Treatment Of Multiple Myeloma Research Articles

Personalized Treatment of Multiple Myeloma in Frail Patients.

As the treatment landscape for multiple myeloma (MM) continues to expand at a rapid pace, management of older adults and frail patients becomes increasingly challenging. As these patients have traditionally been underrepresented on clinical trials, there is limited guidance on the optimal approach to frail patients with newly diagnosed multiple myeloma (NDMM) or relapsed and refractory multiple myeloma (RRMM). Frailty is an independent predictor of tolerability and response to antineoplastic treatment. Stringent eligibility criteria have often excluded these patients, but recently some large trials have included frailty sub-analyses to help guide management. In general, triplet regimens are preferred to doublet regimens in this population and enrollment on a clinical trial should be prioritized when possible. In this review, we summarize the MM frailty scoring tools that have been developed to identify and assess this vulnerable population. We present the clinical trials over the past decade that have enrolled frail patients and/or have included subgroup analyses to help elucidate the response and tolerability of different regimens in this underrepresented group. We provide practical advice regarding assessment and management of frail patients NDMM and RRMM.

Trends in Use and Evidence of Adherence to Risk Evaluation and Mitigation Strategy Pregnancy Testing Requirements for Thalidomide, Lenalidomide, and Pomalidomide in the USA, 2000-2020.

Lenalidomide, pomalidomide, and thalidomide are effective treatments for multiple myeloma but are teratogenic. To mitigate this risk, the US Food and Drug Administration (FDA) required risk evaluation and mitigation strategy (REMS) programs for these drugs, which include pregnancy testing among women of childbearing potential-twice before initiation, weekly in the first month on treatment, and every 2-4 weeks thereafter. We evaluated dispensing trends of lenalidomide, pomalidomide, and thalidomide and assessed adherence to REMS pregnancy testing requirements among at-risk patients taking these drugs. Using three US health insurance claims databases (Optum Clinformatics® [2004-2020], Merative Marketscan [2003-2019], and Medicaid [2000-2018]), we assessed monthly use of the drugs, patient characteristics and treatment persistence among drug initiators, and claims-based evidence for adherence to pregnancy testing requirements among initiators with child-bearing potential. Lenalidomide was the most prescribed agent following its approval in 2006 and through the end of the study period. A total of 48,311 lenalidomide (mean age = 59 years [standard deviation (SD) = 16]), 17,550 thalidomide (mean age = 65 years [SD = 12]), and 6560 pomalidomide initiators (mean age = 65 years [SD = 11]) were identified; 45% of initiators of each drug were women. Among initiators under follow-up on day 90, 70% were still on therapy. Initiators of childbearing potential comprised 3% (N = 1,920) of all initiators; among this cohort, 12% had evidence in claims data of two pregnancy tests before initiation, and 9% with at least 33 days of follow-up of four tests during the first month of treatment. By contrast, 52% who received a refill had claims-based evidence of a pregnancy test within 7 days of dispensing. Although most patients who initiated lenalidomide, pomalidomide, and thalidomide were not of child-bearing potential, further investigation into actual non-adherence to pregnancy testing is needed.

Chinese expert consensus on diagnosis and treatment of high risk multiple myeloma (2024)

High-risk multiple myeloma (HRMM) refers to patients with multiple myeloma whose overall survival time is less than 2-3 years under current standardized diagnosis and treatment. By combining various static and dynamic prognostic factors, risk stratification is performed to identify HRMM patients early and treat patients with personalized strategies, with the aim of significantly improving adverse survival outcomes in HRMM patients. Although the clinical value of HRMM has reached a consensus domestically in recent years, there still exist confusions and ambiguities in the definition, high-risk factors, risk stratification, and treatment of HRMM, necessitating standardization. In order to enhance the diagnostic and treatment capabilities of Chinese physicians in HRMM, the Professional Committee of Hematologic Malignancies of the Chinese Anti-Cancer Association (CACA) and the Multiple Myeloma Expert Committee of the Chinese Society of Clinical Oncology (CSCO) have organized relevant experts to develop this consensus. This consensus aims to clarify the definition of HRMM, high-risk factors, and risk stratification system, and provide treatment recommendations for HRMM, thereby improving the quality of life and prognosis of Chinese HRMM patients.

Cardio-Oncology: A New Discipline in Medicine and Its Relevance to Hematology.

