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Investigation of the cellular and molecular mechanisms of disease progression from precursor plasma cell disorders to active disease increases our understanding of multiple myeloma (MM) pathogenesis and supports the development of novel therapeutic strategies. In this analysis, single-cell RNA sequencing, surface protein profiling, and B lymphocyte antigen receptor profiling of unsorted, whole bone marrow (BM) mononuclear cell samples was used to study molecular changes in tumor cells and the tumor microenvironment (TME). A cell atlas of the BM microenvironment was generated from 123 subjects including healthy volunteers and patients with monoclonal gammopathy of unknown significance (MGUS), smoldering MM (SMM), and MM. These analyses revealed commonalities in molecular pathways, including MYC signaling, E2F targets and interferon alpha response, that were altered during disease progression. Evidence of early dysregulation of the immune system in MGUS and SMM, which increases and impacts many cell types as the disease progresses, was found. In parallel with disease progression, population shifts in CD8 + T cells, macrophages, and classical dendritic cells were observed, and the resulting differences in CD8 + T cells and macrophages were associated with poor overall survival outcomes. Potential ligand-receptor interactions that may play a role during the transition from precursor stages to MM were identified, along with potential biomarkers of disease progression, some of which may represent novel therapeutic targets. MIF, IL15, CD320, HGF and FAM3C were detected as potential regulators of the TME by plasma cells, while SERPINA1 and BAFF (TNFSF13B) were found to have the highest potential to contribute to the downstream changes observed between precursor stage and MM cells. These findings demonstrate that myeloma tumorigenesis is associated with dysregulation of molecular pathways driven by gradually occurring immunophenotypic changes in the tumor and TME. Trial registration: This project has been registered at EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) with protocol number NOPRODMMY0001 and EudraCT Number 2018-004443-23 on 12 December 2018.

Immune profiling in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM) provides the framework for developing novel immunotherapeutic strategies. Here, we demonstrate decreased CD4+ Th cells, increased Treg and G-type MDSC, and upregulation of immune checkpoints on effector/regulatory and CD138+ cells in MM patients, compared MGUS/SMM patients or healthy individuals. Among the checkpoints profiled, LAG3 was most highly expressed on proliferating CD4+ Th and CD8+ Tc cells in MM patients BMMC and PBMC. Treatment with antibody targeting LAG3 significantly enhanced T cells proliferation and activities against MM. XBP1/CD138/CS1-specific CTL generated in vitro displayed anti-MM activity, which was further enhanced following anti-LAG3 treatment, within the antigen-specific memory T cells. Treg and G-type MDSC weakly express LAG3 and were minimally impacted by anti-LAG3. CD138+ MM cells express GAL-3, a ligand for LAG3, and anti-GAL-3 treatment increased MM-specific responses, as observed for anti-LAG3. Finally, we demonstrate checkpoint inhibitor treatment evokes non-targeted checkpoints as a cause of resistance and propose combination therapeutic strategies to overcome this resistance. These studies identify and validate blockade of LAG3/GAL-3, alone or in combination with immune strategies including XBP1/CD138/CS1 multipeptide vaccination, to enhance anti-tumor responses and improve patient outcome in MM.

B cell activation and differentiation yields plasma cells with high affinity antibodies to a given antigen in a time-frame that allows for host protection. Although the end product is most commonly humoral immunity, the rapid proliferation and somatic mutation of the B cell receptor also results in oncogenic mutations that cause B cell malignancies including plasma cell neoplasms such as multiple myeloma. Myeloma is the second most common hematological malignancy and results in over 100,000 deaths per year worldwide. The genetic alterations that occur in the germinal center, however, are not sufficient to cause myeloma, but rather impart cell proliferation potential on plasma cells, which are normally non-dividing. This pre-malignant state, referred to as monoclonal gammopathy of undetermined significance or MGUS, provides the opportunity for further genetic and epigenetic alterations eventually resulting in a progressive disease that becomes symptomatic. In this review, we will provide a brief history of clonal gammopathies and detail how some of the key discoveries were interwoven with the study of plasma cells. We will also review the genetic and epigenetic alterations discovered over the past 25 years, how these are instrumental to myeloma pathogenesis, and what these events teach us about myeloma and plasma cell biology. These data will be placed in the context of normal B cell development and differentiation and we will discuss how understanding the biology of plasma cells can lead to more effective therapies targeting multiple myeloma.

Monoclonal gammopathies comprise a spectrum of clonal plasma cell disorders that include monoclonal gammopathy of undetermined significance, multiple myeloma, and Waldenström macroglobulinemia. In this review, we outline the epidemiology, etiology, classification, diagnosis, and treatment of monoclonal gammopathy–associated peripheral neuropathy. Monoclonal gammopathy of undetermined significance is relatively common in the general population, with a prevalence of 3% to 4% among individuals older than age 50 years. Therefore, the presence of M protein in a patient with neuropathy does not automatically indicate a causal relationship. Monoclonal gammopathy–associated peripheral neuropathy is often a difficult diagnosis with limited treatment options. Studies addressing the optimal approach to diagnosis and management of this entity are limited. In addition to a review of the literature, we present a diagnostic approach to patients with monoclonal gammopathy–associated peripheral neuropathy and discuss available data and options for treatment.

