Refractory Myeloma Patients Research Articles

The UK consensus supporting effective introduction of novel treatments for multiple myeloma in the National Health Service

AbstractIntroductionMultiple myeloma (MM) is a relapsing, debilitating blood cancer which remains incurable despite advances in treatments. Patients typically receive multiple lines of treatment, to which they become refractory, thereby limiting treatment options. B‐cell maturation antigen (BCMA) bispecific antibodies (BsAbs) represent a novel modality of treatment that has significant efficacy for relapsed or refractory patients.The objective was to develop consensus statements for the effective implementation of BCMA BsAbs for relapsed or refractory MM patients within the National Health Service (NHS).MethodsThe process employed a modified Delphi methodology. In March 2023, a literature review on the topic of novel treatments for MM was performed using the PubMed database.The process employed a modified Delphi methodology. Following a literature review, a steering group of eight expert clinicians identified and agreed on five main topics of focus and 44 statements. These were then developed into an online survey which was distributed to healthcare professionals working in Levels 1, 2 and 3 haematology centres in the United Kingdom. Results were then shared with the expert panel to determine conclusions. The threshold for consensus agreement was set at 75%.ResultsA total of 60 responses were received from all three centre levels. There was representation from all targeted centres. Consensus was achieved in 42 statements (95%) across three broad areas: the patient profile, initiation and step‐up dosing, monitoring and ongoing care, the role of multidisciplinary team and service designs for optimal management, consensus was not achieved for two statements. Given the level of agreement and that the stopping criteria were met, it was decided not to undertake further Delphi rounds.ConclusionThis consensus provides a framework to support the effective introduction of novel treatments for MM in the NHS. The results were used to inform a checklist for use within haematology services when considering the provision of MM care specific to BCMA BsAbs.

Joint AI-driven event prediction and longitudinal modeling in newly diagnosed and relapsed multiple myeloma

Multiple myeloma management requires a balance between maximizing survival, minimizing adverse events to therapy, and monitoring disease progression. While previous work has proposed data-driven models for individual tasks, these approaches fail to provide a holistic view of a patient’s disease state, limiting their utility to assist physician decision-making. To address this limitation, we developed a transformer-based machine learning model that jointly (1) predicts progression-free survival (PFS), overall survival (OS), and adverse events (AE), (2) forecasts key disease biomarkers, and (3) assesses the effect of different treatment strategies, e.g., ixazomib, lenalidomide, dexamethasone (IRd) vs lenalidomide, dexamethasone (Rd). Using TOURMALINE trial data, we trained and internally validated our model on newly diagnosed myeloma patients (N = 703) and externally validated it on relapsed and refractory myeloma patients (N = 720). Our model achieved superior performance to a risk model based on the multiple myeloma international staging system (ISS) (p < 0.001, Bonferroni corrected) and comparable performance to survival models trained separately on each task, but unable to forecast biomarkers. Our approach outperformed state-of-the-art deep learning models, tailored towards forecasting, on predicting key disease biomarkers (p < 0.001, Bonferroni corrected). Finally, leveraging our model’s capacity to estimate individual-level treatment effects, we found that patients with IgA kappa myeloma appear to benefit the most from IRd. Our study suggests that a holistic assessment of a patient’s myeloma course is possible, potentially serving as the foundation for a personalized decision support system.

IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model

AbstractMultiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18–secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.

Abstract CT067: The anti-BCMA antibody-drug conjugate HDP-101 with a novel amanitin payload shows promising initial first in human results in relapsed multiple myeloma

Abstract Background: HDP-101 is a new antibody drug conjugatetargeting B-cell maturation antigen (BCMA) that carries a synthetic amanitin payload with a new mode of action. Amanitin inhibits RNA polymerase II, effectively stopping transcription and inducing apoptosis in tumor cells, regardless of their proliferation status. It's shown cytotoxicity in vitro against BCMA-positive myeloma cell lines and non-proliferating primary CD138+ cells from refractory myeloma patients withefficacy even in cells with low BCMA density. Clinical Study: HDP-101-01 is a first-in-human, open label, non-randomized, multicenter, phase 1/2a trial in patients with multiple myeloma whose disease has progressed or is refractory, aiming to determine the Maximum Tolerated Dose and/or the Recommended phase 2 Dose in Phase 1. Dose escalation is guided by an adaptive Bayesian logistic regression model with overdose control. The primary objective in phase 2 is to assess anti-tumor activity. Study Progress: As of November 2023, 18 patients (7 females, 11 males) were enrolled in 5 consecutive dose cohorts of 20, 30, 60, 80, and 100µg/kg. Patients had a median age of 70 years (48-82), were heavily pre-treated and multidrug-resistant, and had a median of 6,5 prior treatments (2-15). Study Results: Preliminary data shows that pharmacokinetics of HDP-101 aligns with expectations, and exposure to HDP-101 is dose proportional. Free payload was not detected in serum at a limit of detection of 30 ng/mL, and no anti-drug antibodiesor immunogenic reactions were noted. 17 of 18 patients were evaluable for dose limiting toxicities (DLT) in the 5 treatment cohorts. Initial cohorts were well tolerated, without any DLTs, including no signs of hepatic and renal toxicities, infusions reactions, or ocular disorders. All patients in Cohort 5 had Grade 1-4 transient thrombocytopeniawith platelet reductions starting on Cycle 1/Day 2 (C1/D2), a nadir on C1D5, and full recovery by C1D15 at the latest without any clinical sequelae or interventions. Notably, subsequent dosing with HDP-101 did not produce similarly deep episodes of thrombocytopenia, supporting the possibility that this event is not due to a direct cytotoxic effect against megakaryocytes. After Cohort 5, mitigation strategies are being considered and further dose and schedule optimization is planned with fractionated dosing and/or with premedication. Efficacy: Cohort3 has a patient with stable disease (SD) after 15 cycles. Cohort 5 has 4 ongoing patients with promising results after 3-4 cycles: 2 patients achieved PR, and 2 have SD. Updated data will be presented at the AACR2024 meeting. Citation Format: Jonathan Kaufman, Marc Raab, Shambavi Richard, Sebastian Grosicki, István Takács, András Strassz, Andreas Pahl, Michael Kulke, Thorsten Michael, Anette Last, Hajnalka Szabóki, Garrit Jentsch, Oliver Schönborn-Kellenberger, Robert Orlowski. The anti-BCMA antibody-drug conjugate HDP-101 with a novel amanitin payload shows promising initial first in human results in relapsed 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 CT067.

