Treatment Of Multiple Myeloma Research Articles

Bispecific Antibodies as Bridging to BCMA CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma.

Establishing a strategy for sequencing of T cell-redirecting therapies for relapsed/refractory multiple myeloma (RRMM) is a pressing clinical need. We longitudinally tracked the clinical and immunologic impact of bispecific T cell-engaging antibodies (BsAb) as bridging therapy (BT) to subsequent B-cell maturation antigen-directed chimeric antigen receptor T (CAR-T) cell therapies in 52 patients with RRMM. BsAbs were a potent and safe option for BT, achieving the highest overall response rate (100%) to BT compared with chemotherapy, anti-CD38, or anti-SLAMF7 antibody-based regimens (46%). We observed early CD4+CAR+ and delayed CD8+CAR+ T-cell expansion in patients receiving BsAbs as BT. In vitro cytotoxicity of CAR-T cells was comparable among BT options. Single-cell analyses revealed increased clonality in the CD4+ and CD8+ T-cell compartments in patients with previous exposure to BsAbs at leukapheresis and on day 30 after CAR-T cell infusion. This study demonstrates the feasibility and efficacy of BT with BsAbs for CAR-T cell therapy in RRMM. Significance: CAR-T cell therapy and BsAbs have revolutionized treatment of triple-class refractory multiple myeloma; however, optimal sequencing is unknown. We demonstrate that BT with BsAb before B-cell maturation antigen-directed CAR-T cell therapy is safe and effective, which might have implications for other hematologic malignancies as well. See related commentary by Bal and Costa, p. 10.

A Review on Impact of Diet and Lifestyle Modifications on Treatment Outcomes in Multiple Myeloma

This study examines the safety, tolerability, and efficacy of anticancer drugs in the treatment of multiple myeloma, a malignancy of plasma cells characterized by overproduction of monoclonal proteins that damage bones and organs. The disease remains largely incurable despite advances in treatment, necessitating ongoing evaluation of therapeutic approaches. This review focuses on the role of key medications like bortezomib, lenalidomide, and daratumumab, highlighting their mechanisms, clinical efficacy, and associated adverse effects. Bortezomib, a proteasome inhibitor, has shown significant efficacy in both newly diagnosed and relapsed/refractory cases, particularly in combination regimens. However, it is associated with adverse effects such as peripheral neuropathy and hematologic and gastrointestinal toxicities, which require careful management. Strategies such as optimized dosing and subcutaneous administration have improved its safety profile. Future directions include enhancing therapeutic outcomes through personalized medicine, combination regimens, and mitigating resistance. This research underscores the critical need for tailored treatment strategies to improve patient survival and quality of life in multiple myeloma. Keywords: BiPN – Bortezomib-induced Peripheral Neuropathy, RRMM –Relapsed and Refractory Multiple Myeloma, NDMM –Newly Diagnosed Multiple Myeloma, PN –Peripheral Neuropathy.

Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma.

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. 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. 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. 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.).

Canagliflozin differentially modulates carfilzomib-induced endoplasmic reticulum stress in multiple myeloma and endothelial cells.

Carfilzomib (CFZ), a second-generation proteasome inhibitor, is a key treatment for multiple myeloma (MM), but its use is associated with significant cardiovascular adverse events (CVAEs), including heart failure and hypertension. Endothelial dysfunction is believed to contribute to these CVAEs. Building on our previous findings that CFZ induces endothelial toxicity and that canagliflozin protects against CFZ-induced endothelial apoptosis, this study aimed to evaluate CFZ-induced endoplasmic reticulum (ER) stress and autophagy in endothelial and MM cells, as well as the impact of canagliflozin on these processes and its impact on the anticancer effects of CFZ in MM cells. Endothelial cells (HUVECs and EA.hy926) and multiple myeloma cells (RPMI8226) were treated with 0.5µM CFZ, either alone or in combination with canagliflozin (5-20µM), to assess the effects on ER stress and autophagy in both cell types. CFZ induced ER stress in endothelial and MM cells. In endothelial cells, canagliflozin mitigated CFZ-induced markers of ER stress, while unexpectedly upregulating CFZ-induced CHOP. Whereas, in MM cells, canagliflozin did not alter CFZ-induced ER stress, but instead further upregulated CFZ-induced ATF-4. In addition, CFZ induced autophagy in endothelial cells while inhibiting it in MM cells. Canagliflozin abrogated CFZ-induced autophagy in endothelial cells. In striking contrast to its effects in endothelial cells, canagliflozin enhanced the cytotoxic effects of CFZ in MM cells. Intriguingly, in an innovative co-culture system, canagliflozin enhanced CFZ-induced apoptosis in MM cells while protecting endothelial cells. These findings underscore the dual role of canagliflozin in reducing CFZ-induced endothelial toxicity, while enhancing its cytotoxic effect in MM.

