Malignant Plasma Cell Disorder Research Articles

Differences in the proteome within extracellular vesicles between premalignant and malignant plasma cell disorders.

Precursor plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) always precede the development of active malignancies such as multiple myeloma (MM). There is a need for novel biomarkers to identify those patients with such precursor plasma cell disorders who rapidly progress to MM. Plasma-derived extracellular vesicles (EVs) may serve as a reservoir of potential biomarkers that can shed light on the pathogenesis and disease biology of MM. This study isolated small EVs (SEVs) and large EVs (LEVs) from the platelet-poor peripheral blood plasma of MGUS (n = 9) and MM (n = 12) patients using the size exclusion chromatography-based method and evaluated their proteome using a label-free proteomics workflow. In total, 2055 proteins were identified in SEVs, while 2794 proteins were identified in LEVs. The transferrin receptor (or CD71) protein was upregulated in both populations of EVs derived from MM patients compared to MGUS patients and was of prognostic significance. Similarly, three isoforms of serum amyloid A (SAA) protein, SAA1, SAA2, and SAA4, were also highly upregulated in SEVs within MM patients relative to MGUS patients. Finally, CD40 expression was also higher in the LEVs derived from MM patients than in MGUS patients. This study demonstrates the feasibility of successfully isolating both SEVs and LEVs from the peripheral blood of patients with plasma cell disorders and quantifying protein biomarkers within these EVs that could be of prognostic and diagnostic interest.

A comparative analysis of transcriptomics of newly diagnosed multiple myeloma: exploring drug repurposing.

Multiple myeloma (MM) is an incurable malignant plasma cell disorder characterized by the infiltration of clonal plasma cells in the bone marrow compartment. Gene Expression Profiling (GEP) has emerged as a powerful investigation tool in modern myeloma research enabling the dissection of the molecular background of MM and allowing the identification of gene products that could potentially serve as targets for therapeutic intervention. In this study we investigated shared transcriptomic abnormalities across newly diagnosed multiple myeloma (NDMM) patient cohorts. In total, publicly available transcriptomic data of 7 studies from CD138+ cells from 281 NDMM patients and 44 healthy individuals were integrated and analyzed. Overall, we identified 28 genes that were consistently differentially expressed (DE) between NDMM patients and healthy donors (HD) across various studies. Of those, 9 genes were over/under-expressed in more than 75% of NDMM patients. In addition, we identified 4 genes (MT1F, PURPL, LINC01239 and LINC01480) that were not previously considered to participate in MM pathogenesis. Meanwhile, by mining three drug databases (ChEMBL, IUPHAR/BPS and DrugBank) we identified 31 FDA-approved and 144 experimental drugs that target 8 of these 28 over/under-expressed MM genes. Taken together, our study offers new insights in MM pathogenesis and importantly, it reveals potential new treatment options that need to be further investigated in future studies.

ST2825, independent of MyD88, induces reactive oxygen species-dependent apoptosis in multiple myeloma cells

Myeloid differentiation factor 88 (MyD88), which is a key regulator of nuclear factor kappa B (NF-κB), plays an important role in tumorigenesis in lymphoid malignancies such as Waldenstrom's macroglobulinemia (WM). However, its biological function in multiple myeloma (MM), which is a malignant plasma cell disorder like WM, remains unexplored. In this article, we first demonstrated that higher expression MyD88 was significantly correlated with poor survival in patients with MM using multiple publicly available datasets. Interestingly, bioinformatic analysis also revealed that MyD88 gene alteration, which is recognized in nearly 80% of patients with WM, was extremely rare in MM. In addition, ST2825 (a specific inhibitor of MyD88) suppressed cell growth followed by apoptosis. Furthermore, ST2825 induced intracellular reactive oxygen species (ROS) in MM cells, and N-acetyl-l-cysteine, which is known as a ROS scavenger, significantly decreased the number of apoptotic MM cells evoked by ST2825 treatment. Taken together, our results indicated that ST2825 leads to ROS-dependent apoptosis in MM cells and could be an attractive therapeutic candidate for patients with MM. By highlighting the pathological mechanism of MyD88 in MM, this study also provides novel treatment strategies to conquer MM.

Ophthalmoplegia Associated With Extramedullary Multiple Myeloma: Case Series From a Tertiary Cancer Center.