Real-world outcomes in relapsed refractory multiple myeloma patients exposed to three or more prior treatments: an analysis from the ANZ myeloma and related diseases registry.

There is no currently available standard of care for triple-class exposed, relapsed refractory myeloma (RRMM) patients in Australia. CARTITUDE-1 (CART-1) was a single-arm, phase 1b/2 study of 97 triple-class exposed RRMM patients, who received BCMA-CAR-T cell therapy with ciltacabtagene autocel. Overall response rate (ORR) was 98%. Median progression free survival (PFS) and overall survival (OS) had not been reached at a median follow-up of 28 months. We performed a retrospective analysis on a cohort of CART-1 comparable RRMM patients participating in the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR), to compare outcomes in triple-class exposed MM patients treated with currently available therapies, in a real-world context. The CE-MRDR cohort (n = 28) fulfilled CARTITUDE-1 eligibility (CE) criteria: ≥3 lines of therapy (LOT) including an immunomodulatory agent, proteasome inhibitor and CD38-directed monoclonal antibody (CD38mAb) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0-2 at diagnosis. The modified-CE-MRDR (n = 132) received ≥3 LOT but may not have received a CD38mAb with an ECOG PS score of 3 (0-3). Responses to the first subsequent therapy after eligibility were poor - ORR was 23% and 0% with progressive disease (PD) reported in 61% and 36%, CE-MRDR and m-CE-MRDR respectively. Responses to the second subsequent therapy after eligibility were worse, ORR 0% and 31%, CE-MRDR and m-CE-MRDR respectively, with high rates of PD, particularly in CE-MRDR. Median OS was 5.4 versus 9.5 months, CE-MRDR versus m-CE-MRDR. This retrospective analysis confirms uniformly poor outcomes for Australian RRMM patients. There remains a critical need for greater accessibility to novel treatments, such as CAR-T, outside clinical trials.

Clinical utility of PET/MRI in multiple myeloma.

This study aimed to evaluate the clinical utility of positron emission tomography/magnetic resonance imaging (PET/MRI), especially in comparison with PET/computed tomography (CT), which has been widely used in clinical practice in multiple myeloma. F-18 fluorodeoxyglucose PET/MRI and PET/ CT studies were done at baseline and when at least a partial response to treatment was achieved. These were done for newly-diagnosed myeloma patients who have not had more than 1 cycle of anti-myeloma treatment, or for relapsed and/or refractory myeloma patients before the start of next line of therapy. PET/MRI correlated significantly with PET/CT, in terms of number of lesions detected, standardised uptake value (SUVmean and SUVmax, both at baseline and post-treatment. PET/MRI and PET/CT correlated with survival at baseline, but not post-treatment. In this study, PET/MRI was more sensitive in detecting early disease and disease resolution post-treatment, compared with PET/CT. However, PET/MRI was less sensitive in detecting lesions in the ribs, clavicle and skull.

Anti-CD38-CAR IPS-Derived Cytotoxic T Lymphocytes Efficiently Eliminate Myeloma Cells Treated with Daratumumab and Isatuximab in Vitro and In Vivo

Patients with myeloma have improved prognosis with proteasome inhibitor (PI), immunomodulatory drugs (IMiDs), and antibodies, especially anti-CD38 antibodies such as daratumumab and isatuximab. However, even introduction of these novel therapeutics still gives dismal prognosis in relapsed and refractory myeloma patients. Recently, although anti-BCMA-CAR-T therapy is clinically available for these patients, this option has profoundly problems including long-time preparation of CAR-T cells and limited number of suitable patients. We previously developed anti-CD38-CAR-T cells and reported that these CAR-T cells efficiently eliminated myeloma cells. To use anti-CD38-CAR-T cells as off-the-shelf, we tried to develop anti-CD38-CAR iPS-derived cytotoxic T lymphocytes (iPS-rCTLs). Firstly, we investigated whether CD38 express on iPS-rCTLs because CD38 is induced or enhanced on T cells in activation for viral transduction. Interestingly, iPS-rCTLs never expressed CD38 even in the case of activation. Thus, we never needed addition of anti-CD38 antibody in the culture medium for blockade of interaction of CD38 and anti-CD38-CAR or knockdown/knockout of CD38 on T cells. Accordingly, we retrovirally transduced iPS-rCTLs with anti-CD38-CAR and then we obtained anti-CD38-CAR iPS-rCTLs with &amp;gt;70% of transduction efficiency. Secondly, we performed co-culture experiments of anti-CD38-CAR iPS-rCTLs and myeloma cells in vitro. Using flow cytometric analysis, these cells efficiently abrogated myeloma cells in time-dependent and in cell number-dependent manner (48-hour incubation of both cells at E:T ratio of 1:2 showed &amp;gt;90 % of cytotoxicity with anti-CD38-CAR iPS-rCTLs). xCELLigence cell analyzer also got results which were almost consistent with those of flow cytometry. Next, we tried to investigate the cytotoxicity of anti-CD38-CAR iPS-rCTLs in the xenograft model of NOG mice inoculated with RPMI8226 cells. Following inoculation of RPMI8226 cells (1x106), anti-CD38-CAR iPS-rCTLs were intravenously injected into mice (1 x 106) twice. Intriguingly, anti-CD38-CAR iPS-rCTLs clearly inhibited myeloma growth in xenografted mice until day 30. Next, we investigated their efficacy to myeloma cells treated with daratumumab or isatuximab. Surprisingly, anti-CD38-CAR iPS-rCTLs efficiently killed myeloma cells in the presence of daratumumab or isatuximab in vitro. Now that, we are investigating the cytotoxicity of anti-CD38-CAR iPS-rCTLs in xenografted mice model of myeloma in vivo. In conclusion, we obtained the cytotoxic results of anti-CD38-CAR iPS-rCTLs against myeloma cells in vitro in the presence of daratumumab or isatuximab. And anti-CD38-CAR iPS-rCTLs definitively inhibited the myeloma growth in vivo. These results suggest that the epitope recognizable by anti-CD38-CAR iPS-rCTLs was different from that of daratumumab and isatuximab. Anti-CD38-CAR iPS-rCTLs could shed light on myeloma patients as an off-the-shelf, leading to the increased number of the cutting edged therapeutic option.