Clinical Characteristics, Cytogenetic Risks, and Prognoses of Young Multiple Myeloma Patients in the Era of Novel Therapies.

Background/Objectives: In recent years, there have been significant advances in the understanding and treatment of multiple myeloma (MM). Despite this progress, there is still limited information on the disease in patients aged 50 or younger, including the impact of young age on disease characteristics, treatment, and outcome. Methods: In this retrospective study, we analyzed 68 newly diagnosed MM patients aged ≤ 50 years (y) who had undergone at least one peripheral blood stem cell transplantation (PBSCT). Additionally, we reviewed data published during 2008-2022 and compared these to our cohort. Results: Of note, the disease characteristics in our cohort were similar to those in older patients. However, the incidence of bone lesions was higher in younger patients (84%). Moreover, 33% had LC-only MM and 7% had high-risk (del17p, t(14;16), t(4;14)) cytogenetics. Advanced ISS and R-ISS II/III were observed in 57% and 78%, respectively. Therapy was intense, with 53% of patients undergoing ≥2 SCTs. Median follow-up was 75 months, median progression-free survival was 57 months, and median overall survival (OS) was not reached. The 10-year OS rate was 72%, with only 19% succumbing to the disease. Notably, no specific therapeutic regimen or risk factors for worse outcomes were identified through uni- or bivariate analyses, even in subgroup analyses of younger patients aged ≤ 40 y. Conclusions: Our, and prior, results of young (<50 y) and very young (<40 y) MM patients underscore the need for further comprehensive studies focused on this significantly affected cohort.

What is the ideal approach-doublet, triplet, or quadruplet(s)?

Significant progress has been made in the treatment of multiple myeloma (MM), with the introduction of several new drugs with different mechanisms of action. The treatment of newly diagnosed MM has evolved dramatically with the development of highly effective combinations that include 1 or more of the new drugs. Despite the continuing improvement in the overall survival of patients with MM, nearly a quarter of the patients have significantly inferior survival, often driven by a combination of factors, including tumor genetics and host frailty. The focus of initial therapy remains rapid control of the disease with reversal of the symptoms and complications related to the disease with minimal toxicity and a reduction in early mortality. The selection of the specific regimen, to some extent, depends on the ability of the patient to tolerate the treatment and the underlying disease risk. It is typically guided by results of randomized clinical trials demonstrating improvements in progression-free and/or overall survival. While increasing risk calls for escalating the intensity of therapy by using quadruplet combinations that can provide the deepest possible response and the use of autologous stem cell transplant, increasing frailty calls for a reduction in the intensity and selective use of triplet or doublet regimens. The choice of subsequent consolidation treatments and maintenance approaches, including duration of treatment, also depends on these factors, particularly the underlying disease risk. The treatment approaches for newly diagnosed myeloma continue to evolve, with ongoing trials exploring bispecific antibodies as part of initial therapy and CAR T cells for consolidation.

Value of Innovative Multiple Myeloma Treatments from Patient and Healthcare Provider Perspectives: Evidence from a Discrete Choice Experiment.

