MBGs network. Thus, the bioactive response as well as drug release of the MBGs were enhanced. During this process, hydroxyapatite easily forms on the surface, which has a therapeutic effect on bone defects caused by MM. The drug (mitoxantrone hydrochloride, MTO) release mechanism is diffusion-driven, suggesting that drug/platform interactions are key determinants of release kinetics and depend on the release medium environment and platform structure. In vitro antibacterial and cytotoxicity experiments proved that the synergistic effect of Li ions and the MTO improved the antibacterial ability of the MBGs (> 98%) and the ability to treat MM. Therefore, the proposed 7Li-MBGs drug delivery platform can effectively release drugs in the long-term, repair bone defects, inhibit bacterial growth and tumor cell activity, and provide new ideas for the treatment of MM.

Oral Domiciliary Therapy of Multiple Myeloma with Cyclophosphamide, Pomalidomide and Dexamethasone Regimen in the Covid Era - A Pilot Study

Background: Multiple myeloma is the 11th most common cancer in India, with a prevalence of 1.1% and a diagnosis age range of 65 to 74 years. Various doublet or triplet combinations of steroids, immunomodulatory medications, proteasome inhibitors, and monoclonal antibodies are used in standard myeloma therapy. Covid 19 pandemic has been extremely challenging especially when it comes to the management of cancer patients. As the incidence of multiple myeloma (MM) is increasing rapidly in Asian countries, and the Asian patients seem to respond differently compared to the western population to the various commonly used treatment regimens, these patients require special consideration and care to ensure optimum treatment and at the same time, precautions must be taken to decrease their exposure to COVID-19. Considering these aspects, we decided to use an all-oral treatment of CyPomDexa (Cyclophosphamide, Pomalidomide and Dexamethasone) for the treatment of myeloma both as a first-line regimen as well as for relapsed and refractory patients who had not been exposed to this regimen in the past, and to observe the feasibility and efficacy of domiciliary, oral treatment with cyclophosphamide, pomalidomide and dexamethasone (Cy-Pom-Dex) for myeloma patients during the COVID-19 pandemic. Methods: A Prospective, observational, single-arm, pilot study was conducted from 1st March 2020 to 30th September 2020 in patients who were newly-diagnosed (NDMM) or relapsed multiple myeloma (RMM) at a tertiary care Centre in Bengaluru. The patients were started on oral treatment with CyPomDexa during lockdown mandated by the COVID-19 pandemic. This regimen was chosen as a replacement for cyclophosphamide, bortezomib, dexamethasone (CyBorD), which was the previous standard of care in our centre. Haematological and biochemical parameters of the patients were checked pre-treatment. Weekly complete blood counts and biochemistry was checked with home collection of blood samples. This was combined with weekly video consultations. Face-to-face visits were conducted monthly, and myeloma parameters were checked at the end of every 2 months. Results: 6 patients underwent the planned treatment. Among these 4 had NDMM and 2 had RMM. 1 patient who received CyPomDexa from the first cycle was lost to follow-up (COVID 19 positive). Among the remaining 5 patients ,3 (50%) achieved VGPR (very good partial response) and 2 (33.33%) achieved SCR (Stringent Complete Response) after 4 cycles of therapy. Conclusion: This regimen achieved good disease control in all the evaluable patients, within 4 cycles. A larger, prospective study is however required to draw definitive conclusions.

TACTUM: Trends in Access to Cellular Therapies in Multiple Myeloma, Perspectives of Treating Versus Referring Physicians

Chimeric antigen receptor T cell therapy (CAR-T) and bispecific T cell engagers (TCE) for multiple myeloma (MM) are readily available at many large US medical centers. However, many potentially eligible patients may not be referred to the specialized centers administering these therapies. Perspectives regarding potential barriers for MM cellular therapy from referring-center oncologists (ROs) versus treating-center oncologists (TOs) have not been reported previously. We conducted TACTUM-23, a survey of US oncologists who treat MM, to identify perceived barriers to these cellular therapies. This 24-question survey, which focused on demographics and perceived barriers to CAR-T and TCE, was conducted between June and August 2023. Of 247 oncologists, 37 (15%) completed the survey including 26 (70%) TOs who prescribed both CAR-T and TCEs, 4 (11%) TOs who only prescribed TCEs, and 7 (19%) ROs who referred patients. The top RO-stated barrier to CAR-T was financial toxicity, while the top TO-stated barrier to CAR-T was leukapheresis/ manufacturing slot availability. The top RO-stated barrier to TCE was financial toxicity, while the top TO-stated barrier to TCE was the hospitalization requirement. In conclusion, financial concerns are perceived by ROs to be the top barrier to both CAR-T and TCEs in myeloma. In contrast, TOs perceive logistical concerns to be the top barrier. Interventions to lower financial toxicity during these therapies, and outreach to raise awareness of such interventions among ROs, are needed alongside strategies to streamline manufacturing (for CAR-T) and monitoring.

