Relapsed Multiple Myeloma Research Articles

Targeting ABCB6 with nitidine chloride inhibits PI3K/AKT signaling pathway to promote ferroptosis in multiple myeloma.

Since multiple myeloma (MM) remains a cureless malignancy of plasma cells to date, it becomes imperative to develop novel drugs and therapeutic targets for MM. We screened a small molecule library comprising 3633 natural product drugs, which demonstrated that Nitidine Chloride (NC), an extract from traditional Chinese medicine Zanthoxylum nitidum. We used Surface Plasmon Resonance-High Performance Liquid Chromatography-Protein Mass Spectrometry (SPR-HPLC-MS), Cellular Thermal Shift Assay (CETSA), molecular docking, and SPR assay to identify the potential targets of NC, in which ABCB6 was the unique target of NC. The effects of ABCB6 on cellular proliferation and drug resistance were determined by CCK8, western blot, flow cytometry, site-mutation cells, transmission electron microscopy, immunohistochemistry staining and xenograft model in vitro and in vivo. NC induced MM cell death by promoting ferroptosis. ABCB6 is the direct target of NC. ABCB6 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. VGSK was the inferred binding epitope of NC on the ABCB6 protein. In the ABCB6-mutated MM cells, NC did not display cancer resistance, implying the vital role of ABCB6 in NC's bioactivity. Moreover, the silencing of ABCB6 significantly inhibited MM cell growth. Mechanistically, the direct binding of NC to ABCB6 suppressed PI3K/AKT signaling pathway to promote ferroptosis. In conclusion, ABCB6 can be a potential therapeutic target and prognostic biomarker in MM, while NC can be considered a novel drug for MM treatment.

Whole-Exome sequencing analysis identified TMSB10/TRABD2A locus to be associated with carfilzomib-related cardiotoxicity among patients with multiple myeloma.

Proteasome inhibitor Carfilzomib (CFZ) is effective in treating patients with refractory or relapsed multiple myeloma (MM) but has been associated with cardiovascular adverse events (CVAE) such as hypertension, cardiomyopathy, and heart failure. This study aimed to investigate the contribution of germline genetic variants in protein-coding genes in CFZ-CVAE among MM patients using whole-exome sequencing (WES) analysis. Exome-wide single-variant association analysis, gene-based analysis, and rare variant analyses were performed on 603,920 variants in 247 patients with MM who have been treated with CFZ and enrolled in the Oncology Research Information Exchange Network (ORIEN) at the Moffitt Cancer Center. Separate analyses were performed in European Americans and African Americans followed by a trans-ethnic meta-analysis. The most significant variant in the exome-wide single variant analysis was a missense variant rs7148 in the thymosin beta-10/TraB Domain Containing 2A (TMSB10/TRABD2A) locus. The effect allele of rs7148 was associated with a higher risk of CVAE [odds ratio (OR) = 9.3 with a 95% confidence interval of 3.9-22.3, p = 5.42*10-7]. MM patients with rs7148 AG or AA genotype had a higher risk of CVAE (50%) than those with GG genotype (10%). rs7148 is an expression quantitative trait locus (eQTL) for TRABD2A and TMSB10. The gene-based analysis also showed TRABD2A as the most significant gene associated with CFZ-CVAE (p = 1.06*10-6). We identified a missense SNP rs7148 in the TMSB10/TRABD2A as associated with CFZ-CVAE in MM patients. More investigation is needed to understand the underlying mechanisms of these associations.

Selinexor-Based Triplet Regimens in Patients With Multiple Myeloma Previously Treated With Anti-CD38 Monoclonal Antibodies