Cardio-oncology, a burgeoning subspecialty, addresses the complex interplay between cardiology and oncology, particularly in light of increased cardiovascular (CV) disease mortality in cancer patients. This review provides a comprehensive overview of cardio-oncology with a focus on the therapies used in hematological malignancies. We explore the bidirectional relationship between heart failure and cancer, emphasizing the need for collaborative care. The review discusses risk stratification, highlighting the importance of baseline CV risk assessment and personalized surveillance regimens. Primary and secondary prevention strategies, including pharmacological interventions, are outlined. The review also delves into the cardiotoxicity associated with hematological cancer therapies, focusing on anthracyclines, Bruton kinase inhibitors, BCR-ABL tyrosine kinase inhibitors, CAR-T cell therapy, immune checkpoint inhibitors, multiple myeloma treatments, and hematopoietic stem cell transplantation. We then highlight the high risk of venous and arterial thromboembolisms in cancer patients and the challenges of anticoagulation management in cardio-oncology. Finally, the review touches on the importance of long-term follow-up and appropriate screening in cancer survivors at high risk of CV morbidity and mortality, based on their CV risk profile and the type and dose of cardiotoxic therapies they received such as anthracyclines or high radiation doses.

Preclinical characterization of a novel investigational monoclonal antibody CM313 with potent CD38-positive cell killing activity.

CM313 is currently under clinical investigation for treatments of multiple myeloma, systemic lupus erythematosus, and immune thrombocytopenia. We aimed to report the preclinical profile of the novel therapeutic anti-CD38 monoclonal antibody (mAb) CM313, with an emphasis on the difference with other CD38-targeting mAb. The binding of CM313 to CD38 recombinant protein across species was assessed using ELISA. The binding of CM313 to CD38-positive (CD38+) cells was detected using flow cytometry assays. CM313-induced complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and apoptosis on different CD38+ cells were assessed by LDH release assays or flow cytometry assays. The effect of CM313 on CD38 enzymatic activity was measured using fluorescence spectroscopy. CM313 immunotoxicity in human blood was assessed using flow cytometry assays, ELISA, and LDH release assays. Anti-tumor activity of CM313 was assessed in multiple mouse xenograft models. Safety profile of CM313 were evaluated in cynomolgus monkeys and human CD38 transgenic (B-hCD38) mice. There exist unique sequences at complementarity-determining regions (CDR) of CM313, which facilitates its affinity to CD38 is consistently higher across a spectrum of CD38+ cell lines than daratumumab. In vitro studies showed that CM313 induces comparable killing activity than daratumumab, including ADCC, CDC, ADCP, apoptosis induced by Fc-mediated cross-linking, and effectively inhibited the enzymatic activity of CD38. However, CM313 showed more potent CDC than isatuximab. In vivo, CM313 dose-dependently inhibited xenograft tumor growth, both as a monotherapy and in combination with dexamethasone or lenalidomide. Furthermore, CM313 was well tolerated with no drug-related clinical signs or off-target risks, as evidenced by 4-week repeat-dose toxicology studies in cynomolgus monkeys and B-hCD38 mice, with the later study showing no observed adverse effect level (NOAEL) of 300mg/kg once weekly. CM313 is a novel investigational humanized mAb with a distinct CDR sequence, showing comparable killing effects with daratumumab and stronger CDC activity than isatuximab, which supports its clinical development.

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.

Nivolumab, Pomalidomide, and Elotuzumab Combination Regimens for Treatment of Relapsed and Refractory Multiple Myeloma: Results from the Phase 3 CheckMate 602 Study