Interleukin-33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species-mediated inhibition of nuclear factor kappa-B signal and stemness properties.

The proteasome inhibitor bortezomib (BTZ) is the first-line therapy for multiple myeloma (MM). BTZ resistance largely limits its clinical application in MM. Interleukin-33 (IL-33) exerts antitumor effects through various mechanisms, including enhancing antitumor immunity and promoting the apoptosis of cancer cells. Here, the synergistic anti-MM effect of IL-33 and BTZ was verified, and the underlying mechanisms were elucidated. Bioinformatic analysis indicated that IL-33 expression levels were downregulated in MM, and that BTZ-treated MM patients with high IL-33 levels had better prognosis than those with low IL-33 levels. Moreover, the patients with high IL-33 levels had a better treatment response to BTZ. Further immune analysis suggested that IL-33 can enhance the anti-MM immunity. IL-33 and BTZ synergistically inhibited proliferation and induced apoptosis of MM cells, which was mediated by the excessive accumulation of cellular reactive oxygen species (ROS). Furthermore, increased ROS hindered the nuclear translocation of NF-κB-p65, thereby decreasing the transcription of target stemness-related genes (SOX2, MYC, and OCT3/4). These effects induced by the combination therapy could be reversed by eliminating ROS by N-acetylcysteine. In conclusion, our results indicated that IL-33 enhanced the sensitivity of MM to BTZ through ROS-mediated inhibition of nuclear factor kappa-B (NF-κB) signal and stemness properties.

Minimal Residual Disease-Adapted Therapy in Multiple Myeloma: Current Evidence and Opinions.

Multiple myeloma (MM) is a biologically heterogeneous malignancy with relatively uniform treatment paradigms. This review aims to assess the growing role of Minimal Residual Disease (MRD) assessment in facilitating response-adapted therapeutic decision making to individualize therapy in MM. MRD has been repeatedly demonstrated to provide strong prognostic information, superseding traditional IMWG response criteria. The use of MRD to modulate therapy remains controversial. Here, we review the existing landscape of MRD-adapted trial designs in both induction/consolidation and maintenance settings, including recent data from influential studies and retrospective analyses. We navigate existing data, leverage the increased resolution of longitudinal MRD assessments, and comment on trials in progress to explain our current utilization of MRD in the clinic. MRD transcends traditional response assessments by providing a window into disease-treatment interaction over time. As a strong patient-level surrogate, MRD has limited current use in individualizing treatment, but is poised to comprehensively shape treatment strategies at many key points in a patient's MM course.

Patient perspectives on BCMA-targeted therapies for multiple myeloma: a survey conducted in a patient advocacy group.

Advances in multiple myeloma (MM) treatment have shifted the therapeutic landscape. Understanding patients' perspectives can assist physicians in helping patients make informed decisions. This study aimed to understand the patient decision-making process and gain insights into patient perspectives on B-cell maturation antigen (BCMA)-targeted therapies for MM. An 18-question survey was completed by patients with MM enrolled in HealthTree® Cure Hub, an online portal helping patients with plasma cell dyscrasias navigate their disease. From October 28, 2022, to January 12, 2023, 325 patients with MM participated in the survey. The mean age (standard deviation) of the respondents was 66 (8) years; 54% were female and 90% were White. Among 218 patients with complete clinical records in the database, the median (min, max) lines of therapy (LOT) was 2 (1,16). Among 61 (28%) patients who had received ≥4 LOTs, 55 (90%) were triple-class exposed. Of the 290 patients who responded to the question about openness to new therapies, 76 (26%) were open to trying a new therapy immediately and 125 (43%) wanted more information on safety and efficacy. Most respondents reported likely or very likely to try a BCMA CAR T-cell therapy (60%) or a bispecific antibody (74%) and some needed more information to decide (16% for CAR T-cell therapy and 13% for bispecific antibody). The most requested information included efficacy, side effects (SEs), eligibility, and administration process for both CAR T-cell and bispecific therapies. When 2 therapies with the same efficacy and duration of response were offered, 69% of respondents would prefer the therapy with a lower risk of severe SEs but requires continuous dosing with no treatment-free interval, and 31% preferred a therapy given once followed by a treatment-free interval but with a potentially higher risk of severe SEs. To receive an effective therapy, the top acceptable trade-offs included frequent monitoring of SEs and initiating a new therapy in a hospital setting, and the least acceptable compromise was caregiver burden. This study found a high level of openness in patients with MM to try BCMA-targeted therapies. Information on efficacy, safety, availability, and eligibility may assist patients on decision-making.