A Phase 2 Study of Daratumumab in Combination with Thalidomide and Dexamethasone in Relapsed and / or Refractory Myeloma: A Report from the Asian Myeloma Network

Introduction Myeloma is a plasma cell dyscrasia characterised by a relapsing remitting course. Patients with relapsed / refractory myeloma (RRMM) with prior exposure to proteosome inhibitor and an immunomodulatory agent have a poor prognosis. In the last few years, CD38 antibodies such as daratumumab and isatuximab have revolutionised the treatment of multiple myeloma. They appear synergistic with immunomodulatory drugs; triplet combinations with lenalidomide 1 (DRd) or pomalidomide 2 (DPd) and dexamethasone have been approved for treatment of RRMM. However, patients face high out-of-pocket costs when attempting to access these drugs. There is hence a pressing need to develop combinations which harness the therapeutic potential of CD38 antibodies while preserving synergistic action of triplet combinations. Methods This was a multi-national, multi-centre, single arm, phase 2 trial of daratumumab in combination with thalidomide and dexamethasone. Patients with myeloma diagnosed according to the International Myeloma Working Group criteria with measurable disease and relapsing after / refractory to at least one prior line of treatment were eligible for enrolment. Satisfactory organ function (neutrophil count ≥ 1,000/mm 3, platelet ≥ 50,000/mm 3, bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN and creatinine clearance ≥ 30ml/min) were pre-requisites for inclusion. Patients with plasma cell leukaemia and those with prior CD38 antibody exposure were excluded. Patients received daratumumab IV 16mg/kg weekly for weeks 1 - 8, every 2 weeks from weeks 9 - 24 and every 4 weeks from week 25 onwards, thalidomide 100mg daily and dexamethasone 20mg twice a week. Treatment was continued for as long as tolerated and clinically indicated, based on physician assessment, or until disease progression. Thromboprophylaxis was allowed but not mandated. The primary outcome measure was progression-free survival (PFS), defined as the time from commencement of treatment to disease progression or death from any cause, whichever occurred first. Secondary outcome measures included overall response rate (ORR, the percentage of patients achieving a partial response (PR) or better), overall survival (OS), duration of response (DOR, the time from first evidence of PR or better till disease progression or death, whichever occurred first) and safety, assessed by the frequency and severity of adverse events. Results 70 patients were recruited. The median age was 66.8 (range 39 - 81) years with 62.7% males. 95.5% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The median number of prior therapies was 2 (range 1 - 6). 91% of patients had prior exposure to bortezomib, while 88% had prior exposure to thalidomide, lenalidomide or both. 50.7% had a prior autologous stem cell transplant. 67 patients completed at least one cycle of treatment. Two died prior to completion of the first cycle, while one withdrew consent and was excluded. Patients were treated for a median of 15.9 (interquartile range, IQR 5.1 - 23) months. 67 (95.7%) patients suffered 544 adverse events, of which 256 (47%) were related to the study treatment, 103 (19%) grades 3-4 and 8 (1%) were fatal. The most common adverse event was infection, which occurred in 26 patients; 4 were fatal. 27 patients had peripheral neuropathy, 25 of which were grade 1 - 2. 14 patients had an infusion reaction, 3 of which required hospitalisation. One patient had a deep vein thrombosis. At a median follow-up of 22.0 (IQR, 9.9 - 31.0) months, the median PFS was 16.3 (95% CI, 12.8 - 24.6) months (Figure 1). The median OS was 32.5 (95% CI, 25.4 - not reached) months. The ORR was 82.1% (95% CI, 70.8 - 90.4). This ORR was comparable to DRd and DPd (Table 2). Of these, 43 (78%) of patients achieved a very good partial response (VGPR) or better, with 9 (16%) of patients achieving a stringent complete response (sCR). The median DOR was 19.3 (95% CI, 12.2 - 36.5) months. Conclusion The combination of daratumumab, thalidomide and dexamethasone is effective in RRMM patients. Thalidomide and dexamethasone are cost-effective drugs which can improve the accessibility of daratumumab-based triplet combinations.

A Phase 1 Trial Evaluating the Addition of Lenalidomide to Relapsed/Refractory Multiple Myeloma Patients Progressing on Ruxolitinib and Methylprednisolone

Background Ruxolitinib (RUX), an orally administered selective JAK 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma (MM) effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both preclinically and clinically. Although we have previously demonstrated that LEN and steroid refractory MM patients respond to the addition of RUX, no studies have evaluated whether LEN can achieve clinical activity among those progressing on the combination of RUX and methylprednisolone. Methods Patients included those with MM showing progressive disease (PD) who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens. Initially, subjects received oral RUX 15 mg twice daily and oral methylprednisolone 40 mg every other day. Those patients who developed PD according to International Myeloma Working Group criteria had LEN 10 mg once daily days 1-21 on a 28-day cycle added to RUX and methylprednisolone which were administered at the same doses they were receiving at the time of PD. Results A total of 29 subjects were enrolled and initially received the combination of RUX and methylprednisolone. Follow up was until June 30, 2023. The median number of prior therapies was 6 (range, 3-12). The overall response rate (ORR) was 31% and the clinical benefit rate (CBR) was 34%. The best responses were 1 very good partial response (VGPR), 8 partial responses (PR), 1 minor response (MR), 12 stable disease (SD), and 7 PD. The median progression-free survival (PFS) was 3.5 mo (range, 0.5-36.2 mo). The median time to response was 3.0 mo (n=10). The median duration of response (DOR) was 12.5 mo (range, 2.8-36.2 mo). Twenty (69%) showed PD and had LEN added to the RUX and methylprednisolone combination: all of these patients were refractory to their last LEN-containing regimen. After the addition of LEN, the ORR was 30% and CBR was 40%. The best responses of patients following the addition of LEN were 2 VGPR, 4 PR, 2 MR, 8 SD, and 4 PD. The majority of patients (71%) who initially achieved a &amp;gt; MR to the two-drug combination responded following the addition of LEN whereas only 23% of patients who did not initially achieve a &amp;gt; MR responded to the addition of the third drug. The median time to response was 2.6 mo (range, 0.7-15 mo). The median DOR was undefined (range, 1.2-10.9 mo). The median PFS was 3.5 mo (range, 0.3-25.9 mo). The median PFS2 (including time from first treatment to end of study or June 30, 2023) was 7.3 mo (range, 0.5-39.9). Treatment was well tolerated with no additional toxicity identified following the addition of LEN. Interestingly, PFS2 was predicted by the patient's baseline serum B-cell maturation level; patients with values above the median (128 ng/mL) had significantly shorter PFS2 than those below it (3.5 mo vs. undefined, p = 0.0337). Conclusion The addition of LEN to heavily, previously treated relapsed/refractory MM patients progressing on RUX and methylprednisolone shows significant clinical activity. This three-drug combination is well tolerated and is able to extend the benefit of RUX-based treatment for these patients. The promising results from this phase 1 clinical trial demonstrate a potential novel, all oral therapeutic approach for treating RRMM patients.