Although innovation generally provides measurable improvements in disease characteristics and patient survival, some benefits can remain unclear. This study aimed to investigate patient and healthcare provider (HCP) preferences for the innovative attributes of multiple myeloma (MM) treatments. A cross-sectional, web-based, discrete choice experiment (DCE) survey was conducted among 200 patients with MM and 30 HCPs of patients with MM in the USA. A literature review, followed by interviews with patients with MM and HCPs, was undertaken to select five attributes (progression-free survival [PFS], chance of severe side effects, how patients live with MM treatments, scientific innovation, and monthly out-of-pocket [OOP] cost) and their levels. A Bayesian efficient design was used to generate DCE choice sets. Each choice set comprised two hypothetical MM treatment alternatives described by the selected attributes and their levels. Each patient and HCP was asked to choose a preferred alternative from each of the 11 choice sets. Mixed logit and latent class models were developed to estimate patient and HCP preferences for the treatment attributes. Overall, patients and HCPs preferred increased PFS, less chance of severe side effects, a treatment that offered life without treatment, scientific innovation, and lower OOP cost. From patients' perspectives, PFS had the highest conditional relative importance (44.7%), followed by how patients live with MM treatments (21.6%) and scientific innovation (16.0%). In addition to PFS, patients and HCPs also valued innovative MM treatments that allowed them to live without treatments and/or offered scientific innovation. These attributes should be considered when evaluating MM treatments.

Use of topical steroids in the setting of corneal subepithelial deposits due to multiple myeloma

Introduction: The aim of this case report was to describe the use of topical steroids in a patient with subepithelial corneal deposits most likely due to multiple myeloma. Case Report: A 58-year-old white female with multiple myeloma was referred to a cornea sub-specialty clinic at Massachusetts Eye and Ear for intermittent blurred vision and development of peripheral corneal deposits in both eyes. On examination, bilateral, superior peripheral corneal deposits were identified with an otherwise clear cornea. There was no corneal neovascularization, epithelial defect, or stromal gelatinous changes. The anterior chamber was quiet without any cell or flare. Dilated fundus examination was unremarkable. The corneal deposits did not resemble nodules found in Salzmann nodular degeneration or pannus from ocular rosacea/contact lens wear/trauma. Given that the patient had no prior history of eye problems or trauma, it was believed that the corneal subepithelial deposits were inflammatory changes due to her relatively recent (within one year) diagnosis of multiple myeloma. The patient was started on loteprednol etabonate 0.5% ophthalmic suspension one drop two times daily in both eyes and one month follow-up was arranged. At her one-month visit, the corneal deposits were much improved and, subsequently, her loteprednol drops were reduced to one drop nightly in both eyes for two months followed by 1 drop Monday/Wednesday/Friday in both eyes for two months. Conclusion: We describe an interesting case in which low dose topical steroid was utilized and may have contributed toward the stabilization and regression of peripheral subepithelial corneal deposits most likely due to multiple myeloma. It is possible that some of the observed improvement in the patient’s corneal deposits were in part due to her systemic treatment of multiple myeloma. Further studies are needed to establish the impact of topical steroids in this patient population, especially in more severely affected eyes.

Genetic disruption of Blimp-1 drastically augments the antitumor efficacy of BCMA-targeting CAR T cells.

Chimeric antigen receptor (CAR) T cells directed against B-cell maturation antigen (BCMA) are an effective treatment for multiple myeloma (MM), but short persistence and frequent relapses are challenges for this immunotherapy. This lack of durability has been attributed to the premature terminal differentiation of CAR T cells, which prevents the formation of long-lived memory cells that maintain antitumor responses. To improve long-term efficacy, we used CRISPR/CRISPR-associated protein 9-mediated gene editing to ablate the expression of the transcription factor Blimp-1. Blimp-1 knockout (KO) CAR T cells displayed a memory-like phenotype compared with control (Mock) CAR T cells, but had reduced effector function, with a striking loss of granzyme B. However, in a murine model of advanced MM, Blimp-1 KO CAR T cells effectively slowed or even prevented disease progression, significantly outperforming Mock CAR T cells in improving survival (P=.006). To understand this enhanced invivo effectiveness, Blimp-1 KO CAR T cells were characterized after being repeatedly challenged with tumor cells invitro. In this setting, Blimp-1 KO CAR T cells maintained a highly active state with high expression of memory markers, but, crucially, demonstrated enhanced effector function and increased energetic capacity. RNA-sequencing analysis of tumor-exposed Blimp-1 KO CAR T cells confirmed the presence of a memory-like transcriptomic signature and, additionally, revealed enhanced ribosome biogenesis and repressed CAR T-cell dysfunction as mechanisms that could contribute to improved antitumor activity. Put together, our findings show that dampening Blimp-1 expression altered the phenotype and function of anti-BCMA CAR T cells, leading to augmented therapeutic efficacy in MM.