BackgroundThe increasing use of anti-CD38 monoclonal antibodies (αCD38 mAbs) for newly diagnosed or early relapsed multiple myeloma (MM), especially in non-transplant eligible patients, may lead to more patients developing αCD38 mAb-refractory disease earlier in the treatment course with fewer treatment options. Patients and methodsWe analyzed the efficacy and safety of selinexor-based triplets (selinexor+dexamethasone [Sd] plus pomalidomide [SPd, n = 23], bortezomib [SVd, n = 16] or carfilzomib (SKd, n = 23]) in a subset of STOMP (NCT02343042) and BOSTON (NCT03110562) study patients treated previously with αCD38 mAbs. ResultsSixty-two patients (median 4 prior therapies, range 1 to 11, 90.3% refractory to αCD38 mAb) were included. Overall response rates (ORR) in the SPd, SVd and SKd cohorts were 52.2%, 56.3%, and 65.2%, respectively. Overall response rate was 47.4% among patients who had MM refractory to the third drug reintroduced in the Sd-based triplet. Median progression-free survival in the SPd, SVd, and SKd cohorts was 8.7, 6.7, and 15.0 months, respectively, and median overall survival was 9.6, 16.9, and 33.0 months, respectively. Median time to discontinuation in the SPd, SVd, and SKd cohorts was 4.4, 5.9, and 10.6 months, respectively. The most common hematological adverse events were thrombocytopenia, anemia, and neutropenia. Nausea, fatigue, and diarrhea were primarily grade 1/2. Adverse events were generally manageable with standard supportive care and dose modifications. ConclusionSelinexor-based regimens may offer effective and well-tolerated therapy to patients with relapsed and/or refractory MM who had disease previously exposed or refractory to αCD38 mAb therapy and could help address the unmet clinical need in these high-risk patients.

Racial differences in outcomes of patients with relapsed/refractory multiple myeloma treated with selinexor.

e20016 Background: Multiple Myeloma (MM) is the 2nd most common hematologic malignancy in the US, though survival in patients with MM has improved over the past decade. Survival improvements in African Americans (AAs) have been smaller, which may be due to disparity in access to therapies. There are also key differences in MM biology between races, including higher rates of IgA disease and genetics. Given underrepresentation of minorities in clinical trials, we analyzed whether outcomes were similar between AAs and other races in the phase 2 STORM trial (NCT02336815) of selinexor. Selinexor, an oral, first-in-class selective inhibitor of nuclear export via exportin 1, has proven efficacy for refractory MM. To our knowledge, this is the first race subgroup analysis of selinexor in any clinical trial. Methods: Pts from STORM who received study drug (N = 202) were included. Pts with heavily pretreated MM, including triple-class and penta- refractory MM refractory to the last line of therapy were given selinexor (80mg) + dexamethasone (20mg) twice weekly. We conducted a retrospective racial subgroup analysis. Cox proportional modeling was used to determine the hazard ratio (HR) for MM relapse between races controlling for covariates. Results: AAs represented 17% of pts (35 AAs, 148 White, 2 Asian, 11 other and 6 missing). AAs were younger compared to other races (median age 60.7 vs 65.3) with more females (74.3% vs 40.7%). Cytogenetic abnormalities and R-ISS staging were similar between races. AAs had a median progression free survival (PFS) of 6.5 mos (95% CI 4.7, NR) compared with 3.7 mos (95% CI 2.8, 4.6; p = 0.035) for other races. Overall response rate (ORR) was 25.7% (95% CI 12.5, 43.3) in AA pts vs 23.4% [17.2, 30.5] in other races), clinical benefit rate (37.1% [21.5, 55.1] vs 35.9% [28.7, 43.7]), median duration of response (5.6 mos [2.1, NR] vs 5.3 [3.6, NR]), median duration of treatment (9 wks [IQR 3-22 wks] vs 8 wks [4-16 wks]), and mean dose intensity (117.9 mg/wks [STD 35.1] vs 117.1 [34.7]) were similar between grps. Rates of Adverse Events (AEs) ≥ grade 3 (94.3% vs 95.8%), and AE-related dose reductions (45.7% vs 54.5%), discontinuations (22.9% vs 30.5%), and deaths (5.7% vs 10.8%) were also similar. The adjusted HR for MM relapse in AAs was 0.45 (95% CI 0.22, 0.92; p = 0.028) after controlling for gender, age and prior therapy. Conclusions: This subgroup analysis showed that compared with other races, AAs pts were younger and included a greater percentage of women. Although ORRs were similar, AAs had a longer PFS compared with other races after adjusting for covariates. Despite small sample size, the differences were statistically significant. It is unclear if the better PFS reflects a different biology, pharmacology of selinexor or both. Dose adjustments and tolerability were relatively comparable. These results could assist in the placement of selinexor in the treatment sequence of relapsed refractory MM for AAs.