Multiple myeloma (MM) is a malignant disorder of plasma cells that results in tumor cells replacing the bone marrow. In extramedullary MM (EMM), however, tumor cells proliferate outside the bone marrow. EMM may produce ophthalmoplegia through direct invasion of the superior orbital fissure, cavernous sinus, and/or sphenoidal sinus. Several mechanisms have been proposed including cranial nerve palsies, direct infiltration of bone, extraocular muscle metastasis, myelomatous meningitis, and parenchymal or paraneoplastic effects. We retrospectively reviewed the medical records of 7 patients at MD Anderson Cancer Center who suffered from ophthalmoplegia secondary to extramedullary MM between 2019 and 2021. We collected information regarding the symptoms, signs, radiographic and laboratory findings, management, complications, and prognosis of these patients throughout their disease course. Skull base MRI revealed 4 patients with ophthalmoplegias secondary to superior orbital fissure invasion, 2 patients with ophthalmoplegias secondary to cavernous sinus invasion, and 1 patient with ophthalmoplegia secondary to sphenoid sinus invasion. This is a case series describing 7 patients with ophthalmoplegias secondary to EMM. Our article is unique because of the size of the included cohort, which is large when compared with most English language publications detailing such ophthalmoplegias.

Prognostic value of circulating plasma cells detected by flow cytometry in newly diagnosed multiple myeloma patients: a systematic review and meta-analysis

ObjectivesMultiple myeloma (MM) is a malignant plasma cell disorder. The most widely accepted staging system for MM is the revised International Staging System based on cytogenetic and clinical biomarkers. The...

Spatial Transcriptomics Unveils Novel Potential Mechanisms of Disease in a MI cγ1 Multiple Myeloma in vivo Model

Multiple Myeloma (MM) is a malignant plasma cell (PC) disorder characterized by a heterogeneous distribution of PCs in the bone marrow (BM) where the interactions between the PCs and the BM microenvironment guide the pathogenesis of the disease. The development of single cell technologies has contributed to understand the transcriptional heterogeneity of the disease both from the tumor and the microenvironment point of view, yet the spatial organization of cellular states and niche-specific regulatory programs remain to be investigated. To address the role of spatially resolved interactions in MM, we performed spatial transcriptomic analysis in BM from the MI cγ1mice strain (Larrayoz et al Nat Med. 2023) a recently described mouse model that recapitulates the characteristics of a MYC driven human MM disease using the Visium Spatial Gene Expression analysis (10x Genomics). Using formalin-fixed paraffin-embedded (FFPE) BM tissues from the femur of control mice, we first characterized the healthy BM. Considering that each spot contains an averaged transcriptomic profile of 3-10 cells, we generated a single-cell reference set that included the most prevalent cell types in the BM to identify the cell type contribution per spot. The relative proportions of the estimations are consistent with percentage estimations observed by previous works (Hongzhe et al, eLife. 2023). Next, using the “cell proportion estimations per spot” we identified four different clusters of spots. A deeper characterization of those clusters revealed a positive correlation between erythroblasts and B cells, and a negative correlation between both cell types and neutrophils. Additionally, we spatially defined clusters 1 and 2, those with larger proportion of erythroblasts, in the metaphysis trabecular regions of the bone marrow. We followed the same analysis framework to characterize the spatial configuration in the MI cγ1 mice BM with a developed MM. To this end, we incorporated the MM-derived single-cell PCs in the single-cell reference set. Importantly, the pathological PCs were identified and organized in large groups in the BM space. Cell proportion estimations in these samples revealed a distribution in 7 clusters, 4 of them concentrated in the periphery of the PC hot spots and 3 mirroring the PC gradient observed in previous analysis (Figure 1A). We next performed a targeted differential analysis to confirm previous observed markers identities of different MM processes as Cd44 (de Jong et al, Nat Immunol. 2021), a signature of dormant cells (Khoo et al, Blood. 2019), the 38 MM-associated surface-protein-encoding genes (Yao et al, Cancer Res. 2023), Mmp9 and different profiles of T cell exhaustion markers within the 3 clusters with higher PC concentration. These analyses allowed us to verify two different markers, Cd44 and Mmp9 localized in the periphery of the hot spots of PC which may explain an invasive mechanism of the cells localized in the outer areas of the MM combining an inflammatory environment, manifested by a Cd44 increment, with a degradative mechanism driven by Mmp9. Simultaneously, an untargeted differential analysis aimed to identify markers characterizing the clusters with high PC prevalence, revealed novel marker genes never described before in MM and not associated with PC proportion, as the Transmembrane Immune Signaling Adaptor ( Tyrobp) in the cluster 5 (peripheral cluster), which is predictive of a poor prognosis and high tumor immune infiltration in other described tumors (Lu et al BMC Cancer 2021) (Fig 1B). Finally, as a proof of principle of this technology potential in human samples, spatial transcriptomic was applied to FFPE samples from BM biopsies of 7 MM patients with different degrees of PC infiltration, providing a source for validation of the results obtained in the mouse model. In conclusion, our findings demonstrate that the application of spatial transcriptomics represents a useful tool for understanding the spatial architecture and niche specific interactions in human diseases, offering a systemic approach to dissect the role of the spatial interactions in the pathogenesis of MM.