Venetoclax in the Treatment of Multiple Myeloma: A Retrospective Analysis of 79 Patients.

Venetoclax, the first-in-class BCL-2 inhibitor, has shown efficacy in multiple myeloma (MM), particularly in patients with the t(11;14) translocation. This single-center retrospective analysis included MM patients treated with venetoclax from November 2017 to March 2023. Data encompassed demographics, disease characteristics, treatment regimens, and outcomes using median progression-free-survival (mPFS). Eligibility required patients to be aged 21 and older and to have received at least one venetoclax cycle. Seventy-nine patients (median age 61, 58.2% female) were included, with 31.6% having t(11;14). Patients had received a median of 5 lines of therapy (LOT) before venetoclax. The mPFS was 3.4 months, with a significant difference between t(11;14) positive (7.8 months) and negative patients (2.4 months, p < 0.01). Patients achieving a very good partial response or better had a mPFS of 7.1 months. Common adverse events included fatigue (31.6%), diarrhea (26.5%), and respiratory infections (30.3%). Univariable and multivariable analyses identified sex, disease response, and t(11;14) presence as significant survival predictors. Our real-world study suggests that venetoclax demonstrates moderate efficacy in heavily pretreated patients with relapsed/refractory MM (RRMM), compared to previous studies where patients received 1-3 prior LOT, such as the BELLINI study (mPFS of 22.4 months). Notably, the efficacy was higher in patients with t(11;14). Despite the heavily pretreated nature of our cohort, venetoclax was well tolerated, with a manageable safety profile and low incidence of severe infections, largely due to effective prophylactic measures. Venetoclax should be carefully considered in heavily pretreated populations, and further multicenter research is essential to better define its role in RRMM.

Minimal Residual Disease as an Early Endpoint for Accelerated Drug Approval in Myeloma: A Roadmap.

Improvements in multiple myeloma (MM) treatments have extended patient survival to a decade or more. Treatment response rates >90% have introduced new challenges for drug development, including a need for early endpoints with greater sensitivity. The FDA, based on data from two academic research groups and industry, evaluated minimal residual disease (MRD) negativity as an intermediate endpoint for progression-free and overall survival, culminating in a unanimous vote by the Oncology Drugs Advisory Committee in April 2024 supporting MRD-negative complete response as an early endpoint reasonably likely to predict clinical benefit in MM that may be used to support accelerated approval.

Doxorubicin synergizes bortezomib-induced multiple myeloma cell death by inhibiting aggresome formation and augmenting endoplasmic reticulum/Golgi stress and apoptosis

BackgroundBortezomib is a standard treatment for multiple myeloma (MM), working by the accumulation of toxic misfolded proteins in cancer cells. However, a significant clinical challenge arises from the development of resistance to bortezomib in MM treatment. Aggresome, a subcellular structure enclosed within Vimentin, forms in response to proteasome inhibitors and sequesters misfolded proteins that are transported by histone deacetylase 6 (HDAC6) and Dynein for degradation via autophagy, thereby reducing bortezomib’s cytotoxic effects. Therefore, in this study, we screened several anticancer agents to identify those that could synergize with bortezomib to enhance cell death and block aggresome formation in the MM cell line U266B1.MethodsTo enhance bortezomib’s efficacy, we screened a range of anticancer compounds for their potential to promote cell death and inhibit aggresome formation in U266B1 MM cells. We utilized the trypan blue exclusion assay and immunofluorescence for evaluation, and explored the underlying mechanisms through Western blot analysis.ResultsDoxorubicin enhanced bortezomib-induced cytotoxicity while inhibiting aggresome formation. Mechanistic studies revealed that doxorubicin downregulated key aggresome components, including Vimentin, HDAC6, and Dynein, leading to accumulation of misfolded proteins and augmentation of proapoptotic and necroptotic pathways by intensifying endoplasmic reticulum (ER) and Golgi stress responses. Notably, doxorubicin did not enhance cell death triggered by proteasome inhibitors that do not induce aggresome formation. Furthermore, the combination of bortezomib and doxorubicin failed to produce synergy in the killing of MM cell lines that lacked aggresome-forming ability.ConclusionsDoxorubicin enhances bortezomib-induced cell death in MM by inhibiting aggresome formation and amplifying ER/Golgi stress and apoptosis. This study highlights the potential therapeutic benefits of combining bortezomib with doxorubicin for MM treatment.Graphical

The Antibody Drug Conjugate, Belantamab-Mafodotin, in the Treatment of Multiple Myeloma: A Comprehensive Review.