Real-world treatment patterns of triple-class refractory (TCR) multiple myeloma (MM) across the United States (US), Canada, and western Europe: A retrospective chart study.

e18826 Background: Many patients with MM relapse or become refractory to various therapeutic approaches and typically cycle through many lines of treatment. The present study sought to understand how patients with TCR MM (ie, refractory to ≥1 PI, ≥1 IMiD, and ≥1 anti-CD38 therapy) are managed across various countries. Methods: A non-interventional, retrospective chart review study was conducted across the US, Canada (CA), the UK, France (FR), Germany (DE), Italy (IT), and Spain (ES). Oncologists/hematologists were recruited to abstract medical chart information into an electronic case report form from eligible MM patients (eg, refractory to ≥1 IMiD, ≥1 PI, and ≥1 anti-CD38 antibody treatment, ECOG≤2, and initiated their first therapy after their TCR status [ie, their index therapy] between 1/1/2018 and 12/31/2020 to ensure at least 1 year of follow-up). Abstractions were performed from January through April 2022. Demographics, clinical characteristics, and treatment patterns were descriptively analyzed and reported here. Results: N = 314 patients with TCR MM were included (56.7% male; median age = 70). Clinical characteristics were similar to other TCR MM studies (eg, 26.1% had an ECOG score of 2, 25.8% had high cytogenetic risk (ie, t(4:14), t(14:16), and/or del(17p), and 10.2% had extramedullary disease). Patients received a median of 3 treatment lines prior to their index therapy, with 70 unique treatment regimens reported as part of their index therapy line (Table 1). The most common regimens (> 10%) were Pd and Kd. Conclusions: This global chart review across the US, Canada, and Western Europe highlights the consistent lack of a standard of care for the management of MM among patients who are refractory to the three main classes of therapies. [Table: see text]

Sequencing bispecific antibodies and CAR T cell therapy in multiple myeloma with prior exposure to BCMA-targeted therapies.

e20049 Background: In patients with heavily pretreated relapse and refractory multiple myeloma (MM), novel approaches such as immunotherapies and B-cell maturation antigen (BCMA) targeted therapies have been utilized to show favorable responses Despite these therapies however, patients continue to have disease progression leaving them with fewer options. A need exists to investigate the optimal sequencing strategies in the treatment approach for MM with novel bispecific antibodies (BsAbs) and CAR T cell therapy in patients previously exposed to BCMA-directed therapies. Methods: A comprehensive review of active clinical trials, published primary literature, and meeting abstracts was performed to gather efficacy endpoints and overall response rates (ORR) in patients receiving BsAbs or CAR T therapy with previous exposure to BCMA directed therapy. Results: A variety of BCMA and non-BCMA directed BsAbs along with CAR T cell therapy have been evaluated for ORR in patients who received previous BCMA-targeted therapies. Teclistamab, a BCMA BsAb induced an adequate response of 40% in patients who received previous BCMA directed antibody drug conjugate (ADC) or CAR-T- cell therapy, with a deepening of response observed in 28%. Elranatamab, an investigational BCMA-targeted BsAb demonstrated a preliminary ORR of 54% in a cohort of 13 pts. Talquetamab, a first in class GPRC5D BsAb induced an ORR of 50% in pts with previous BCMA-directed therapy as monotherapy and resulted in an ORR of 72% in combination with daratumumab. Cevostamab, an investigational FcRH5 directed BsAb demonstrated an adequate ORR of 47% in 20 pts who received previous BCMA-directed therapy. In parallel to evaluating responses for BsAbs, CAR T cell therapies including cilta-cel and ida-cel have also induced favorable and durable responses in their prior BCMA therapy exposed cohorts with an ORR of 60.0% and 74% respectively. Comparable safety profiles across both BCMA treatment exposed and BCMA treatment-naive cohorts were observed among all studies. Additional endpoints including minimal residual disease and incidence of infections are to be included in final results. Conclusions: This analysis indicates that sequencing BsAbs and CAR -T cell therapy after previous BCMA-targeted treatments offers meaningful clinical benefit with durable response rates in patients who have few other options. Longer follow up and larger studies are needed to further evaluate their enhanced benefit and generate greater insight for optimal sequencing strategies in heavily pretreated MM patients who have exhausted other options. [Table: see text]

Incidence, clinical characteristics and prognosis of tumor lysis syndrome following B-cell maturation antigen-targeted chimeric antigen receptor-T cell therapy in relapsed/refractory multiple myeloma.