Multiple Myeloma Disease Model to Predict PFS Outcomes across Lines of Therapy, an Analysis Based on Commpass Observational Study

Introduction Multiple Myeloma (MM) remains incurable despite advances in treatment. Model-based approaches based on tumor dynamics have successfully been used to optimize drug-development in oncology. Model-derived tumor dynamics also called tumor growth inhibition (TGI) metrics capture the treatment effect as tumor biomarkers and are predictive of the overall survival (OS) benefit, based on TGI-OS models, this mathematical framework has been shown to be drug-independent in most cases. M-protein is measured longitudinally during clinical trials, it reflects tumor burden and is one of the criteria used to assess clinical response according to the International Myeloma Working Group Uniform Response Criteria. A drug-independent link between M-protein dynamic metrics and OS was previously established and confirmed for refractory MM patients. The primary endpoint in MM clinical trials is usually progression free survival (PFS). New immunotherapies are currently in development and there is a need for early and robust drug development decision making. Therefore there is strong interest to expand this modeling framework to leverage M-protein dynamics to predict PFS outcomes. Methods CoMMpass (https://www.themmrf.org/finding-a-cure/personalized-treatment-approaches/) is a prospective, longitudinal, observational study in newly diagnosed symptomatic patients with multiple myeloma. It represents a unique source of clinical data to investigate the link between M-protein dynamic and survival outcomes across lines of therapy and treatments. Individual M-protein and PFS Data from 804 patients within the CoMMpass study were used. Given patients are enrolled at their initial treatment regimen and observed over 8 years, they can receive several lines of therapy. Due to the characteristics of the modeling framework, allowing to analyze only one line of therapy for each patient, the latest line of therapy for each subject was selected for which they had at least 2 M-protein assessments available. M-protein dynamic metrics (M-protein ratio to baseline at different time points, time to growth, growth rate, shrinkage rate) derived using an empirical bi-exponential model, 42 prognostic factors and potential treatment effects were first tested in a univariate analysis using a Cox proportional hazards regression model. Statistically significant covariates in the univariate analysis (p&amp;lt;0.05) were included in a full multivariate parametric distribution survival model. A backward deletion stepwise procedure was performed (p&amp;lt;0.01) to retain covariates in the final PFS model. Model qualification was performed using posterior predictive checks based on Kaplan Meier plots. Results Among 804 patients, 490 patients received only 1 line of therapy (LoT), 157 received 2 LoTs, 93 received 3 LoTs, 31 received 4 LoTs,18 received 5 LoTs, 10 received 6 LoTs, finally 7 patients got up to 7 to 11 LoTs. PFS distribution followed a log-normal distribution. Table 1 shows the parameter estimates of the PFS model. Among all tested M-protein dynamic metrics and prognostic factors, the logarithmic value of the growth rate (log(KG)), in red in Table 1, was found to be the best predictor of PFS. Patients with slower growth rate, who received a transplantation, with higher albumin and lower lactate dehydrogenase values had longer PFS. Those findings are consistent with previous modeling works conducted in MM. Also, the PFS model was confirmed to be drug-independent. As shown in Figure 1, prediction intervals derived from model-based simulations well captured observed PFS data for each line of treatment although the line of therapy is not included as a predictor in the PFS model. Similar results were obtained across treatments. In a next step, external validations assessing the model performance to reproduce Phase 3 clinical trial outcomes will be performed. Conclusions A model linking M-protein dynamic to PFS in MM was developed across a wide range of lines of therapy and treatments. The model can support drug development in MM: enabling early predictions of clinical trial outcomes and inform study design e.g. by simulating the probability of success of upcoming pivotal clinical trials.

A Single Center Real-World Data Comparing Salvage Autologous Hematopoietic Stem-Cell Transplantation, Selinexor Combo and Elranatamab Alone Among Triple Class Refractory Myeloma Patients: Better Efficacy with Elranatamab