BackgroundPreclinical studies suggest that combining nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, with pomalidomide/dexamethasone (Pd) with or without elotuzumab, an antisignaling lymphocytic activation molecule F7 monoclonal antibody, may improve multiple myeloma (MM) treatment efficacy. Patients and MethodsThe phase 3 CheckMate 602 study (NCT02726581) assessed the efficacy and safety of nivolumab plus pomalidomide/dexamethasone (NPd) and NPd plus elotuzumab (NE-Pd). Eligible patients (aged ≥ 18 years) had measurable MM after ≥ 2 prior lines of therapy, that included an immunomodulatory drug (IMiD) and proteasome inhibitor (PI), each for ≥ 2 consecutive cycles, alone or combined, and were refractory to their last line of therapy. Patients were randomized 3:3:1 to receive NPd, Pd, or NE-Pd. The primary endpoint was progression-free survival (PFS); overall response rate (ORR) was a key secondary endpoint. ResultsAt a median follow-up of 16.8 months, PFS was similar between treatment arms (Pd, 7.3 months [95% CI, 6.5-8.4]; NPd, 8.4 months [95% CI, 5.8-12.1]; NE-Pd, 6.3 months [95% CI, 2.4-11.1]). ORR was similar in the Pd (55%), NPd (48%), and NE-Pd (42%) arms. Nivolumab-containing arms were associated with a less favorable safety profile versus Pd, including a higher rate of thrombocytopenia (NPd, 25.0%; NE-Pd, 16.7%; Pd, 15.7%), any-grade immune-mediated adverse events (NPd, 13.9%; NE-Pd, 16.7%; Pd, 2.9%), and adverse events leading to discontinuation (NPd, 25.0%; NE-Pd, 33.3%; Pd, 18.6%). No new safety signals were identified. ConclusionCheckMate 602 did not demonstrate clinical benefit of nivolumab (+/- elotuzumab) plus Pd versus Pd for patients with relapsed/refractory MM (RRMM).

Proteasome inhibitor bortezomib prevents proliferation and migration of pulmonary arterial smooth muscle cells.

Pulmonary vascular remodeling is a key pathological process of pulmonary arterial hypertension (PAH), characterized by uncontrolled proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Bortezomib (BTZ) is the first Food and Drug Administration (FDA)-approved proteasome inhibitor for multiple myeloma treatment. Recently, there is emerging evidence showing its effect on reversing PAH, although its mechanisms are not well understood. In this study, anti-proliferative and anti-migratory effects of BTZ on PASMCs were first examined by different inducers such as fetal bovine serum (FBS), angiotensin II (Ang II) and platelet-derived growth factor (PDGF)-BB, while potential mechanisms including cellular reactive oxygen species (ROS) and mitochondrial ROS were then investigated; finally, signal transduction of ERK and Akt was examined. Our results showed that BTZ attenuated FBS-, Ang II- and PDGF-BB-induced proliferation and migration, with associated decreased cellular ROS production and mitochondrial ROS production. In addition, the phosphorylation of ERK and Akt induced by Ang II and PDGF-BB was also inhibited by BTZ treatment. This study indicates that BTZ can prevent proliferation and migration of PASMCs, which are possibly mediated by decreased ROS production and down-regulation of ERK and Akt. Thus, proteasome inhibition can be a novel pharmacological target in the management of PAH.

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.

OA16 Clinical and biochemical improvement following daratumumab therapy for anti-MDA5 antibody positive dermatomyositis with rapidly progressive interstitial lung disease: a case report