Despite recent advancements in treatments, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains mostly incurable with patients frequently experiencing disease relapses due to therapy resistance. Hence there is an urgent need for innovative treatments for patients with relapsed and/or refractory MM (RRMM). This review examines Belantamab mafodotin, the first antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA), which has shown efficacy in pre-clinical and clinical settings for RRMM. BCMA, a type III transmembrane glycoprotein critical for B cell functions, is predominantly expressed in malignant plasma cells making it a promising therapeutic target. ADCs, comprising a monoclonal antibody, a cytotoxic payload, and a linker, offer a targeted and potent therapeutic approach to cancer treatment. Belantamab mafodotin integrates an afucosylated monoclonal antibody and monomethyl auristatin F (MMAF) as its cytotoxic agent. It induces apoptosis in MM cells by disrupting microtubule formation and interfering with important signaling pathways. The series of DREAMM (Driving Excellence in Approaches to MM) studies have extensively evaluated Belantamab mafodotin in various clinical settings. This review provides a comprehensive overview of pre-clinical and clinical data supporting Belantamab mafodotin as a future therapeutic option for RRMM.

Expert opinion on multiple myeloma treatment in Brazil in the bispecific antibody era

Expert opinion on multiple myeloma treatment in Brazil in the bispecific antibody era

Evolving strategies in the management of transplant-eligible patients with newly diagnosed multiple myeloma.

Multiple myeloma treatment has evolved significantly with the introduction of triplet and quadruplet regimens, notably incorporating anti-CD38 antibodies. While autologous stem cell transplantation remains a cornerstone of therapy, its role in the context of increasingly effective upfront treatments is debated. Current guidelines still recommend transplant for all eligible patients, especially those with high-risk features at diagnosis, despite concerns regarding the lack of overall survival benefits and the potential long-term toxicities associated with high-dose melphalan. Delaying transplantation until first relapse has been proposed, but this approach carries the risk of patients becoming ineligible for transplantation due to worsening health or disease progression. Consolidation therapy after transplant is not strongly endorsed in recent guidelines, and studies show mixed results regarding its efficacy. Some data suggests a progression-free survival advantage with post-ASCT consolidation; others found no significant differences in outcomes among various strategies. Nonetheless, tandem transplant may be beneficial for high-risk patients. Maintenance therapy, particularly with lenalidomide, has proven effective, offering substantial progression-free and overall survival benefits. While lenalidomide remains the standard, emerging data indicate that combinations with proteasome inhibitors or anti-CD38 antibodies could enhance outcomes, particularly in high-risk populations. As our understanding of myeloma biology deepens, tailoring treatment approaches based on risk profiles and response depth will be crucial for optimizing patient outcomes.

Treatment of dexamethasone and lenalidomide-resistant multiple myeloma via RAD51 degradation using PROTAC and synergistic effects with chemotherapy.

Multiple myeloma (MM) is a clonal B-cell malignancy arising from plasma cells in the bone marrow that can lead to various symptoms such as bone pain and fractures, anemia, renal failure and repeated infection. Treatment involves steroids, chemotherapy, targeted therapy and stem cell transplantation. On the other hand, resistance to these treatments often develops, particularly in relapsed/refractory MM, necessitating new strategies. This study examined the degradation of RAD51 recombinase (RAD51) in MM cell lines resistant to existing treatments using proteolysis targeting chimeras (PROTACs). Resistant cell lines were established by exposing human B lymphoblast cell lines, MM.1S and MM.1R, to increasing doses of lenalidomide or pomalidomide. Targeted RAD51 degradation (TRD) 2, a novel PROTAC targeting RAD51, reduced the RAD51 protein levels and cell proliferation. TRD2, combined with chemotherapy drug cisplatin, showed enhanced efficacy in cell proliferation compared to single-agent treatment. In vivo studies confirmed the synergistic effects of TRD2 and cisplatin in inhibiting tumor growth in lenalidomide-resistant MM.1R xenograft models without significant toxicity. MM cells exhibit increased RAD51 expression as they develop resistance to chemotherapy. This study shows that targeting RAD51 with TRD2 enhances the efficacy of DNA-damaging treatments, providing a promising approach for overcoming drug resistance in MM. The inhibition of RAD51 combined with cisplatin therapy can maximize the treatment efficacy of MM patients resistant to dexamethasone and lenalidomide. Nevertheless, further research will be needed to explore the clinical applications of these findings.