Introduction: A vast majority of multiple myeloma (MM) patients may experience relapse and require multiple lines of therapy. The choice of the next treatment depends on multiple factors including the response, tolerance to prior therapies, as well as access to novel treatments. Among triple-class refractory patients, in real-world settings where CAR-T therapies are not available, options are limited. Here we report a single-center experience comparing salvage autologous hematopoietic stem-cell transplantation (sAHCT), selinexor combinations, and elranatamab in this highly unmet needed group. Patients &amp; Methods: Between January 2015 and June 2023, 50 patients at our center underwent sAHCT for treatment of refractoriness to all available drugs. Salvage AHCT is defined as being transplanted for treatment of MM after evidence of disease progression not responding to second-generation proteasome inhibitors (PI), immunomodulating agents (IMID), or antiCD38 monoclonal antibody. We compared the outcomes of these patients with RRMM patients who had exhausted their treatment options and were progressing on their last line of therapy to receive single agent Elranatamab at a step-up dosing starting with escalating to 72 mg once a week for six months and on alternate weeks thereafter. Selinexor was administered with either Bortezomib(n:8) or Pomalidomide(n:9) at a dose of 60-100 mg/week every 5-6 weeks. Response and disease progression were assessed according to the IMWG criteria. Results: Patients' characteristics and the outcomes are shown in Table. The median age of patients was similar in both groups. Patients were heavily treated with a median of 4 prior lines of therapy (1-17) and 7 out of 13 carried high-risk cytogenetics in elranatamab group. All patients were triple-class refractory. Five patients responded to DCEP bridging therapy prior to sAHCT. Selinexor (n: 11, 64.7%) and elranatamab (n:5 patients,38.5%) were administered after sAHCT. One patient underwent sAHCT due to progression under Selinexor treatment. In the sAHCT group, 68% of patients relapsed within a median of 7.4 months. Median DFS was significantly prolonged with single agent elranatamab (NR) compared to sAHCT (7.3 mos) and Selinexor-combos (7.3 mos) (p=0.4) (Figure). Adverse events on selinexor regimens included fatigue, nausea, and thrombocytopenia which were managed with Selinexor dose adjustment and supportive care. All patients received the recommended step-up priming dose elranatamab regimen, 69.2% of our patients experienced a Grade 1 cytokine release syndrome (CRS) during the first cycle. None of these patients had to stop treatment due to toxicity. Early sAHSCT mortality was not observed either. At the time of the analysis, all patients on Selinexor have progressed after a median follow-up of 14.7 months. Elranatamab patients are currently at 5 months follow-up and 7/ 13 are still on treatment. Conclusion: Upfront AHCT is a cost-effective treatment option with a decreasing efficacy in late relapses. In this RWE study, we have been able to confirm the inferiority of AHCT at late stages. As seen in our series cytogenetic profile worsens with an increase in the prior number of lines of treatment which are both highest among patients who have received elranatamab. Despite these unfavorable features, single-agent elranatamab has been able to attain the highest overall response rates, unfortunately not reflecting on PFS yet, due to short follow-up. Furthermore, two of these had progressed while on a BCMA immunotoxin Rx and have responded to elranatamab. In conclusion, even with short follow-up single-agent elranatamab is a tolerable and highly effective regimen

Early Intervention with Celmods, but Not Imids, Prevents Relapse to Forimtamig Driven By GPRC5D-Negative Myeloma Cells

Despite novel therapeutic options leading to a substantial increase in survival rates, multiple myeloma (MM) still represents an incurable disease. T cell bispecific antibodies (TCBs) have become a novel therapeutic option for relapsed refractory myeloma (RRMM) patients based on their promising objective response rates (ORR), favorable safety profile and off-the-shelf availability as compared to CAR-T cell therapies. Although BCMA- and GPRC5D-targeted TCBs have been reported to induce deep clinical responses, antigen drift represents a tumor intrinsic resistance mechanism limiting durability of responses 1. Here, we report that the combination of forimtamig, a 2:1 GPRC5D-targeted TCB, with CELMoDs, but not IMIDs, prevents tumor relapse driven by target-negative myeloma cells in a preclinical model of multiple myeloma. In order to mimic acquired TCB resistance in vivo, stem-cell humanized mice were engrafted with NCI-H929 tumors and treated once weekly (QW) with fixed duration forimtamig at 0.1 mg/kg for 6 cycles with a treatment-free follow up of more than 2 weeks. Single administration of forimtamig reduced tumor load by 80% at the end of cycle 1 (C1). At the end of cycle 4 (C4), all mice achieved a complete response (CR) with no detectable tumors. However, between C4 and cycle 6 (C6), tumor escape was observed in 47% of animals and progression free survival rate (PFS) at study termination was 53%. Relapsed tumors were subjected to quantitative immunohistochemistry and while prevalence for BCMA was comparable to baseline, GPRC5D expression was lost. To evaluate if cereblon modulation represents a strategy to improve PFS, we combined fixed-duration forimtamig with either pomalidomide (pom) or iberdomide (iber) at C1 day 1 (C1D1). Combination with pom and iber increased anti-tumor response compared to monotherapy during C1 deleting 88% and 92% of tumors, respectively. PFS for the combination with pom was not improved (~50%) as tumor escape was observed after treatment was stopped at C6. In contrast, no tumor relapse was observed for the combination with iber increasing PFS to 100%. Notably, as compared to forimtamig monotherapy, combination with pom and iber further increased serum levels of IFNg, IP-10, IL-2 and TNFa 48h after TCB dosing. We next explored if a sequential start of the combination would impact PFS and cytokine release and started co-administration at C3 instead of C1. Forimtamig induced strong tumor regressions in 90% of animals during C1-C4, but tumor escape was observed in 100% of animals starting after C4. When combined with pom or iber, PFS rates increased to 30% and 60%, respectively. Overall cytokine release was significantly lower compared to C1 and neither addition of pom nor iber led to an increase in cytokine production as compared to forimtamig monotherapy. To explore the potential of CELMoD combination at significantly lower TCB starting and target doses, we introduced step up dosing for forimtamig reflecting clinically relevant exposures and combined with thrice weekly (Q3W) or five time a week (Q5W) dosing of mezigdomide (mezi) starting at C1D1. Although forimtamig induced transient tumor regressions at C1D1 as well C1D15, mice showed progressive disease at the end of C1 and only 20% of mice achieved a CR at the end of the study. In contrast, combination with mezi led to rapid onset of tumor regression during C1 correlating with significantly improved PFS rates of 80% (Q3W) and 100% (Q5W). Cytokine release was measured after each step up and target dose and a maximal 2-fold increase in combination with mezi was detected. Interestingly, in contrast to IL-2 or IP-10, serum levels of IL-8 as well as MIP-1a decreased for the Q3W mezi schedule. Taken together, our data suggest that combination with CELMoDs but not IMIDs can prevent relapse to forimtamig driven by GPRC5D negative tumor cells. We confirm timing of intervention with CELMoDs to have an significant impact on PFS and cytokine release and suggest a broad therapeutic window using low dose forimtamig and intermittent dosing of iberdomide or mezigdomide.