Abstract Background/Aims Anti-melanoma differentiation-associated 5 gene autoantibody (anti-MDA5) positive dermatomyositis (DM) with rapidly progressive interstitial lung disease (RP-ILD) represents the most severe and difficult-to-treat form of autoimmune myositis with unfavourable 6-month survival rates despite intensive treatment strategies of combination therapy with glucocorticoids, cyclophosphamide, calcineurin inhibitors, mycophenolate mofetil and rituximab. We describe a case of anti-MDA5 positive DM with RP-ILD that was refractory to intensive combination therapy, requiring courses of rescue plasmapheresis, before eventually responding to intravenous daratumumab. Methods A 30-year-old non-smoking Chinese man who was previously well was hospitalised after 3 weeks of intermittent pyrexia, non-productive cough, lethargy, rashes and myalgia. Examination revealed typical cutaneous changes of dermatomyositis, bilateral mid-to-lower zone inspiratory crepitations in his chest with no proximal muscle weakness or synovitis. Initial investigations demonstrated elevations in creatine kinase, C-reactive protein, erythrocyte sedimentation rate, lactate dehydrogenase, ferritin and neutrophil-to-lymphocyte ratio. Although an initial chest radiograph was normal, CT thorax 4 days later showed non-specific ground-glass opacities with consolidation in both lower lobes. Anti-MDA5 antibodies were strongly positive on EUROLINE Inflammatory Myopathies 16 Ag (IgG) commercial line immunoblot. He was transferred to our centre for further care one week after hospitalisation and was intubated on arrival for type I respiratory failure. He was initiated on combination therapy of intravenous methylprednisolone, intravenous rituximab, hydroxychloroquine, tofacitinib and was also treated with plasmapheresis to remove pathogenic anti-MDA5 antibodies. Although his condition improved initially with successful extubation within one week, the disease remained active in the following months with several admissions for infection-related issues and progression of RP-ILD. Despite various combinations of immunosuppressives and further courses of plasmapheresis, at 6 months post-diagnosis he continued to require a minimum daily prednisolone dose of 45mg (0.625mg/kg/day), remaining positive for anti-MDA5 antibodies on the immunoblot assay, with persistently elevated serum ferritin and transaminases. As such, he was treated with four doses of intravenous daratumumab in an attempt to deplete the long-lasting plasma cells that may be driving the disease. Results Following daratumumab treatment, the anti-MDA5 antibody turned negative on the immunoblot assay with normalisation of ferritin and transaminases, with corresponding improvement in lung function tests and chest radiograph findings. 3 months post-daratumumab, he remains clinically well on hydroxychloroquine, tofacitinib and nintedanib, with successful continuing taper of prednisolone. Conclusion Daratumumab is an anti-CD38 monoclonal antibody licensed for the treatment of multiple myeloma which has been used off-label for other refractory autoimmune conditions such as SLE. It is postulated that besides CD19/20 positive B cells, CD38 positive long-lived autoantibody-secreting plasma cells are essential drivers of chronic inflammation in these autoimmune diseases. In our patient with anti-MDA5 DM and RP-ILD, the use of daratumumab was well-tolerated and led to definite clinical and biochemical improvement. Disclosure L. Koh: None. G. Chai: None. M. Manghani: None. X. Lim: None. B.P.L. Leung: None. C. Chua: None.

An up-conversion fluorescence lateral-flow immunoassay for rapid detection of Daratumumab in serum protein electrophoresis clinical samples

BackgroundDaratumumab (DARA) is a commonly used monoclonal antibody (mAb) drug for the treatment of multiple myeloma (MM). Its appearance as a visible abnormal band in the γ-region of a serum protein electrophoresis (SPEP) gel may interfere with the SPEP result interpretation. With the advantages of portability and rapid testing capabilities, up-conversion fluorescence lateral-flow immunoassay (LFA) can be an ideal solution to detect DARA interference. MethodsAn up-conversion fluorescence LFA strip was designed and constructed to perform semi-quantitative DARA testing in clinical samples. The LFA strip test was evaluated for limit of detection (LOD), dynamic range, and analytical interference. ResultsTo demonstrate the clinical utility of the LFA strip, 43 SPEP-positive patient serum samples were tested for the presence of DARA, and the results exactly matched the DARA usage history in patient medical records. ConclusionsThe performance of the up-conversion fluorescence LFA strip meets the purpose of clarifying DARA interference in SPEP results. It may be used as an independent and objective confirmation of the presence of DARA in clinical samples. The LFA strip offers a cost-effective rapid on-site test to check for DARA interference alongside standard SPEP equipment, which significantly improves the interpretation of ambiguous SPEP results involving DARA, and does not intervene the current SPEP workflow in clinical laboratory practice.

Abstract P07: Extracellular Vesicles Secreted from Daratumumab Resistant Cells Promote Resistance and Proliferation of Daratumumab Sensitive cells, possibly Through the Transfer of miRNA Cargo