B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). However, CAR-T-related tumor lysis syndrome (TLS) has been observed. We aimed to elucidate the incidence, clinical and laboratory characteristics, and prognosis of CAR-T cell-related TLS. Patients (n=105) with r/r MM treated with BCMA-targeted CAR-T cell therapy were included. Patient characteristics, laboratory parameters, and clinical outcomes were assessed. Eighteen (17.1%) patients developed TLS after BCMA-targeted CAR-T cell therapy. The median time till TLS onset was 8 days. Patients with TLS had steep rise in uric acid (UA), creatinine, and lactate dehydrogenase (LDH) within 6 days following CAR-T cell infusion and presented earlier and persistent escalation of cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-γ [IFN-γ], and ferritin levels). All 18 patients had cytokine release syndrome (CRS), of which 13 (72.2%) developed grade 3-4 CRS. Three of 18 patients (16.7%) developed immune effector cell-associated neurotoxicity syndrome (ICANS): two patients with grade 1 ICANS and one with grade 2 ICANS. TLS development had a negative effect on the objective response rate (77.8% in the TLS group vs. 95.4% in the non-TLS group, p<0.01). During the median follow-up of 15.1 months, the median PFS was poorer of patients with TLS (median: 3.4 months in the TLS group vs. 14.7 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.5 [95% confidence interval [CI] 1.5-8.5]). Also, TLS development exhibited significant effects on OS (median: 5.0 months in the TLS group vs. 39.8 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.7 [95% CI 1.3-10.3]). TLS was associated with a higher tumor burden, elevated baseline creatinine and UA levels, severe CRS, pronounced CAR-T cell expansion, and corticosteroid use. TLS is a frequently observed CAR-T therapy complication and negatively influences clinical response and prognosis. Close monitoring for TLS should be implemented during CAR-T cell therapy, especially for those at high TLS risk.

Pleural plasmacytomas in a Patient with Multiple Myeloma Relapse

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MO-0949 Phase 1 study of escalated total marrow irradiation and melphalan at 1st relapse in multiple myeloma

MO-0949 Phase 1 study of escalated total marrow irradiation and melphalan at 1st relapse in multiple myeloma

An atlas of the bone marrow bone proteome in patients with dysproteinemias

Multiple myeloma (MM) bone disease is a significant cause of morbidity but there is a paucity of data on the impact of malignant plasma cells on adjacent trabecular bone within the BM. Here, we characterize the proteome of trabecular bone tissue from BM biopsies of 56 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM), newly diagnosed (NDMM), relapsed MM (RMM), and normal controls. Proteins involved in extracellular matrix (ECM) formation and immunity pathways were decreased in SMM and active MM. Among the proteins most decreased were immunoglobulins, type IV collagen, and TIMP3, suggesting increased immunoparesis and decreased ECM remodelling within trabecular bone. Proteins most increased in SMM/MM were APP (enhances osteoclast activity), ENPP1 (enhances bone mineralization), and MZB1 (required for normal plasmablast differentiation). Pathway analyses showed that proteins involved in gamma -carboxylation, a pathway implicated in osteocalcin function, osteoblast differentiation, and normal hematopoiesis, were also overexpressed in SMM/MM. This study is the first comprehensive proteomic atlas of the BM bone proteome in dysproteinemias. We identify new key proteins and pathways for MM bone disease and potentially impaired hematopoiesis, and show for the first time that gamma -carboxylation pathways are increased in the bone tissue of SMM/MM.

TRIM21 enhances bortezomib sensitivity in multiple myeloma by halting prosurvival autophagy

AbstractBortezomib (bort) is an effective therapeutic agent for patients with multiple myeloma (MM); however, most patients develop drug resistance. Autophagy, a highly conserved process that recycles cytosol or entire organelles via lysosomal activity, is essential for the survival, homeostasis, and drug resistance in MM. Growing evidence has highlighted that E3 ligase tripartite motif–containing protein 21 (TRIM21) not only interacts with multiple autophagy regulators but also participates in drug resistance in various cancers. However, to date, the direct substrates and additional roles of TRIM21 in MM remain unexplored. In this study, we demonstrated that low TRIM21 expression is a factor for relapse in MM. TRIM21 knockdown (KD) made MM cells more resistant to bort, whereas TRIM21 overexpression (OE) resulted in increased MM sensitivity to bort. Proteomic and phosphoproteomic studies of TRIM21 KD MM cells showed that bort resistance was associated with increased oxidative stress and elevated prosurvival autophagy. Our results showed that TRIM21 KD MM cell lines induced prosurvival autophagy after bort treatment, suppressing autophagy by 3-methyladenine treatment or by the short hairpin RNA of autophagy-related gene 5 (ATG5)-restored–bort sensitivity. Indeed, ATG5 expression was increased and decreased by TRIM21 KD and OE, respectively. TRIM21 affected autophagy by ubiquitinating ATG5 through K48 for proteasomal degradation. Importantly, we confirmed that TRIM21 could potentiate the antimyeloma effect of bort through in vitro and in vivo experiments. Overall, our findings define the key role of TRIM21 in MM bort resistance and provide a foundation for a novel targeted therapeutic approach.