Pomalidomide, Dexamethasone, and Daratumumab Versus Other Triplet Regimens in Patients with Relapsed or Refractory Multiple Myeloma: A Population-Adjusted Indirect Treatment Comparison

Introduction: Multiple myeloma (MM) is an incurable malignant plasma cell disorder in which most patients eventually relapse or become refractory to treatment. Lenalidomide (LEN) is typically administered as part of first-line regimens; however, patients who receive LEN usually relapse, necessitating improved options in later lines of therapy. The phase 2, non-randomized MM-014 trial (NCT01946477) demonstrated promising efficacy of pomalidomide (POM) plus dexamethasone and daratumumab (DPd) among patients with relapsed or refractory MM (RRMM), with an overall response rate of 77.7% and a median overall survival (OS) of 56.7 months at a median follow-up of 41.9 months. With the evolving treatment landscape of RRMM, however, there is limited head-to-head data comparing DPd to other standard of care therapies to inform clinical decision-making. Objective: To investigate the comparative efficacy of DPd versus non-POM-containing triplets in adult patients with RRMM using population-adjusted indirect comparison (PAIC) approaches. Methods: A PAIC was conducted using individual patient-level data of 112 adult patients with RRMM who were exposed to LEN (75.9% refractory to LEN) from cohort B of the MM-014 trial. Investigator-assessed OS was the primary endpoint of this analysis. A systematic literature review was performed to identify comparable interventional studies assessing the efficacy of non-POM-containing triplets for RRMM as well as potential prognostic variables (PVs). PVs verified by clinicians were selected for inclusion if significantly associated with OS (p < 0.1) in the MM-014 trial based on univariate Cox regression model. The suitability of these potential trials for PAIC was assessed by considering the comparability of study design, inclusion/exclusion criteria, patients' baseline characteristics, and outcomes. A retrospective analysis utilizing Flatiron electronic health record data from Jan 2011 to July 2022 was previously performed to evaluate the effect of LEN-refractory status on OS using multivariable Cox regression. Given the lack of a common comparator, unanchored PAIC was performed for OS using matching-adjusted indirect comparison (MAIC) and confirmatory simulated trial comparison (STC). A sensitivity analysis was conducted to explore the impact of LEN-refractory status as a PV. Results: Six trials were systematically identified as eligible comparators in initial screening including TOURMALINE-MM1, CANDOR, CASTOR, POLLUX, ASPIRE, and LEPUS. The analyses using Flatiron data showed that patients who were refractory to LEN had significantly shorter OS than those exposed to LEN but not refractory (Hazard ratio: 1.51; 95% CI: 1.17, 1.94), indicating the unsuitability to compare treatments based on studies with large variations in proportion of LEN-refractory patients. Four trials were excluded due to differences violating the transitivity assumption (0% LEN-refractory patients in TOURMALINE-MM1 and POLLUX; LEN-refractory status not reported in ASPIRE; only Chinese patients in LEPUS). The remaining two trials are phase 3 randomized controlled trials investigating carfilzomib plus dexamethasone and daratumumab (DKd) (CANDOR; NCT03158688; Usmani et al. Blood Adv. 2023; Epub ahead of print) and daratumumab plus bortezomib and dexamethasone (DVd) (CASTOR; NCT02136134; Sonneveld et al. J Clin Oncol. 2023; 41:1600-1609). In the base case MAIC adjusting for creatinine clearance, time from diagnosis, International Staging System score, and refractory to LEN, DPd was associated with numerical reduction in the risk of death compared to DKd and DVd (Table). In addition, the base case STC showed significant improvement of OS for DPd over DKd and DVd, confirming the findings from MAIC (Table). In the sensitivity analyses excluding LEN-refractory status, the effect estimates were substantially different from those in the base case analyses (>40% difference), demonstrating the importance of adjusting for LEN refractory status. Conclusions: In patients with RRMM, consistent OS benefit was found for DPd versus DKd and DVd regardless of the PAIC technique used. These findings support the use of DPd over DKd and DVd in treating patients with RRMM, especially given the oral route of administration of pomalidomide. This study also highlighted the importance of considering LEN refractory status when comparing efficacy of treatments for RRMM across trials.