Abstract Daratumumab (dara) is an anti-CD38 monoclonal antibody used for Multiple Myeloma (MM) treatment, but responses are heterogeneous, and resistance is inevitable. We established three dara resistant (dara R) cell lines in Natural Killer T-cell Lymphoma (NKTL), T-cell acute lymphoblastic leukaemia (T-ALL) and MM via long-term exposure to increasing concentrations of dara. We have previously demonstrated that the exosome biogenesis pathway plays a significant role in the survival of dara R cell lines. Coculture of dara sensitive (dara S) cell lines with dara R cell lines separated by a cell-impermeable transwell insert promoted cell proliferation and reduced response to dara treatment in dara S cell lines thereby suggesting a potential role for extracellular vesicles (EVs) in mediating these responses. To assess the specific role of EVs, we isolated dara R EVs and added it to the culture of dara S cells. We observed that uptake of dara R EVs directly promote proliferation and reduced cytotoxic response to dara treatment in dara S cells. In this study, we seek to investigate the role of EVs secreted by dara R cells, in particular, that of EV-derived miRNAs. Exosomal miRNAs are known to play a role in regulating cellular pathways driving cancer cell resistance and survival. To evaluate the potential role of EV-derived miRNA cargo, we performed miRNA sequencing of EVs isolated from the plasma fraction of bone marrow samples obtained from MM patients. We found that the EVs from patients with a progression free survival (PFS) of less than 2 years after dara based therapy had an enrichment of mir-155 and mir-181a as compared to those with a PFS longer than 2 years. These data align with our findings in the cell lines and suggest that these miRNAs may be utilised as potential biomarkers for daratumumab resistance. Citation Format: Muhamad Irfan Bin Azaman, Wee Joo Chng, Sanjay de Mel, Nurulhuda Mustafa. Extracellular Vesicles Secreted from Daratumumab Resistant Cells Promote Resistance and Proliferation of Daratumumab Sensitive cells, possibly Through the Transfer of miRNA Cargo [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P07.

A real‑world pharmacovigilance study of FDA adverse event reporting system events for daratumumab

ABSTRACT Background Daratumumab, a first-in-class humanized IgG1κ monoclonal antibody that targets the CD38 epitope, has been approved for treatment of multiple myeloma by FDA. The current study was to evaluate daratumumab-related adverse events (AEs) through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS). Research design and methods Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS) algorithms were employed to quantify the signals of daratumumab-associated AEs. Results Out of 10,378,816 reports collected from the FAERS database, 8727 reports of daratumumab-associated AEs were identified. A total of 183 significant disproportionality preferred terms (PTs) were retained. Unexpected significant AEs such as meningitis aseptic, leukoencephalopathy, tumor lysis syndrome, disseminated intravascular coagulation, hyperviscosity syndrome, sudden hearing loss, ileus and diverticular perforation were also detected. The median onset time of daratumumab-related AEs was 11 days (interquartile range [IQR] 0–76 days), and most of the cases occurred within 30 days. Conclusion Our study found potential new and unexpected AEs signals for daratumumab, suggesting prospective clinical studies are needed to confirm these results and illustrate their relationship.

Lenalidomide‐induced posterior reversible encephalopathy syndrome: A case report

AbstractPosterior reversible encephalopathy syndrome (PRES) is a disorder of cerebrovascular dysregulation. To our knowledge, we present the first case of lenalidomide‐induced PRES in English. A 59‐year‐old woman with history of multiple myeloma status post stem cell transplant and induction triple therapy 6 months ago with partial remission and subsequent high‐dose melphalan 1 month ago presented with progressive vision loss for 1 week. Her systolic blood pressure was >180 mmHg, and neurological examination demonstrated decreased vision bilaterally. Brain MRI revealed significant T2 hyperintensity restricted to temporal and occipital lobes and left occipital parenchymal hemorrhage and diffuse leptomeningeal enhancement. She had a witnessed generalized tonic–clonic seizure and EEG that captured an electrographic seizure originating from the occipital lobe. Her vision improved rapidly after discontinuing the lenalidomide. She was discharged to rehab with a normal neurological examination. We report the first English case of presumed lenalidomide induced PRES in a patient undergoing multiple myeloma treatment.

Comparison of two autologous hematopoietic stem cell mobilization strategies in patients with multiple myeloma: CE plus G-CSF versus G-CSF only: A single-center retrospective analysis.

Despite recent advances in the treatment of multiple myeloma, high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) remains an essential therapeutic keystone. As for the stem cell mobilization procedure, different regimens have been established, usually consisting of a cycle of chemotherapy followed by application of granulocyte-colony stimulating factor (G-CSF), although febrile neutropenia is a common complication. Following national guidelines, our institution decided to primarily use G-CSF only mobilization during the COVID-19 pandemic to minimize the patients' risk of infection and to reduce the burden on the health system. In this retrospective single-center analysis, the efficacy and safety of G-CSF only mobilization was evaluated and compared to a historic control cohort undergoing chemotherapy-based mobilization by cyclophosphamide and etoposide (CE) plus G-CSF. Although G-CSF only was associated with a higher need for plerixafor administration (p < .0001) and a higher number of apheresis sessions per patient (p = .0002), we were able to collect the target dose of hematopoietic stem cells in the majority of our patients. CE mobilization achieved higher hematopoietic stem cell yields (p = .0015) and shorter apheresis sessions (p < .0001) yet was accompanied by an increased risk of febrile neutropenia (p < .0001). There was no difference in engraftment after ASCT. G-CSF only mobilization is a useful option in selected patients with comorbidities and an increased risk of serious infections, especially in the wintertime or in future pandemics.