Phase 2 Trial of Anti-PD1 and 8 Gy in 1 Fraction for Relapse/Refractory Myeloma

Relapsed, refractory multiple myeloma is associated with poor outcome. Role of radiotherapy is mainly for palliation. Anti-PD1 inhibitors have failed to show efficacy in relapsed refractory myeloma patients. A phase 2 trial (NCT03267888) was conducted to see if radiotherapy (8 Gy in 1 fraction) and anti-PD1 (Pembrolizumab) could provide early signals of safety and response. A prospective single-center phase 2 trial involving patients >18 years of age with ECOG 0-1 was conducted after obtaining IRB approval. Patients had to have ISS stage I-III multiple myeloma that was either relapsed or refractory, an osseous and/or extraosseous lesion that could be radiated, and who were candidates for pembrolizumab. Patients had to have either measurable disease per the International Myeloma Working Group Criteria (IMWG) and/or had to have progressive disease on imaging. Radiotherapy was given on day 0, cycle 1 followed by pembrolizumab (200 mg/kg iv on day 2 or 3, then every 3 weeks +/- 7 days) on day 2-3 for at least 2 years or until progression. Primary endpoint was toxicity. Secondary endpoints were IMWG response, abscopal response, overall survival, and immunological changes in patient's blood. Patients were assessed at 3 months, 6 months, and 12 months IMWG criteria as well as serial PET/CT based imaging. Patients with stable disease or better were continued on the trial. Patients that progressive were removed. Standard statistical analysis was performed, and included Kaplan-Meier to estimate OS and PFS. From June, 2018 until October, 2021, 32 patients were screened and 25 were enrolled. Of the enrolled patients, 76% were Caucasian, 64% had ECOG 1, and the mean age was 60 years. Prior to enrollment, the mean number of prior lines of therapy that the patients had failed was 5.20 (range: 2 - 11), suggesting a cohort with poor expected outcome. These cohort also had limited alternative options. Toxicity, as its primary endpoint, was acceptable. There were no grade 2 or higher radiation related toxicity within the irradiated volume. Only one case of grade 3 or higher pembrolizumab-related toxicity was noted amongst the 25 patients. Abscopal response was noted in 5 of 25 patients (20% patients). Several patients showed robust reductions in the paraproteins and other myeloma labs, suggesting response to radiotherapy and anti-PD1 combination. These patients were also associated to have a robust CD 8 T cell activation and an abscopal response. The secondary outcomes were better than expected for this cohort. Combination therapy of single-fraction, low-dose radiation therapy with pembrolizumab in patients with relapsed or refractory multiple myeloma is worth assessing in future trials.

Abstract 4074: Cellular immunotherapy targeting kappa myeloma antigen for the treatment of multiple myeloma

Abstract Multiple myeloma (MM), the second most common blood cancer, is characterized by the accumulation of malignant plasma cells in the bone marrow. Chimeric Antigen Receptor (CAR)-T cell therapy has recently entered the standard of care for relapsed and refractory MM, following the recent FDA-approval of two CAR-T cell products, ide-cel® and cilta-cel®, which target the B cell maturation antigen (BCMA). However, despite impressive response rates, most patients relapse within 1-3 years. Kappa (κ) myeloma antigen (KMA) is a tumour specific membrane associated protein expressed on malignant plasma cells in patients with kappa light-chain restricted (κ-type) MM. KMA is absent on normal plasma cells and haematopoietic stem cells, making it an attractive and alternative target antigen for CAR-T cell therapy for MM. The monoclonal antibody, KappaMab (MDX-1097), binds to a conformational epitope on KMA, and has been assessed in phase I, IIa and IIb clinical trials in relapse refractory myeloma patients (1). Here, we have engineered a lentiviral vector encoding a second-generation CAR expressing a scFv from MDX-1097, fused to a 4-1BB co-stimulatory domain and CD3 zeta chain. We successfully generated human anti-KMA CAR-T cells with high and stable CAR expression and a predominately memory T cell phenotype. The CAR-T cells selectively killed KMA-expressing tumour lines, secreted interferon-gamma upon target recognition, and demonstrated potent anti-tumour activity in a xenograft model. Anti-KMA CAR-T cell therapy therefore represents a novel and potent treatment ready to enter a phase I clinical trial for patients with myeloma. (1) Spencer et al. Blood Cancer Journal (2019) 9:58 Citation Format: Jessica Li, Nicole Haynes, Katherine Cummins, Kavitha Gowrishankar, Kenneth Micklewaithe, Halley Hilton, Rosanne Dunn, Jane Oliaro, Simon Harrison. Cellular immunotherapy targeting kappa myeloma antigen for the treatment of multiple myeloma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4074.

Management and Outcomes of Anti-CD38 Refractory Myeloma Patients: The Impact of Retreatment and of Subsequent Therapies