Development of First in Class DNA-Zip Code Drug Conjugate (ZDC) in Multiple Myeloma

Multiple myeloma is a heterogeneous malignant plasma cell disorder with complex molecular and genetic abnormalities. Significant advances have been made in the treatment of multiple myeloma; however, a large proportion of patients fail to attain a favorable response and relapse. Due to efficacy and toxicity, the development of drug conjugates for multiple myeloma has been limited. Our lab discovered that circulating tumor DNA (ctDNA) serves as a cell-specific mechanism for genetic transmission. Certain retrotransposon sequences within the ctDNA were identified as being crucial for the tropism of ctDNA to target tumor cells (Cinar et al bioRxiv.2022). We therefore query whether these transposons can be exploited for the targeted drug delivery. To do so, chemically synthetize and CY5-labeled multiple retrotransposons DNA sequences (a.k.a Zip Codes, ZC) to perform high through put screening assessing for cell targeting. Our findings showed that the AluSp and MER11c DNA sequences (MM-ZC1 and 2) with unique MM mutations were the most efficient and specific DNA sequences for targeting myeloma cells. Furthermore, Flow cytometry and CYTOF validated the specific MM cell targeting on full bone marrow samples from MM patients. Based on this analysis we used MMZC1 for further drug development. We design a drug conjugation approach for the MMZC and screen various drugs for their killing potential. Two potent MM ZC drug conjugates (ZDC) were identified by high throughput viability screening assay: ZC-DM4, a microtubule inhibitor, and ZC-Carfilzomib, an irreversible proteasome inhibitor. We move forward exploration with ZC-DM4 due to limited carfilzomib-linker drug availability. Experiments cancer cell lines in vitro demonstrated that MMZC-DM4 had a potent killing effect on MM cells (IC50: 3.25 nM) but not on other cancer cell lines. These results were the validated in vivo. Maximum tolerated dosing studies (MTD) demonstrated excellent tolerability in all doses (ranges from 1 to 20 mg of MMZC-DM4/Kg (equivalent to 0.007-0.149 mg of DM4/kg). To look for an efficacy signal of MMZC-DM4, MM xenograft mice were given MMZC-DM4 twice a week for three weeks. Due to limitations in production, we treated the animals biweekly with three distinct low doses of MMZC-DM4: 1.9, 3.75, and 7.5 mg/kg (equivalent to 0.014, 0.028, and 0.056 mg of DM4/kg) and compared their response to mice not treated with MMZC-DM4 and mice treated weekly with bortezomib. MMZC-DM4 at such small doses reduced the tumor by 30% without affecting body weight, WBC, HB, AST, or platelets. In contrast, Bortezomib was associated with 90% growth inhibition at the expense of significant weight loss that required treatment interruptions and thrombocytopenia. Currently, investigations are being conducted to examine the therapeutic efficacy of greater doses of MMZC-DM4. This study described the first-in-class MM targeted medicine delivery employing an MM zic code drug conjugate. Our findings suggest new method for targeted delivery therapeutic cargo material directly to cancer cells that could revolutionize cancer treatment.

Active STAT3 Prevents Selinexor-Induced Caspase-Independent Apoptosis in Multiple Myeloma