Abstract CT262: Durable responses following anti-TIGIT (BMS-986207) and anti-LAG3 (BMS-980616) in combination with pomalidomide in relapsed myeloma: MMRF MyCheckpoint trial

Abstract Background: T cell redirection with agents such as Chimeric Antigen Receptor T cells or bispecific T cell engagers is remarkably effective in relapsed multiple myeloma (MM), however, they are not curative. Translational studies suggest that T cell exhaustion, characterized by upregulation of immune checkpoints LAG-3 and TIGIT, is a potential resistance mechanism to T cell redirection. These findings support the hypothesis that checkpoint inhibition with anti-LAG-3 or anti-TIGIT mAbs may restore anti-myeloma T cell activity. There is an unmet need to assess the feasibility and safety of checkpoint blockade in this malignancy. Patients and Methods: MyCheckpoint (NCT04150965) is a phase 1/2 platform trial for relapsed MM patients who have received ≥3 lines of therapy, including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 mAb. Primary objectives were safety and tolerability of the investigational agents alone and in combination with pomalidomide (Pom) and dexamethasone (Dex) and overall response rates in each arm. In the phase 1 portion subjects were randomized to Arm B (anti-LAG-3) or Arm C (anti-TIGIT mAb). Subjects received one cycle (C1) of mAb therapy alone, with the addition of Pom and Dex starting with cycle 2 (C2) onward. Bone marrow aspirates and peripheral blood were obtained at screening, C2D1, C3D1, and end of study for correlative analysis. Results: Fourteen (14) eligible subjects were enrolled (seven subjects in Arm B dose level (DL) 1, one not evaluable; six subjects in Arm C DL1, and 1 subject Arm C DL2 not evaluable). The most common adverse events (AE) were anemia and dyspnea. Grade 3-4 AEs related to therapy in the anti-LAG-3 arm were dyspnea and neutropenia; those in anti-TIGIT arm were neutropenia, thrombocytopenia, and anemia. There was 1 death due to progression of disease unrelated to the study treatment. There was 1 death due to a serious adverse event of pneumonia (unrelated). There was one adverse event of special interest in Arm B DL1 (grade 1 AST elevation). No autoimmune AEs were reported. Best overall responses for Arm B DL1 were 1 very good partial response (VGPR), 1 partial response (PR), 4 stable disease (SD); for Arm C DL1, 1 VGPR, 2 PR, and 3 SD. Eight subjects withdrew from treatment for disease progression, 2 for AE, and 2 for patient decision. Two subjects continue in Arm C DL1 as of December 2022, 1 PR as of C16D1 and 1 VGPR (C23D1). Conclusion: Anti-LAG-3 and anti-TIGIT mAb alone and in combination with Pom are safe, feasible and clinically active in relapsed MM after Pom and anti-CD38 mAb. These data provide the first evidence of clinical activity of TIGIT and LAG-3 blockade in MM. Translational results utilizing serial analyses with mass cytometry suggest evidence of immune activation following combination therapy. Citation Format: Hearn J. Cho, Shambavi Richard, Alex Lesokhin, Noa Biran, Barry Paul, Ravi Vij, Matthew Pianko, Deon Doxie, Mercedes Martillo, Katie Wozniak, Kavita Dhodapkar, Madhav Dhodapkar. Durable responses following anti-TIGIT (BMS-986207) and anti-LAG3 (BMS-980616) in combination with pomalidomide in relapsed myeloma: MMRF MyCheckpoint trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT262.

Abstract LB209: An ADC composed of daratumumab and lenalidomide is extremely powerful in killing multiple myeloma cells