Bortezomib for the treatment of Multiple Myeloma: A Systematic Review and Meta-Analysis

Introduction Multiple myeloma (MM) is an incurable malignant neoplasm that accounts for approximately 1% of all cancers and 10% of hematological malignancies. Bortezomib is one of the most commonly used medications in first-line treatment and subsequent relapses, either as a single agent or in combination with other therapies. Objective: To assess the effects of bortezomib on progression-free survival (PFS), overall response rate (ORR), adverse events in patients with MM. Methods We have performed a systematic review and included randomized (RCT) and non- -randomized controlled studies where bortezomib was compared in similar or dissimilar background therapies in each arm. Embase, Medline, LILACS, and CENTRAL were our data source. Two reviewers independently selected studies, assessed the risk of bias, and extract data from the included studies. Similar outcomes were plotted in the meta-analysis using the Stata Statistical Software 18. The relative risk (RR) was calculated with a 95% confidence interval as the effect size of bortezomib. For the OS and PFS, we calculate the overall odds ratio (OR) from the hazard ratios of each included study. We used the Grading of Recommendations Assessment, Development, and Evaluation system to evaluate the certainty of evidence. Results We identified 7,996 references, and 28 studies fulfilled our eligibility criteria. Sixteen studies were randomized, and 12 were non-randomized (retrospective studies). In the studies with similar background therapies in each arm, bortezomibe improves PFS ( Peto OR 0.71, 95% CI 0.64 to 0.78, , 7 RCTs, 2572 participants, moderate-quality evidence), , and there was no difference in ORR between the groups. In studies with different background therapies in each arm, bortezomib continued to improve PFS (Peto OR 0.86, 95% CI 0.80 to 0.93, , 8 RCTs, 4209 participants, moderate-quality evidence), but not in studies where participants had previously used bortezomib (Peto OR 1.7, 95% CI 1.46 to 1.97 , 2 RCTs, 1084 participants), the same occurred in ORR (RR 1.14, 95% CI 1.01 to 1.29 and RR 0.81, 95% CI 0.75 to 0.89, respectively). In both similar and dissimilar background therapies bortezomibe increases the risk of neuropathy adverse events (RR 2.9, 95% CI 2.18 to 3.87, 5 RCTs, 1901 participants, and RR 4.57, 95% CI 2.50 to 8.35, 9 RCTs, 1901 participants, respectively). In all non-RCT studies bortezomibe was compared with active control. The meta-analysis of PFS was not performed due to study design (retrospective studies), from the 5 studies that evaluated this outcome, in 2 studies patients had a significantly longer PFS, and in 3 studies although bortezomib had better PFS, there was no statistically significant difference between groups. Discussion e conclusions Regarding PFS in the studies with dissimilar background therapies, bortezomib has often been compared with newer therapies. Even though we were unable to isolate the effect of bortezomib, when we performed subgroup analysis according to previous use of bortezomib, it is clear that for those patients without previous use, there is a better intervention effect. Patients who had previous contact with the drug, and were later re-exposed to it, clearly did not benefit from this re-exposure. Conclusion:Bortezomib has been approved by the FDA and other regulatory agencies for about 20 years. Thus, we have data from RCT and retrospective studies that highlight their effectiveness and long-term safety profile. This project was funded by the Call for Financial Support for Studies in Health Technology Assessment of the National Council for Scientific and Technological Development (CNPq) in partnership with the Brazilian Health Ministry through the DGITIS/SCTIE, grant number: 423641/2021-2.