Multiple myeloma (MM) is an acquired malignant plasma cell disorder that typically develops late in life with a median age at diagnosis of 69 years and results in approximately 12,000 deaths per year. Currently, the standard treatment strategy for MM is a combination of 3 drugs with different mechanisms: dexamethasone, a proteasome inhibitor, and an immunomodulatory agent. Many MM patients acquire a “double-hit” of their TP53 on Chromosome 17p region after multple rounds of treatment and become resistant to these conventional therapeutics. Thus, novel effective treatments for high-risk and relapsed and refractory (RR)-MM are urgently needed to overcome drug-resistance, especially in TP53 null patients. In many cancers, nuclear exporter protein XPO1 overexpression is induced by c-Myc and/or loss of p53. Previous studies have demonstrated that many RR-MM patients show increased expression/activity of XPO1, which is associated with aberrant cytosolic localization of its protein and RNA cargoes. Selective XPO1 inhibitor Selinexor (Sel) has been approved by FDA to treat relapsed and refractory multiple myeloma (RR-MM) in combination with a bortezomib + DEX regimen. Addition of Sel to this regiment significantly improves the overall response rate (~75% vs. ~60%) and progress free survival (13.9 months vs 9.5 months), regardless of risk factors including TP53 status. However, only ~50% of RR-MM patients benefit from Sel treatment. In addition, Sel has significant dose dependent side effects. It is important to determine the mechanism of Sel-resistance in order to identify biomarker(s) to predict Sel-resistance and develop novel effective combination therapies. . In this study, we compared the response of 10 human MM cell lines to Sel treatment and identified Sel sensitive and resistant cell lines. Based on EC50, we divided the cell lines into Sel-sensitive group with EC 50 values between 80.4 nM to 211.8 nM, and Sel-resistant groups with EC 50 values >741.4 nM. We found that Sel sensitivity was notably independent of TP53 mutation status, as well as other genetic mutations and chromosomal translocations. In resistant cells, high dose of Sel induces an off-target Caspase-mediated apoptosis because it could not be influenced by XPO1-knockdown but could be prevented using a pan-caspase inhibitor Z-VAD. In sensitive cell lines, low dose of Sel induces a Caspase-independent type of cell death because it could not prevented by pre-treated with Z-VAD. To investigate which programmed cell death pathways Sel works through, sensitive cells were treated using with Sel + inhibitors for necroptosis, ferroptosis, pyroptosis, and parthanatos. We found only parthanatos inhibitor could significantly prevent Sel-induced cell death. The parthanatos death pathway functions via DNA-damage/poly (ADP-ribose) polymerase-1 (PARP-1) activation. While proper PARP-1 levels are required for DNA damage repair, over-activation results in the release of apoptosis-inducing factor (AIF) from mitochondria to cytoplasm which then trans-localize to the nucleus where it functions with macrophage migration inhibitory factor (MIF) to induce DNA fragmentation and cell death. We show via Western blotting and immunofluorescence imaging that upon Sel treatment, AIF shifts from the cytosol into the nucleus. Sel treatment was further assessed in combination with with Dex, where it showed a low synergistic effect with Dex in the sensitive cells but not in resistant cells, specifically when used sequentially. When assessing mechanisms of Sel resistance, phosphorylated STAT3 was uniquely observed in the resistant cell lines. To determine if STAT3 mediates resistance, resistant cell lines were pre-treated with a STAT3-PROTAC (SD36). Our study suggested that p-STAT3 predicts Sel-resistance, and Sel + STAT3 inhibitor combination is a novel effective regimen for MM, especially for these Sel-resistant cases.

The MYC-Regulated RNA-Binding Proteins hnRNPC and LARP1 Are Drivers of Multiple Myeloma Cell Growth and Disease Progression and Negatively Predict Patient Survival

Multiple myeloma (MM) is a malignant plasma cell disorder in which the MYC oncogene is frequently dysregulated. Due to its central role, MYC has been proposed as a drug target; however, the development of a clinically applicable molecule modulating MYC activity remains an unmet challenge. Consequently, an alternative is the development of therapeutic options targeting proteins located downstream of MYC. Therefore, we aimed to identify undescribed MYC-target proteins in MM cells using Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) and mass spectrometry. We revealed a cluster of proteins associated with the regulation of translation initiation. Herein, the RNA-binding proteins Heterogeneous Nuclear Ribonucleoprotein C (hnRNPC) and La Ribonucleoprotein 1 (LARP1) were predominantly downregulated upon MYC depletion. CRISPR-mediated knockout of either hnRNPC or LARP1 in conjunction with redundant LARP family proteins resulted in a proliferative disadvantage for MM cells. Moreover, high expression levels of these proteins correlate with high MYC expression and with poor survival and disease progression in MM patients. In conclusion, our study provides valuable insights into MYC’s role in translation initiation by identifying hnRNPC and LARP1 as proliferation drivers of MM cells and as both predictive factors for survival and disease progression in MM patients.

Association of monoclonal gammopathy of undetermined significance and C3 glomerulopathy.