Abstract Introduction: Multiple myeloma (MM) is a neoplastic malignancy characterized by the abnormal proliferation of plasma cells with excessive antibody production in the bone marrow. It accounts for approximately 1.8% of all new cancer cases and 2.1% of cancer deaths in the United States and occurs most frequently among older adults (age &amp;gt; 75). While there are a number of treatments with high response rates, MM relapses frequently within a few years and is considered incurable. Herein, experimental studies and results of a new therapeutic agent under development, TE-1146, are reported. TE-1146 is an antibody drug conjugate (ADC) composed of two therapeutic agents already in use in MM, namely, an anti-CD38 antibody, daratumumab (Dara), and lenalidomide (Lena). Method: TE-1146 is designed by employing “HIDAR” technology platform, which enables the preparation of homogeneous ADCs with high DAR (drug to antibody ratio). In the TE-1146 molecules, the Fab is replaced by scFv and a cysteine-containing Zn2+-binding motif is engineered at the C-termini of the H chains. Lena molecules are assembled into drug bundles containing 3 Lena molecules and a maleimide group. Two drug bundles are conjugated site-specifically to the Zn2+-activated SH groups of the reconfigured antibody molecule, creating an ADC with DAR of 6. TE-1146 was investigated for cytolytic effects against human MM cell lines H929 in cell cultures in vitro and transplanted H929 tumor in NOD-SCID mice in vivo, in comparison with Dara, Lena, and their combination. Results: In human plasma, TE-1146 has stability comparable with Dara, and the Lena molecules in the drug bundles remain conjugated. In cultures of H929 cells, TE-1146 caused the lysis of H929 cells at least 100 times more effectively than Dara, Lena, and Dara/Lena combination, based on IC50 comparison. It was shown that H929 cells internalized and degraded TE-1146 and freed Lena. In NOD-SCID mice, the subcutaneously transplanted H929 cells were allowed to grow into solid tumors in 14 days, and TE-1146 and other agents for comparison were administered intraperitoneally. It was found that one single dose of TE-1146 at 20 nmol/kg (conjugated with Lena at 120 nmol/kg) could retard the growth of the transplanted tumor and ultimately eliminate the tumor over 28-42 days, while the combination of one dose Dara at 20-80 nmol/kg and Lena of 46 μmol/kg given daily could not eliminate the tumor. The amount of Lena used in the combination treatment over a 28-day course is 10,700 times that of Lena in TE-1146. Conclusion: Lenalidomide is extremely powerful in killing multiple myeloma cells if brought into the MM cells. It is estimated that a very minute amount, probably less than 0.01%, of intraperitoneally injected lenalidomide gets into the transplanted MM tumor in the mouse model. TE-1146 may be a more effective and less toxic drug than Daratumumab/Lenalidomide combination in treating patients with hard-to-treat MM. Citation Format: Yueh-Hsiang Yu, Ming-Yu Hsieh, Pei-Wen Wu, Hui-Ju Lee, Pei-Hsuan Lin, Carmay Lim, Hsing-Mao Chu, Tse Wen Chang. An ADC composed of daratumumab and lenalidomide is extremely powerful in killing multiple myeloma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB209.

Abstract 6785: Dendritic cell/myeloma fusion vaccine with lenalidomide maintenance following autologous hematopoietic cell transplant induced T cell activation and expansion

Abstract Introduction: Multiple myeloma (MM), a clonal disorder of terminally differentiated plasma cells, is the second most common hematologic malignancy with ~57.9% 5-year survival rate. Current MM therapies are not curative and in most patients MM relapse. Aiming to restore antitumor immunity and counteract MM evolution, we have developed a personalized dendritic(DC)/MM cell fusion vaccine, whereby several tumor antigens are presented in the context of DC mediated co-stimulation. BMT CTN 1401 is a multicenter randomized phase II clinical trial (NCT02728102) evaluating the efficacy of the DC/MM vaccine combined with lenalidomide maintenance (Len) after autoHCT. 203 patients were enrolled from 18 centers. Aim: To evaluate the impact of the DC/MM vaccine on the establishment of anti-MM immune response we profiled the peripheral blood (PB) immune landscape at the single-cell level, with particular focus on the T cell compartment. Method: We performed single-cell immunoprofiling (gene expression + V(D)J sequencing) on 40 patients (3xDC/MM vaccine/Len/GM-CSF: N=20; Len/GM-CSF: N=10; Len: N=10). 160 PB mononuclear cells (PBMC) samples were collected at enrollment, prior to Len, after 1 and 3 vaccines and were processed using the 10x Genomics single cell 5' assay. Here we present the analysis relative to 52 PBMC samples from 13 vaccinated patients included in the initial study cohort. The remaining 108 PBMC samples have already been subjected to single-cell immunoprofiling and the analysis is ongoing. Results: 309,423 cells passed quality-check identifying 47 cell populations, corresponding to 20 major compartments. The T cell compartment (146,373 cells) was divided into 14 different cell populations including activated CD8, CD4, and NKT cells that exhibited a gradual increase during the course of the study. Relatively, TCR sequencing demonstrated a recovery of T cell clonal diversity and a progressive rise in the frequency of expanded clonotypes within the activated CD4 and cytotoxic T cell populations after vaccination. Consistently, we observed a progressively raised number of shared TCR clonotypes within the activated CD8 and CD4 T cell subsets. The identification of common epitope/paratope hotspots among the expanded clonotypes and the different patients revealed a higher proportion of shared TCR clonotype groups across patients after vaccination compared to the early post-transplant period, predominantly after 3 vaccinations. Conclusions: Assessment of PBMC samples from 13 vaccinated patients provided a detailed picture of the PBMC landscape. The constant T cell expansion in patients following vaccination coupled with the shared paratope/epitope hotspots and TCR signatures among patients indicated the TCR cross-reactivity and suggested for the establishment of an anti-MM immune response. Citation Format: Giulia Cheloni, Dimitra Karagkouni, Daniela Torres, David J. Chung, Nina Shah, Natalie S. Callander, Thinle Chodon, Yvonne Efebera, Nancy Geller, Peiman Hematti, Hillard Lazarus, Ehsan Malek, Philip L. McCarthy, Ajay K. Nooka, Jacalyn Rosenblatt, Aaron P. Rapoport, Robert J. Soiffer, Dina Stroopinsky, Edmund K. Waller, Marcelo C. Pasquini, Ioannis Vlachos, David Avigan. Dendritic cell/myeloma fusion vaccine with lenalidomide maintenance following autologous hematopoietic cell transplant induced T cell activation and expansion [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 6785.