Abstract LB128: A novel tri-specific T cell engager targeting BCMA and GPRC5D for treatment of multiple myeloma

Abstract Introduction Multiple myeloma (MM) accounts for 10% of all hematologic cancers. Recent advances in MM therapy have greatly increased the overall response and survival rate. However, almost all patients eventually relapse. The prognosis still remains poor. BCMA and GPRC5D are overexpressed in myeloma cells. Although CAR-T and T cell engager (TCE) targeting BCMA or GPRC5D have been efficacious in MM patients, resistance does occur. Since the expression of BCMA and GPRC5D in MM are heterogeneous, to further improve the overall response and survival, we have recently generated a novel tri-specific T-cell engager, GBD218, targeting both BCMA and GPRC5D. GBD218 has demonstrated potent in vitro and in vivo activity against myeloma cells. Methods Anti-BCMA and GPRC5D nanobodies were screened from alpaca immune libraries, and anti-CD3 antibody was engineered from mouse hybridoma clone. The tri-specific antibodies were constructed in a “1+1+1” format through “knob into hole” technology fused with silenced IgG1 Fc. The format of the tri-specific antibodies was optimized by multiple rounds of in vitro activity and druggability evaluation. The in vivo tumor growth inhibition effects were evaluated in PBMC-humanized xenograft mouse models. Results GBD218 has been designed to potently bind hBCMA (KD=0.4nM) and hGPRC5D (cell binding EC50 ~ 2nM). To reduce CRS and other potential AEs associated with TCEs, a low affinity of anti-CD3 Fab was used. In cell-based functional assays, GBD218 showed efficient cytotoxicity against single and double positive MM cell lines with various expression levels of BCMA and GPRC5D. T cell activation and cytokine release induced by GBD218, in the presence or absence of MM cancer cells, is nicely balanced for great killing efficacy and the low risk of CRS. Importantly, the results showed that GBD218 exhibited superior in vitro killing activity compared to benchmarks, including teclistamab, talquetamab, the combination of teclistamab and talquetamab, suggesting a synergistic effect of GBD218 by targeting BCMA and GPRC5D. In xenograft models, GBD218 showed excellent anti-tumor activity, indicating great potential for GBD218 as a promising therapeutics for MM. Conclusion GBD218 is a novel tri-specific antibody that showed potent in vitro and in vivo anti-tumor activity. GBD218 efficiently kills both BCMA and/or GPRC5D expressing MM cells, which may hold promise to increase response rate and improve survival in MM patients in clinic. Citation Format: Yongcong Tan, Xuezhen Li, Fan Yu, Juehua Xu, Zhen Qian, Yiqi Cao, Xueyan Yang, Qinglin Du, Fei Peng, Shuhua Han, Qian Ding. A novel tri-specific T cell engager targeting BCMA and GPRC5D for treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB128.

Sequence not salvage.

Chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of multiple myeloma (MM) has fundamentally changed the relapsed and refractory therapeutic landscape, but the disease remains incurable. Two CAR-T products, idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel, Carvykti), have been FDA- and EMA-approved for the treatment of relapsed/refractory MM (RRMM); both target B-cell maturation antigen (BCMA), a surface glycoprotein highly expressed on MM cells. Despite deep and durable responses following CAR-T therapy, most patients will need subsequent treatment, and the optimal next-line therapy is presently unclear. Commentary on: Liu etal. Outcomes in patients with multiple myeloma receiving salvage treatment after BCMA-specific CAR-T therapy: A retrospective analysis of LEGEND-2. Br J Haematol 2024;204:1780-1789.

Allogeneic CAR T Cells: Complex Cellular Therapy Designs Test the Limits of Our Preclinical Models.