Monoclonal gammopathy of undetermined significance (MGUS) is usually an asymptomatic pre-malignant condition caused by the proliferation of clonal plasma cells. Often considered a benign condition, it has the potential to progress to malignant plasma cell or lymphoproliferative disorders. Moreover, MGUS can rarely cause glomerular disease by activating the alternative complement pathway resulting in immunoglobulin-negative C3-positive glomerulonephritis called C3 glomerulopathy. Because of its rarity, the diagnosis might not be considered by the treating physicians, leading to delayed diagnosis or misdiagnosis. Untreated C3 glomerulopathy can lead to irreversible glomerular damage and end-stage renal failure, and a high index of suspicion is essential for timely diagnosis and management. Here, we present the case of a patient with a prior diagnosis of MGUS who presented with proteinuria and microscopic haematuria and was diagnosed with C3 glomerulopathy. The patient had complete resolution of the disease after receiving treatment with a combination of dexamethasone, lenalidomide and bortezomib for the underlying MGUS.

Analytical correlation of Laboratory tests with clinical findings in cases of Paraproteinemia

Multiple myeloma is a malignant plasma cell disorder identified with M spikeon serum protein electrophoresis (SPE) during routine laboratory work up. This study aimed to analyze the utility of laboratory tests suchas SPE, immunofixation electrophoresis (IFE), CBC, RFT, LFT, calcium, phosphorus, beta 2 microglobulins, LDH, serum-free light chain assay (SFLC), Bence Jones Proteinuria (BJP), BM biopsy, BM smear and radiological evidence for lytic lesionsin cases of paraproteinemia. Data for the above parameters from 2017 January to 2021 March were obtained from the data management system of the central lab. Biochemical parameters were correlated with M spike value using Karl Pearson’s correlation coefficient (P-value <0.05 will be significant).7.7% SPE reports had M spike with a mean age of 64 years in males and 63 years in females (male/female ratio, 1: 0.76). M spike showed a significant positive association with total protein, globulin, uric acid and negative association with albumin. IgG kappa type (51%) predominant in IFE reports. The common presentation from hematological data was normocytic normochromic anemia with occasional rouleaux formation. Osteolytic lesion was present in 86% of reported cases. Associated biochemical, hematological, and radiological correlates of the positive cases could be documented in only less than 20% of the positive cases. Ours is a tertiary care hospital and the associated lab is also a reference lab where samples from in and around the city are tested. After the preliminary SPE, it could be possible that the patients were further evaluated and continued treatment at some other facility.

Management of Multiple Myeloma: A Review for General Practitioners in Oncology

Multiple myeloma (MM) is a malignant clonal plasma cell disorder in the bone marrow and is the second-most common hematologic malignancy in adults. Although patients with MM have a moderate life expectancy, it remains a heterogeneous disease that often requires multiple lines of chemotherapy for durable control and long-term survival. This review outlines current management strategies for both transplant-eligible and transplant-ineligible patients as well as for relapsed and refractory disease. Advances in drug therapies have widened management options and improved survival. In this paper, we also discuss implications for special populations and survivorship care.

Chimeric antigen receptor T-cell therapy for multiple myeloma.

Multiple myeloma (MM) is a malignant plasma cell disorder that remains incurable for most patients, as persistent clonal evolution drives new mutations which confer MM high-risk signatures and resistance to standard care. The past two decades have significantly refashioned the therapeutic options for MM, especially adoptive T cell therapy contributing to impressive response rate and clinical efficacy. Despite great promises achieved from chimeric antigen receptor T-cell (CAR-T) therapy, the poor durability and severe toxicity (cytokine release syndrome and neurotoxicity) are still huge challenges. Therefore, relapsed/refractory multiple myeloma (RRMM), characterized by the nature of clinicopathologic and molecular heterogeneity, is frequently associated with poor prognosis. B Cell Maturation Antigen (BCMA) is the most successful target for CAR-T therapy, and other potential targets either for single-target or dual-target CAR-T are actively being studied in numerous clinical trials. Moreover, mechanisms driving resistance or relapse after CAR-T therapy remain uncharacterized, which might refer to T-cell clearance, antigen escape, and immunosuppressive tumor microenvironment. Engineering CAR T-cell to improve both efficacy and safety continues to be a promising area for investigation. In this review, we aim to describe novel tumor-associated neoantigens for MM, summarize the data from current MM CAR-T clinical trials, introduce the mechanism of disease resistance/relapse after CAR-T infusion, highlight innovations capable of enhanced efficacy and reduced toxicity, and provide potential directions to optimize manufacturing processes.