Medicare characteristics, treatment, cost and survival in triple class exposed relapsed or refractory multiple myeloma.

Background: This study describes real-world treatment patterns of Medicare beneficiaries with relapsed or refractory multiple myeloma (RRMM) who are triple class exposed (TCE). Materials & methods: Retrospective analysis of Medicare fee for service claims to identify a cohort age >65 with RRMM + TCE, 1 January 2016 to 30 June 2019. Outcomes: Initiation of a new treatment regimen (TCE1), healthcare resource utilization, cost and mortality. Results: Of 5395 patients with RRMM + TCE, 1672 (31.0%) initiated a new therapy (TCE1). During TCE1, 97 TCE1 drug combinations were observed and RRMM treatments were the largest cost driver. Median time to TCE1 discontinuation was 3.3months. Few patients received subsequent treatment and 41.3% of study patients died. Conclusion: There is no clear standard-of-care for Medicare patients with RRMM + TCE and prognosis remains poor.

HBV reactivation in patients with chronic or resolved HBV infection following BCMA-targeted CAR-T cell therapy.

B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). Concern of the safety and efficacy of CAR-T cell therapy in patients with chronic or resolved HBV infection is raised. In this study, we retrospectively reviewed 99 patients with r/r MM treated with BCMA-targeted CAR-T cell therapy, of which 7 (7.1%) patients had chronic HBV infection, 43 (43.4%) with resolved HBV infection, and the remaining 49 (49.49%) HBV-uninfected. Patients' characteristics before CAR-T cell administration were comparable in different status of HBV infection. Patients' liver function, cytokine levels, CAR-T cell expansion and cytokine release syndrome (CRS) grade after CAR-T cell therapy did not differ in different HBV serologic status. Furthermore, chronic HBV infection or resolved HBV infection did not affect clinical response, progress-free survival (PFS), or overall survival (OS). Four (4.04%) patients experienced HBV reactivation, 3 (6.98%) with resolved HBV infection, and 1 (14.29%) chronic HBV infection. Of 4 patients with HBV reactivation, 2 cases (50%) of severe hepatitis were noted and reported. Drops of serum IgG and elevation of alanine aminotransferase (ALT), alanine aminotransferase (AST), total bilirubin (TB) were observed in all four patients around the date of HBV reactivation.

LAMP5 may promote MM progression by activating p38.