The management of refractory myeloma patients (pts) to anti-CD38-based therapies is challenging despite the increasing number of treatment options. In addition, the use of anti-CD38 monoclonal antibodies (MoAbs) in earlier lines of treatment increases the number of refractory pts to these drugs. Management of such pts is based either in the use of drugs with new mechanisms of action (if available) or in the retreatment with same agents or drug classes used in prior lines. Herein, we describe the outcomes of pts who failed on anti-CD38-containing therapy. The analysis included 183 pts with RRMM who progressed during therapy with a daratumumab- or isatuximab-based regimens (index therapy) and who received further therapy. Pts were treated in a single center (Department of Clinical Therapeutics, University of Athens, Greece) and started anti-CD38 therapy from 1/1/2015 to 31/12/2021. The pts received index anti-CD38 therapy after a median of 2 prior lines of therapy (range 1-10). Their median age was 68 years (range 35-89); 38% had prior ASCT, 61% were PI-, 71% lenalidomide- and 29% pomalidomide-refractory. Anti-CD38 was given as monotherapy (+/- dexa) in 50% of pts, while its combination with IMiD was given in 25% of pts and with PI in 25% of them. On ITT, ORR was 55% (CR: 5%, VGPR: 25%, PR:25%). Median PFS on anti-CD38 therapy for the whole cohort was 6.4 months; it was 5.5 months for anti-CD38 +/- dexa vs 7.4 months for anti-CD38 triplets (p=0.055). Post anti-CD38 progression (median 3 prior lines) all pts were PI and lenalidomide exposed, 82% were PI refractory, 75% lenalidomide refractory and 46% pomalidomide refractory. Treatment post anti-CD38 failure included PI-based regimens in 40% of pts (23% carfilzomib-based), 30% pomalidomide containing, 23% anti-CD38 triplet combinations, 15% belantamab mafodotin, 5% selinexor (+/-PI); 50% received a triplet and 50% a doublet. On ITT, ORR in the post anti-CD38 line was 43% and the median PFS was 6.4 months; PFS was 5.5 months for pts that had progressed on anti-CD38+/-dexa, post-anti-CD38 and 7.4 months for those progressing on anti-CD38-combinations (p=0.195). Given the high rates of PI and lenalidomide resistance, only pomalidomide sensitivity was associated with better PFS post anti-CD38, which remained poor (median 7.5 vs 5.2 months, p=0.007). Median PFS in the post anti-CD38 line was 4 months for those who received anti-CD38 containing regimens, 6.4 months for PI-based regimens (for carfilzomib-containing 6.7 months), 4.5 months for pomalidomide-based, 6 months for triplets (vs 6.8 for doublets) while it was 9.1 months (95% CI 4.5-13.9) for belantamab mafodotin and 3.7 months in the small group of selinexor treated pts. A PFS ≥12 months during index anti-CD38 therapy was the most important prognostic factor for PFS post anti-CD38 failure (median PFS post anti-CD38 of 11.3 months vs 5.2 months, p=0.001). This prognostic effect was independent of the number of prior lines, type of treatment or pomalidomide resistance. Notably, the use of anti-CD38 combinations was associated with a PFS of 11.6 months in pts with a PFS ≥12 months during initial anti-CD38 therapy. The median OS post anti-CD38 progression was 17.6 months; 12.8 vs 22.5 months for pts who had progressed on antiCD38+/-dexa vs antiCD38 combinations respectively (p=0.327), The median OS post index therapy was 16.6 months for those who received anti-CD38 containing regimens, 22.9 months for PI-based regimens (for carfilzomib 22.7 months), 20.9 months for pomalidomide-based therapies, 21 months for triplets (vs 19.3 for doublets), 24.5 months for belantamab and 30 months for the small group of selinexor-treated pts. OS post anti-CD38 was 39 months for those with PFS ≥12 months on index antiCD38 therapy (vs 12 months, p<0.001) and this was the only important prognostic factor. In conclusion, outcomes after progression to anti-CD38 therapy are poor, despite recent therapeutic advances. Drugs with new mechanisms of action may improve PFS, but their use needs to be optimized, probably in the context of triplet combinations. Recycling prior therapies, even anti-CD38 drugs, may be beneficial especially for pts who had prolonged remission during the index anti-CD38 treatment and could be useful as a bridge to other options. In this subgroup of pts, maintaining an antiCD38 backbone could be a valid option but participation in clinical trials should be highly encouraged. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Validation of a Novel Rac1 Inhibitor As Potent Secdrug Against Activating Ras Mutant and Drug-Resistant Multiple Myeloma

Multiple myeloma is the second-most common hematopoietic malignancy in the United States. Although several drugs have so far been approved by the FDA, myeloma still remains an incurable disease with dose-limiting toxicities and resistance to primary drugs like proteasome inhibitors (PIs) and Immunomodulatory drugs (IMiDs). Furthermore, activating Ras gene (NRAS, KRAS, and HRAS) mutations are known to occur in >50% of myeloma patients, which are also associated with greater tumor burden, cancer aggressiveness, high recurrence rates, and poor survival. We have recently established a novel drug development/re-purposing pipeline called secDrug that incorporates a pharmacogenomics data-driven computational algorithm to introduce several new drug candidates (secDrugs), including EHT1864 (a Rac1 (Ras superfamily GTPase) inhibitor), CCT018159 (Hsp90 inhibitor), and CP466722 (a reversible ATM inhibitor) as synergistic partners of primary drugs against drug-resistant myeloma. The overall objective of this study is to validate EHT1864 using in vitro and ex vivo models of relapsed and refractory myeloma (RRMM) patients. First, we used single-cell RNA sequencing (scRNAseq) as a novel screening tool to demonstrate that EHT1864 is potentially effective against myeloma subclones based on the enrichment of target genes (Figure 1). For in vitro validation, we used a human myeloma cell line (HMCL) panel representing drug-sensitive (FLAM76), innate/refractory resistance (LP1), and acquired/relapsed resistance (parental and clonally derived PI-resistant and IMiD-resistant HMCL pairs U266 P/VR, RPMI P/VR, MM1S P/VR/LenR). FLAM76 KRas (FLAM76-K12) and FLAM76 Nras (FLAM76-N12) cell lines were generated using Adeno-associated viral (AAV) vector-mediated delivery of CRISPR-Cas9 for genome editing in humans. Ras mutations were confirmed using Sanger DNA sequencing method. Cell viability measured using CellTiter-Glo luminescent cell viability assay showed the potency of EHT1864 as a single-agent (IC50 range 15-40µM) as well as in combination with PIs (represented by Ixazomib) and IMiDs (represented by Lenalidomide). Combination index (CI) values calculated using Chou-Talalay's CI theorem were consistently less than 0.9, while all the four synergy scores (HSA, Bliss, Loewe, and ZIP) were higher than 5, demonstrating high synergy. Cell death due to apoptosis was confirmed using flow cytometry (Annexin-V-Propidium Iodide staining), Caspase 3/7 activity assay, and immunoblotting. Interestingly, EHT1864 was most potent against drug-resistant and Ras-mutant HMCLs. Further, we showed that EHT1864 treatment also affects ROS generation and mitochondrial membrane potential, indicating that EHT1864 induces apoptosis via mitochondria-mediated pathway. Finally, we performed pre-vs-post-treatment genome-wide transcriptome analysis (tumor mRNAseq) and single-cell multi-ome analysis (single-cell RNA sequencing/scRNAseq + single-cell Assay of Transposase Accessible Chromatin sequencing/scATACseq) analysis to derive molecular signatures and pathways representing the basis of (on-target and off-target) efficacy of EHT1864 and drug synergy at the bulk tumor and subclonal levels. Finally, we will perform single-cell proteomics (high-dimensional immunophenotyping using mass cytometry/CyTOF/Cytometry time of flight) in CD138+ bone marrow cells derived from newly-diagnosed and relapsed myeloma patients (ex vivo) to demonstrate efficacy in RRMM. Thus, our work lays a framework to establish EHT1864 as a clinical trial-ready therapeutic option for the management of drug-resistant myeloma. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Novel Antigens LMA and Kma Are Expressed on Malignant Bone Marrow Plasma Cells from Patients with Relapsed Refractory Multiple Myeloma and Plasma Cell Dyscrasias