Myelomatous Malignant Pleural Effusion: A Rare Case Report

Abstract Background Multiple myeloma (MM) is a malignant disorder of plasma cells and includes 1% of all malignancies and 10% to 13% of hematologic cancers. Multiple myeloma, characterized by malignant proliferation of plasma cells, leads to the production of monoclonal immunoglobulins. Pleural involvement by plasma cells in multiple myeloma is rare. Case Report We report a 61-year-old woman with myelomatous pleural effusion in MM. Conclusion A few cases of pleural effusion secondary to MM, in literature, with an incidence of less than 1%, were reported.

Efficacy and toxicity of carfilzomib- or bortezomib-based regimens for treatment of transplant-ineligible patients with newly diagnosed multiple myeloma: A meta-analysis.

Background:Multiple myeloma is a clonal disorder of malignant plasma cells that comprises approximately 10% of hematologic malignancies. The aim of this study was to investigate the efficacy and toxicity of carfilzomib- or bortezomib-based regimens for treatment of transplant-ineligible patients with newly diagnosed multiple myeloma by performing a meta-analysis of randomized controlled trials (RCTs).Methods:Data mining was conducted in March 2022 across PubMed, EMBASE and ClinicalTrials.gov. All published RCTs which assessed efficacy and toxicity of carfilzomib-based regimens treatment for transplant-ineligible patients with newly diagnosed multiple myeloma when compared with a bortezomib-based regimens were included.Results:Our meta-analysis showed that the overall response rate (ORR) (Odds ratio = 1.33, 95% CI 1.05–1.69, P = .02) was significantly higher in the carfilzomib-based regimens group than in the bortezomib-based regimens group. However, the difference in ORR did not translate into improvements in progression-free survival (PFS), overall survival (OS) and complete response rate (CRR). Adverse events of grade 3 or worse that occurred with a higher incidence in the carfilzomib-based regimens group compared with the bortezomib-based regimens group were dyspnea, hypertension, acute kidney injury, and heart failure.Conclusions:The carfilzomib-based regimens did not improve PFS, OS and CRR compared with the bortezomib-based regimens in transplant-ineligible patients with newly diagnosed multiple myeloma, and they showed higher toxicity.

Identification of CD8+ T-cell epitope from multiple myeloma-specific antigen AKAP4.

Multiple myeloma (MM) is a malignant plasma cell disorder affecting mainly the elderly population. Revolutionary progress in immunotherapy has been made recently, including monoclonal antibodies and chimeric antigen receptor T cell (CAR-T) therapies; however, the high relapse rate remains problematic. Therefore, combination therapies against different targets would be a reasonable strategy. In this study, we present a new X-chromosome encoded testis-cancer antigen (CTA) AKAP4 as a potential target for MM. AKAP4 is expressed in MM cell lines and MM primary malignant plasma cells. HLA-A*0201-restricted cytotoxic T lymphocytes (CTLs) induced by dendritic cells (DCs) transduced with an adenovirus vector encoding the full-length AKAP4 gene were demonstrated to lyse AKAP4+ myeloma cells. Seven of the 12 candidate epitopes predicated by the BIMAS and SYFPEITH algorithms were able to bind HLA-A*0201 in the T2 binding assay, of which only two peptides were able to induce CTL cytotoxicity in the co-culture of peptide-loaded human mature dendritic cells and the autologous peripheral blood mononuclear cells (PBMCs) from the same HLA-A*0201 donor. The AKAP4 630–638 VLMLIQKLL was identified as the strongest CTL epitope by the human IFN-γ ELISPOT assay. Finally, the VLMLIQKLL-specific CTLs can lyse the HLA-A*0201+AKAP4+ myeloma cell line U266 in vitro, and inhibit tumor growth in the mice bearing U266 tumors in vivo. These results suggest that the VLMLIQKLL epitope could be used to develop cancer vaccine or T-cell receptor transgenic T cells (TCR-T) to kill myeloma cells.