Multiple myeloma (MM) is the second most common tumor of the hematologic system. MM remains incurable at this time. In this study, we used bioinformatics analysis to find key genes in the pathogenesis of MM. We first found that Lysosome associated membrane protein 5 (LAMP5) expression was sequentially increased in healthy donors (HD), monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and newly diagnosed MM (NDMM), relapsed MM (RMM). We collected bone marrow from patients with NDMM, HD and post-treatment MM (PTMM) and performed qPCR analysis of LAMP5, and found that the expression of LAMP5 is stronger in NDMM than in HD, and decreases after treatment. Western blotting assay also found more expression of LAMP5 in NDMM than in HD. Patients with high LAMP5 expression have a higher DS (Durie-Salmon) stage and worse prognosis. We next verified the expression of LAMP5 in four MM cell lines and silenced LAMP5 expression in RPMI-8226 and AMO-1, and explored the effects of LAMP5 silencing on MM cell apoptosis and cell cycle by flow cytometry and western blotting. Knockdown of LAMP5 promoted apoptosis in MM cells, but had no effect on the cell cycle. Mechanistically, LAMP5 may exert its pro-tumor effects in MM in part through activation of p38 protein. We screened LAMP5 for the first time as a key gene for MM progression and recurrence, and found that LAMP5 may exert its pro-tumor effects in MM through activation of p38 protein.

Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance

Acquired chemoresistance to proteasome inhibitors is a major obstacle in managing multiple myeloma but key regulators and underlying mechanisms still remain to be explored. We find that high level of HP1γ is associated with low acetylation modification in the bortezomib-resistant myeloma cells using SILAC-based acetyl-proteomics assay, and higher HP1γ level is positively correlated with poorer outcomes in the clinic. Mechanistically, elevated HDAC1 in the bortezomib-resistant myeloma cells deacetylates HP1γ at lysine 5 and consequently alleviates the ubiquitin-mediated protein degradation, as well as the aberrant DNA repair capacity. HP1γ interacts with the MDC1 to induce DNA repair, and simultaneously the deacetylation modification and the interaction with MDC1 enhance the nuclear condensation of HP1γ protein and the chromatin accessibility of its target genes governing sensitivity to proteasome inhibitors, such as CD40, FOS and JUN. Thus, targeting HP1γ stability by using HDAC1 inhibitor re-sensitizes bortezomib-resistant myeloma cells to proteasome inhibitors treatment in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in inducing drug resistance to proteasome inhibitors of myeloma cells and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in refractory or relapsed multiple myeloma patients.

Potential Multiple Myeloma Therapeutic Strategies through Targeting Macrophages and Mesenchymal Stromal Cells

Multiple Myeloma (MM), a bone marrow plasma cell hematopoietic cancer, remains a critical but incurable hematological malignancy, prone to deadly relapses even after existing treatment. In this review, I describe the origins of pro-tumor myeloma-associated macrophages. I specifically outline how classically activated anti-tumor macrophages that home to the cancerous bone marrow tumor microenvironment is polarized into pro-tumor macrophages. We then explain how these myeloma-associated macrophages play an important role in supporting multiple myeloma by enabling drug resistance, improved growth, angiogenesis, and protection. We also describe several treatments in development aimed to sever the supportive link between myeloma-associated macrophages and MM by blocking signaling pathways, destroying, or repolarizing macrophages and even preventing macrophage polarization in the first place. We conclude that careful study is needed to improve the reliability of targeting myeloma-associated macrophages to reduce MM relapse and comprehensively treat this cancer.

Evaluation of the Simplified Score to Predict Early Relapse in Multiple Myeloma (S-ERMM) in the MMRF CoMMpass study

BackgroundZaccaria and colleagues recently proposed a new risk score to identify patients at high risk for relapse within 18 months of diagnosis (ER18), the Score for Early Relapse in Multiple Myeloma (S-ERMM). We performed external validation of the S-ERMM using data from the CoMMpass study. Patients and methodsClinical data was obtained from the CoMMpass study. Patients were assigned S-ERMM risk scores and risk categories by the three iterations of the International Staging System (ISS): ISS, R-ISS and R2-ISS. Patients with missing data or early mortality in remission were excluded. Our primary endpoint was the relative predictive ability of the S-ERMM versus other risk scores for ER18 as assessed by area-under-the-curve (AUC). Results476 patients had adequate data to assign all four risk scores. 65%, 25% and 10% were low, intermediate and high risk by S-ERMM. 17% experienced ER18. All four risk scores stratified patients by risk for ER18. S-ERMM (AUC: 0.59 [95% CI 0.53–0.65]) was similar to R-ISS (0.63 [95% CI 0.58–0.69]) and statistically inferior to ISS (0.68 [95% CI 0.62–0.75]) and R2-ISS (0.66 [95% CI 0.61–0.72]) for prediction of ER18. Sensitivity analyses were performed and did not significantly impact results. ConclusionThe S-ERMM risk score is not superior to existing risk stratification systems for predicting early relapse in NDMM and further studies are needed to identify the optimal approach.