Immune escape of multiple myeloma cells results from low miR29b and the ensuing epigenetic silencing of proteasome genes

BackgroundActivation of CD28 on multiple myeloma (MM) plasma cells, by binding to CD80 and CD86 on dendritic cells, decreases proteasome subunit expression in the tumor cells and thereby helps them evade being killed by CD8+ T cells. Understanding how CD28 activation leads to proteasome subunit downregulation is needed to design new MM therapies.MethodsThis study investigates the molecular pathway downstream of CD28 activation, using an in vitro model consisting of myeloma cell lines stimulated with anti-CD28-coated beads.ResultsWe show that CD28 engagement on U266 and RPMI 8226 cells activates the PI3K/AKT pathway, reduces miR29b expression, increases the expression of DNA methyltransferase 3B (DNMT3B, a target of miR29b), and decreases immunoproteasome subunit expression. In vitro transfection of U266 and RPMI 8226 cells with a miR29b mimic downregulates the PI3K/AKT pathway and DNMT3B expression, restores proteasome subunit levels, and promotes myeloma cell killing by bone marrow CD8+ T cells from MM patients. Freshly purified bone marrow plasma cells (CD138+) from MM patients have lower miR29b and higher DNMT3B (mRNA and protein) than do cells from patients with monoclonal gammopathy of undetermined significance. Finally, in MM patients, high DNMT3B levels associate with shorter overall survival.ConclusionsAltogether, this study describes a novel molecular pathway in MM. This pathway starts from CD28 expressed on tumor plasma cells and, through the PI3K-miR29b-DNMT3B axis, leads to epigenetic silencing of immunoproteasome subunits, allowing MM plasma cells to elude immunosurveillance. This discovery has implications for the design of innovative miR29b-based therapies for MM.

Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma.

Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8+ T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma.

Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma

In multiple myeloma (MM), B cell maturation antigen (BCMA)-directed CAR T cells have emerged as a novel therapy with potential for long-term disease control. Anti-BCMA CAR T cells with a CD8-based transmembrane (TM) and CD137 (41BB) as intracellular costimulatory domain are in routine clinical use. As the CAR construct architecture can differentially impact performance and efficacy, the optimal construction of a BCMA-targeting CAR remains to be elucidated. Here, we hypothesized that varying the constituents of the CAR structure known to impact performance could shed light on how to improve established anti-BCMA CAR constructs. CD8TM.41BBIC-based anti-BCMA CAR vectors with either a long linker or a short linker between the light and heavy scFv chain, CD28TM.41BBIC-based and CD28TM.CD28IC-based anti-BCMA CAR vector systems were used in primary human T cells. MM cell lines were used as target cells. The short linker anti-BCMA CAR demonstrated higher cytokine production, whereas in vitro cytotoxicity, T cell differentiation upon activation and proliferation were superior for the CD28TM.CD28IC-based CAR. While CD28TM.CD28IC-based CAR T cells killed MM cells faster, the persistence of 41BBIC-based constructs was superior in vivo. While CD28 and 41BB costimulation come with different in vitro and in vivo advantages, this did not translate into a superior outcome for either tested model. In conclusion, this study showcases the need to study the influence of different CAR architectures based on an identical scFv individually. It indicates that current scFv-based anti-BCMA CAR with clinical utility may already be at their functional optimum regarding the known structural variations of the scFv linker.