Introduction Previous studies have identified the lambda myeloma antigen (LMA) and kappa myeloma antigen (KMA) on the surface of malignant plasma cells in myeloma patient bone marrow samples, human myeloma cell lines and other plasma cell dyscrasias1-3. LMA and KMA are not present on normal B cells and are found on occasional mononuclear cells in tonsillar tissue and secondary mucosal lymphoid tissue. Targeting KMA and LMA through cellular and other immunological therapies has the potential advantage of leaving a population of normal plasma cells untouched and minimising the risk of serious post-treatment infection. Characteristics of the antibodies called KappaMab and LambdaMabs (10B3 and 7F11) that bind to specific conformational epitopes in the constant regions of these surface-bound light chains have been described in clinical trials and in vitro experiments1, 2, 4-6. Here, we present data on a larger series of patients with plasma cell dyscrasias, demonstrating the expression of LMA on plasma cells from patients in whom myeloma evolves from monoclonal gammopathy of unknown significance (MGUS). We also describe the difference in phenotype between LMA and KMA expressing malignant plasma cells and the frequent expression of KMA in relapsed refractory myeloma patient (RRMM) samples. Methods Patient BM samples (κ=49 and λ=31) were analysed using multiparametric FCM immunophenotyping with APC labelled LambdaMab (10B3) and KappaMab Fab'2 fragments, CD38, CD138, CD269 (BCMA), CD319 (SLAM F7), CD56 and CD45 monoclonal antibodies. Plasma cells were identified as previously described by initial gating using CD38 and CD138. LMA and KMA expression was determined and compared with the other cell markers. Results Nine of 12 (75%) newly diagnosed λ-type patients with MGUS or SMM expressed LMA on the surface of BM plasma cells. Longitudinal data from two patients was available. One patient showed LMA expression and antigen density increasing on the surface of bone marrow plasma cells during progression from MGUS (2020) to smoldering myeloma (SMM) (2022) (% of plasma cells positive for LMA rose from 61% to 92%, antigen density increased from 532 to 5164 molecules of PE/cell). In a second individual, LMA expression and antigen density increased on bone marrow plasma cells during progression from SMM (2020) to myeloma (2022) (% of plasma cells positive for LMA rose from 94% to 100%, antigen density increased from 3981 to 8941 molecules of PE/cell). KMA expression continued to be observed on plasma cells in 4 of 6 patients after autologous stem cell transplant. KMA was expressed in 86% of patients with ĸRRMM (n=14). LMA expression was observed in 2 of 4 patients with λRRMM. Both KMA and LMA antigen densities were higher than BCMA in the RRMM population (KMA mean 1802, range 468-7943 vs BCMA mean 1306, range 350-2630 molecules of PE/cell), (LMA mean 2439, range 263-6664 vs BCMA mean 817, range 537-1065 molecules of PE/cell). Conclusions In an enlarged cohort of patients with myeloma, we have confirmed that KMA and LMA are expressed at all stages of disease. Our data examining longitudinal expression in individual patients suggests that expression of LMA on BM plasma cells increases from MGUS to MM. The majority of patients with relapsed refractory kappa myeloma expressed KMA. Further data is required to confirm LMA expression in this population. The antigen density of both LMA and KMA is higher than BCMA on RRMM BM plasma cells. KMA and LMA expression is independent of serum Ig and FLC levels and % marrow plasma cells. These data show that KappaMab and LambdaMab have therapeutic potential in the treatment of myeloma patients, especially in the setting of relapsed refractory disease where the combination of high antigen density and restriction of the target antigen to the malignant subpopulation of plasma cells will confer valuable clinical benefit.

BCMA-Targeted Biologic Therapies: The Next Standard of Care in Multiple Myeloma Therapy.

With recent advances in myeloma therapy, patients can achieve long-term remissions, but eventually relapses will occur. Triple-class refractory myeloma (disease that is refractory to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody) and penta-refractory myeloma (disease that is refractory to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 antibody) are associated with a particularly poor prognosis, and novel treatments are desperately needed for these patients. Targeting B cell maturation antigen (BCMA), which is ubiquitously expressed on plasma cells, has emerged as a well-tolerated and highly efficacious strategy in patients with relapsed and refractory myeloma. Several mechanisms of targeting BCMA are currently under investigation, including antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T cells and natural killer (NK) cells, all with unique side effect profiles. Early phase clinical trials showed unprecedented response rates in highly refractory myeloma patients, leading to the recent approvals of some of these agents. Still, many questions remain with regard to this target, including how best to target it, how to treat patients who have progressed on a BCMA-targeting therapy, and whether response rates will deepen if these agents are used in earlier lines of therapy. In this review, we examine the rationale for targeting BCMA and summarize the data for several agents across multiple classes of BCMA-targeting therapeutics, paying special attention to the diverse mechanisms and unique challenges of each therapeutic class.

Guidance for Use and dosing of Selinexor in Multiple Myeloma in 2021: Consensus From International Myeloma Foundation Expert Roundtable

Selinexor is a first in class selective inhibitor of nuclear export (SINE), blocks exportin 1 (XPO1), a protein transporter, that among other actions, shuttles cargo proteins such as tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and oncoprotein messenger RNAs (mRNAs) across the nuclear membrane to cytoplasm. By blocking XPO1, selinexor facilitates nuclear preservation and activation of TSPs, and prevents mRNA translation of the oncoproteins leading to induction of apoptosis. The therapeutic value of selinexor in combination with dexamethasone has been successfully demonstrated in treating relapsed and/or refractory myeloma (RRMM), leading to the Food and Drug Administration (FDA) approval of selinexor in combination with dexamethasone in 2019 for the treatment of adult patients with RRMM who received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody (mAb) – a pentarefractory myeloma. More recently, selinexor in combination with bortezomib and dexamethasone was approved by the FDA in December 2020, based on the BOSTON study among RRMM patients who had received at least one prior line of therapy. With more available safety and efficacy data supporting the increased interval between dosing of selinexor (and lesser cumulative weekly dosing) and schedule, contrary to the originally approved dose of 160 mg per week, the supportive care guidelines needed to be revisited. The current manuscript summarizes the supportive care solutions with weekly dosing of selinexor and identifies the ideal potential patient for selinexor treatment.

Daratumumab with Pomalidomide and Dexamethasone at First Relapse in Relapsed and/or Refractory Multiple Myeloma (RRMM) Patients

Daratumumab with Pomalidomide and Dexamethasone at First Relapse in Relapsed and/or Refractory Multiple Myeloma (RRMM) Patients