Spectrum of Bone Complications in Newly diagnosed Multiple Myeloma patients

Abstract Multiple myeloma is a malignant disorder of plasma cells that seed throughout the bone marrow and usually produce a monoclonal immunoglobulin in the blood, urine, or both, cause lytic bone lesions. A total of 159 newly diagnosed multiple myeloma patients aged 24 to 85 were included in this study. The median age of 159 patients was 56 years. Highest incidence of multiple myeloma was found in 50-59 years age group and P value was statistically significant. Male patient was 103 (65%) and female patient was 56 (35%). The median age of male patients was 56 years and the female patients was 57 years. There was no statistically significant age difference between male and female patients. 76.1% patients had bone involvement. Lytic bone lesions were found in 45.9% cases. Among them 15.1% patient had single lytic lesion and 30.8% patient had multiple lytic lesions. Most common site of lytic lesion was skull (33.3%).Pelvis was the second most common site of lytic lesion (15.7%).The prevalence of fracture was 44.7%, among them vertebral fracture was in 37.1% cases, rib fracture was in 9.4% cases, humerus fracture was in 3.1%, femur fracture was in 3.8%, fracture of neck of femur in 0.6%. Nerve root compression found in 12.6% cases. Lytic lesion and fracture are most common features of bone involvement in multiple myeloma patients. MRI study instead of radiographic study may increase the detection of bone lesion especially in the thoraco-lumber spine, pelvis and proximal femurs. Further studies incorporating MRI study are necessary to determine skeletal changes of MM patients.

Thymic plasmacytoma presenting as polyneuropathy and revealing multiple myeloma: a case report

BackgroundMultiple myeloma (MM) is the most frequent malignant plasma cell disorder with proliferation of neoplastic plasma cells in the bone marrow or other tissue, most commonly in the upper aerodigestive tract. The invasion of the thymus is exceptional. Neurological complications are usual, but represent exceptionally the revealing symptom.Case presentationWe report a case of polyneuropathy revealing a thymic plasmacytoma as a mediastinal invasion of MM in a 48-year-old woman. She was admitted after developing progressive ascending distal paresthesias and weakness in lower limbs. Examination showed symmetrical distal sensorimotor impairment with axillary and inguinal adenopathies. Electroneuromyography revealed a sensorimotor length-dependent neuropathy. Serum protein electrophoresis showed monoclonal protein peak in β-γ globulin region. Immunoelectrophoresis showed IgA lambda monoclonal gammapathy. Myelogram and bone marrow biopsy revealed plasmocytosis of 5%. Chest computed tomography showed a histologically confirmed thymic plasmacytoma associated with a lytic lesion of the 5th rib leading to the diagnosis of MM.ConclusionsThe association between a thymic plasmacytoma and peripheral neuropathy is rare and a workup for MM is necessary to guide therapeutic management.

T-cell redirected bispecific antibodies in relapsed and refractory multiple myeloma: A systematic review and meta-analysis.

e20014 Background: Multiple myeloma (MM) is a malignant plasma cell disorder which remains incurable, and in relapsed and refractory treatment, chimeric antigen receptor therapy shows promise. Bispecific antibodies (bsAbs) utilize the exact mechanism by engaging BCMA and other potential tumor-associated antigens on myeloma cells and T-cells. We have conducted a systematic review and meta-analysis to evaluate the efficacy and safety of bsAbs in heavily pretreated MM cohorts. Methods: We searched PubMed, Clinicaltrials.gov, Cochrane, Google Scholar, Embase, and major conferences (oral and poster presentation), with MeSH terms and keywords for “multiple myeloma” or “relapsed refractory multiple myeloma,” AND “bispecific antibody” or “BiTE”. We included all original studies reported in the English language published from inception until January 2022. After primary and secondary screening, eleven clinical trials were included. Pooled analysis was done with the help of random effects model (Freeman-Tukey Double Arcsine Transformation) in OpenMetaAnalyst software. Results: We identified nine phase I and two phase II trials (n=837), with a mean age of 64.5 years. Most cohorts being triple-, quad- or penta-refractory MM. Complete response (CR) or stringent CR (sCR) reported is 12% (95% CI 9-15.3%, I² 16.54%, n=66), very good partial response (VGPR) 14.8% (95% CI 8.3-22.7%, I² 80.57%, n=93) and partial response (PR) 11.8% (95% CI 0.2-3.41%, I² 93.21%, n=26). The overall response rate (ORR) reported is 59.5% (95% CI 44.7-73.5%, I² 90.71%, n=307). Among the most common adverse events anemia is seen in 44.2% (95% CI 38.1-50.4%, I² 17.86%, n=152), neutropenia in 33.8% (95% CI 18.4-51.2%, I² 93.27%, n=179), thrombocytopenia in 32% (95% CI 21.4-43.6%, I² 75.96%, n=113) and cytokine release syndrome in 57.1% (95% CI 45.5-68.4%, I² 85.63%, n=315). Conclusions: Bispecific antibodies have shown promising efficacy in relapsed and refractory MM cohorts with a very well safety profile. Upcoming phase II/III trials are much awaited, along with combination studies of bsAbs with other agents to gauge response.[Table: see text]