Therapeutic progress in relapsed/refractory multiple myeloma.

Improvement in the therapeutics for multiple myeloma (MM) has been continuously developed owing to the application of novel drugs and technologies in the last 20 years. The standard first-line therapy for MM consists of a three-drug induction regimen based on immunomodulatory drugs and proteasome inhibitors combined with autologous stem cell transplantation. However, MM remains incurable; therefore, therapies for relapsed/refractory MM (RRMM) are emerging and evolving rapidly. This study aimed to summarize and review the results of RRMM trials over the past 5 years to provide a holistic overview and insights for practitioners in related fields and to provide additional ideas for clinical trialists. This study shows that daratumumab and isatuximab continue to significantly advance as treatment options. Additionally, novel antibody drugs, such as elotuzumab and selinexor, as well as bispecific antibodies, teclistamab and talquetamab, are currently undergoing clinical research with promising outcomes. However, chimeric antigen receptor-T cell therapy targeting B-cell maturation antigen remains the optimal approach for MM treatment.

Targeted therapy for multiple myeloma: an overview on CD138-based strategies.

Multiple myeloma (MM) is an incurable hematological disease characterized by the uncontrolled growth of plasma cells primarily in the bone marrow. Although its treatment consists of the administration of combined therapy regimens mainly based on immunomodulators and proteosome inhibitors, MM remains incurable, and most patients suffer from relapsed/refractory disease with poor prognosis and survival. The robust results achieved by immunotherapy targeting MM-associated antigens CD38 and CD319 (also known as SLAMF7) have drawn attention to the development of new immune-based strategies and different innovative compounds in the treatment of MM, including new monoclonal antibodies, antibody-drug conjugates, recombinant proteins, synthetic peptides, and adaptive cellular therapies. In this context, Syndecan1 (CD138 or SDC1), a transmembrane heparan sulfate proteoglycan that is upregulated in malignant plasma cells, has gained increasing attention in the panorama of MM target antigens, since its key role in MM tumorigenesis, progression and aggressiveness has been largely reported. Here, our aim is to provide an overview of the most important aspects of MM disease and to investigate the molecular functions of CD138 in physiologic and malignant cell states. In addition, we will shed light on the CD138-based therapeutic approaches currently being tested in preclinical and/or clinical phases in MM and discuss their properties, mechanisms of action and clinical applications.

BPI24-017: Optimizing the Implementation of New Therapies in Multiple Myeloma.

BPI24-017: Optimizing the Implementation of New Therapies in Multiple Myeloma.

Isatuximab-Specific Immunofixation Electrophoresis Assay to Remove Interference in Serum M-Protein Measurement in Patients with Multiple Myeloma.

Isatuximab, an IgG-kappa (IgGκ) anti-cluster of differentiation 38 (CD38) monoclonal antibody approved for use in patients with relapsed or refractory multiple myeloma (MM), can potentially interfere with the visualization of endogenous monoclonal protein (M-protein) on standard immunofixation electrophoresis (IFE) and lead to inaccurate classification of a patient's response to therapy. The Hydrashift 2/4 isatuximab IFE assay (Hydrashift isatuximab assay) removes isatuximab interference from IFE. Using samples from patients enrolled in clinical trials of isatuximab-based therapy for MM, we demonstrate how the Hydrashift isatuximab assay improves the ability to detect residual M-protein and offer recommendations for when the assay is most useful. Samples from 141 patients with a variety of known M-protein isotypes were selected and analyzed by standard IFE and the Hydrashift isatuximab assay. A positive control containing isatuximab was run on every standard IFE and Hydrashift gel. The Hydrashift isatuximab assay reliably shifted the migration of isatuximab in patient samples. Standard IFE was adequate for determining 104 patients' M-protein status, and the Hydrashift isatuximab assay confirmed these results. In samples from 37 patients with a history of IgGκ MM and a single IgGκ band visible on standard IFE near the isatuximab migration site, the Hydrashift isatuximab assay was able to separate isatuximab from endogenous M-protein, identifying residual M-protein in 17 samples and preventing false-positive interpretations of standard IFE in 20 samples. The Hydrashift isatuximab assay is most useful in patients with known IgGκ MM when a single IgGκ band appears near the isatuximab migration site on standard IFE during isatuximab-based therapy. NCT03275285 and NCT03319667.