All chimeric antigen receptor (CAR) T-cell products currently approved by the FDA are autologous, which poses several challenges for widespread use. In this issue, Degagné and colleagues present their preclinical research on creating off-the-shelf CAR T cells for multiple myeloma. They utilized the CRISPR/Cas12a genome editing platform and gene knock-in techniques to eliminate alloreactivity and decrease susceptibility to natural killer (NK)-cell elimination. This work has led to an ongoing phase I trial of off-the-shelf CAR T cells for multiple myeloma treatment. See related article by Degagné et al., p. 462 (2).

Genetic Risk Factors for Bortezomib-induced Neuropathic Pain in an Asian Population: A Genome-wide Association Study in South Korea

Bortezomib-induced neuropathic pain (BINP) poses a challenge in multiple myeloma (MM) treatment. Genetic factors play a key role in BINP susceptibility, but research has predominantly focused on Caucasian populations. This research explored novel genetic risk loci and pathways associated with BINP development in Korean MM patients while evaluating the reproducibility of variants from Caucasians. Clinical data and buffy coat samples from 185 MM patients on bortezomib were collected. The cohort was split into discovery and validation cohorts through random stratification of clinical risk factors for BINP. Genome-wide association study was performed on the discovery cohort (n = 74) with Infinium Global Screening Array-24 v3.0 BeadChip (654,027 single nucleotide polymorphism [SNPs]). Relevant biological pathways were identified using the pathway scoring algorithm. The top 20 SNPs were validated in the validation cohort (n = 111). Previously reported SNPs were validated in the entire cohort (n = 185). Pathway analysis of the genome-wide association study results identified 31 relevant pathways, including immune systems and endosomal vacuolar pathways. Among the top 20 SNPs from the discovery cohort, 16 were replicated, which included intronic variants in ASIC2 and SMOC2, recently implicated in nociception, as well as intergenic variants or long noncoding RNAs. None of the 17 previously reported SNPs remained significant in our cohort (rs2274578, P = .085). This study represents the first investigation of novel genetic loci and biological pathways associated with BINP occurrence. Our findings, in conjunction with existing Caucasian studies, expand the understanding of personalized risk prediction and disease mechanisms. PerspectiveThis article is the first to explore novel genetic loci and pathways linked to BINP in Korean MM patients, offering novel insights beyond the existing research focused on Caucasian populations into personalized risk assessment and therapeutic strategies of BINP.

In silico Identification of HDAC Inhibitors for Multiple Myeloma: A Structure-based Virtual Screening, Drug Likeness, ADMET Profiling, Molecular Docking, and Molecular Dynamics Simulation Study

Background: Multiple myeloma (MM) is a hematological malignancy of plasma cells that produce a monoclonal immunoglobulin protein. Despite significant advances in the treatment of MM, currently available therapies are associated with toxicity and resistance. As a result, there is an increasing demand for novel, effective therapeutics. Inhibition of histone deacetylases (HDACs) is emerging as a potential method for treating cancer. HDAC6 is one of 18 different HDAC isoforms that regulate tubulin lysine 40 and function in the microtubule network. HDAC6 participates in tumorigenesis and metastasis through protein ubiquitination, tubulin, and Hsp90. Several studies have found that inhibiting HDAC6 causes AKT and ERK dephosphorylation, which leads to decreased cell proliferation and promotes cancer cell death via the PI3K/AKT and MAPK/ERK signaling pathways. Objective: The objective of this study is to target HDAC6 and identify potent inhibitors for the treatment of multiple myeloma by employing computer-aided drug design. Materials and Methods: A total of 199,611,439 molecules from five different chemical databases, such as CHEMBL25, ChemSpace, Mcule, MolPort, and ZINC, have been screened against HDAC6 by structure- based virtual screening, followed by filtering for various drug-likeness, ADME, toxicity, consensus molecular docking, and 100 ns MD simulation. Results: Our research work resulted in three molecules that have shown strong binding affinity (CHEMBL2425964 -9.99 kcal/mol, CHEMBL2425966 -9.89 kcal/mol, and CSC067477144 -9.86 kcal/mol) at the active site HDAC6, along with effective ADME properties, low toxicity, and high stability. Inhibiting HDAC6 with these identified molecules will induce AKT and ERK dephosphorylation linked to reduced cell proliferation and promote cancer cell death. Conclusion: CHEMBL2425964, CHEMBL2425966, and CSC067477144 could be effective against multiple myeloma.