PARP1 promotes tumor proliferation in lenalidomide-resistant multiple myeloma via the downregulation of microRNA-192-5p-AKT signaling.

Lenalidomide-based therapies are recommended as first-line treatment for multiple myeloma (MM) patients, regardless of the transplant eligibility. Resistance to lenalidomide is a clinical problem that urgently needs to be addressed. The expression of poly(ADP-ribose) polymerase 1 (PARP1) is abnormally high in a variety of tumor tissues including MM. However, in lenalidomide-resistant MM, it is not yet known whether the abnormally high expression of PARP1 is involved in the occurrence of drug resistance, and whether the inhibition of PARP1 can reverse lenalidomide resistance. The aim of this study was to investigate the mechanism of PARP1 promoting lenalidomide-resistant in MM patients. Samples of bone marrow from patients with MM who were sensitive or resistant to lenalidomide were collected. The expression levels of PARP1 at the messenger RNA and protein levels were detected through polymerase chain reaction and western blot. MM cell lines were cultivated in vitro, cell lines resistant to lenalidomide were screened out, and the expression levels of PARP1 in the resistant cell lines were detected. The apoptosis level was also detected in the lenalidomide-resistant MM cell lines treated with a PARP1 inhibitor. The proliferation rates of the two groups of cells at different time points were evaluated by mono-methyl terephthalate (MMT) experiments. Finally, the effect of PARP1 on the proliferation of lenalidomide-resistant MM through the microRNA-192-5p-AKT signaling pathway was analyzed. In the lenalidomide-resistant cell lines, the expression level of PARP1 was higher, the proliferation more rapid, and the apoptosis rate was lower than lenalidomide-sensitive cell lines. Additionally, the activated AKT pathway was suppressed by downregulating the expression of microRNA-192-5p. MM resistance can be inhibited to some extent by impacting PARP1. PARP1 is involved in the production of lenalidomide resistance in MM, and could serve as a potential target for the treatment of MM in the future.

Development of BCMA-Targeted Bispecific Natural Killer Cell Engagers for Multiple Myeloma Treatment.

B-cell maturation antigen (BCMA)-targeted T cell-redirecting immunotherapies, including Chimeric Antigen Receptor (CAR) T-cell therapy and T-cell engagers have demonstrated remarkable success in treating relapsed/refractory (RR) multiple myeloma (MM), a malignancy of plasma cells. However, a significant challenge is the severe side effects associated with T-cell overactivation, leading to cytokine release syndrome and neurotoxicity in MM patients undergoing such therapies. Bispecific NK cell engagers (NKCEs) may offer a promising alternative by redirecting NK cell cytotoxic activity towards tumor cells without triggering cytokine release syndrome. In this study, we designed a series of BCMA × CD16 NKCEs that simultaneously engage BCMA and CD16 on MM and NK cells, respectively. We evaluated the functionality of these NKCEs in vitro with respect to their molecular design. Our results indicate that the format design of NKCEs influences their functionalities, underscoring the importance of format selection in optimizing NKCE-based therapies for MM. This study provides valuable insights for developing next-generation NKCEs and advancing therapeutic strategies for MM and potentially other malignancies.

The significance of RB1 in multiple myeloma.

The treatment of multiple myeloma (MM) has significantly advanced; however, the underlying genetic mechanisms remain elusive. Clonal events and genetic alterations are recognized as pivotal in the pathogenesis of MM. It is now understood that a multitude of gene mutations, including those affecting RAS, TP53, RB1, and 1q21 amplification, are prevalent in this disease. The incorporation of several high-risk genetic factors into the Second Revision of the International Staging System (R2-ISS) underscores the prognostic significance of genetic aberrations in MM. The retinoblastoma gene (RB1), located in 13q14, encodes the retinoblastoma protein (pRB), a tumor suppressor that regulates cell cycle progression. Deletion of RB1, which is a frequent event in MM, contributes to tumorigenesis by disrupting cell cycle control. In this respect, RB1 loss has been implicated in the progression of MM through its influence on interleukin-6 (IL-6) secretion and cell proliferation. This review comprehensively summarizes the role of RB1 in MM and expounds on the potential of targeting RB1 as a therapeutic strategy for this malignancy.