Tumor immune microenvironmental alterations occur early in multiple myeloma (MM) development. In this study, we aim to systematically characterize the tumor immune microenvironment (TME) and the tumor-immune interactions from precursor stages, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), to newly diagnosed MM, comparing these to healthy donors. Using CIBERSORT, mass cytometry (CyTOF), and single-cell RNA sequencing (scRNA-Seq), we examined innate and adaptive immune changes across these stages. We found a decrease in granulocytes in the TME predicts MM outcomes. HLA-DR is reduced in CD16 + monocytes and plasmacytoid dendritic cells, while myeloid dendritic cells show decreased expression of stress and immune-response genes. NK cells and CD8 + T cells shift from a GZMK + to a GZMB + cytotoxic phenotype in the TME, with increased inhibitory markers TIM3 and TIGIT. In paired samples, the proportion and gene expression pattern in patient-specific GZMB + CD8 + T cells remain largely unchanged despite MM progression. Our findings provide a comprehensive immune landscape of MM and its precursors, offering insights into therapeutic strategies. Enhancing neutrophil and NK cell cytotoxicity, tumor antigen presentation, and CD8 + T cell versatility in precursor stages may prevent MM progression.

We report a complex case of neutrophilic dermatosis (ND) in a 61-year-old woman with a 19-year history of recurrent, pruritic, and painful vesiculopustular eruptions. Her clinical course was marked by evolving diagnoses, from pustular vasculitis to IgA pemphigus and pyoderma gangrenosum (PG). Concurrent investigations revealed an IgA-κ type monoclonal gammopathy of undetermined significance (MGUS). This case highlights the rare association between neutrophilic dermatoses (ND) and haematological disorders, and illustrates the therapeutic challenges posed by comorbidities such as osteoporosis and a history of tuberculosis. Management with dapsone and low-dose corticosteroids led to significant clinical improvement.

To understand neutrophil impairment in the progression from MGUS through active MM, we investigated the function of mature, high-density neutrophils (HDNs), isolated from peripheral blood. In 7 MM, 3 MGUS and 3 healthy subjects by gene expression profile, we identified a total of 551 upregulated and 343 downregulated genes in MM-HDN, involved in chemokine signaling pathway and FC-gamma receptor mediated phagocytosis conveying in the activation of STAT proteins. In a series of 60 newly diagnosed MM and 30 MGUS patients, by flow-cytometry we found that HDN from MM, and to a lesser extend MGUS, had an up-regulation of the inducible FcγRI (also known as CD64) and a down-regulation of the constitutive FcγRIIIa (also known as CD16) together with a reduced phagocytic activity and oxidative burst, associated to increased immune-suppression that could be reverted by arginase inhibitors in co-culture with lymphocytes. In 43 consecutive newly-diagnosed MM patients, who received first-line treatment based on bortezomib, thalidomide and dexamethasone, high CD64 could identify at diagnosis patients with inferior median overall survival (39.5 versus 86.7 months, p = 0.04). Thus, HDNs are significantly different among healthy, MGUS and MM subjects. In both MGUS and MM neutrophils may play a role in supporting both the increased susceptibility to infection and the immunological dysfunction that leads to tumor progression.

This case report describes the successful use of ofatumumab, a fully humanized anti-CD20 monoclonal antibody, in a 62 years old male with monoclonal gammopathy of undetermined significance (MGUS) associated chronic inflammatory demyelinating polyneuropathy. The patient presented with acute limb weakness, glove-like paresthesia, and respiratory involvement, alongside elevated anti-ganglioside antibodies (anti-GM4 IgM and IgG) and λ-type IgM-M proteinemia. Despite initial therapies including intravenous immunoglobulin, efgartigimod, and immunosuppressants, he experienced recurrent relapses. Treatment with ofatumumab combined with methylprednisolone resulted in complete peripheral CD19+ B cell depletion, improved nerve conduction velocities, and sustained clinical remission. The findings highlight the efficacy of ofatumumab in targeting pathogenic CD20+ B cell clones, thereby disrupting autoantibody production implicated in immune mediated peripheral nerve injury. This case underscores the potential of B cell directed therapy for refractory MGUS associated neuropathies, offering a novel approach when conventional immunotherapies fail. Further multicenter studies are warranted to establish standardized protocols and optimize long term outcomes through combination regimens targeting both B cell and plasma cell compartments.

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated chronic fibrotic inflammatory disorder. The coexistence of IgG4-RD with monoclonal gammopathy of undetermined significance (MGUS) is relatively rare, with only a few cases reported in the literature. This article reports a case of a 79-year-old male patient with clinical manifestations of persistent upper abdominal pain of unknown cause and recurrent pleural effusion. Auxiliary examinations indicated positive serum antinuclear antibodies and persistently positive IgG4; three-dimensional imaging reconstruction showed mild pancreatic swelling and the peripancreatic fat planes appeared blurred, which was consistent with the manifestations of pancreatitis. According to the “International Consensus Diagnostic Criteria for Autoimmune Pancreatitis (AIP)”of the diagnostic criteria of the International Pancreatic Disease Association, the patient was diagnosed with IgG4-RD AIP. At the same time, the patient’s serum protein electrophoresis M protein was 2.34 g/L, and immunofixation electrophoresis confirmed it to be IgG-λ-type M protein. Combined with bone marrow smear and biopsy results, it was diagnosed as having MGUS. To our knowledge, this represents a rare case of IgG4-RD AIP concomitant with MGUS, and we provide an in-depth discussion of its clinical management and potential pathogenic association.

T-cell receptor (TCR) repertoire diversity has been implicated in the progression and prognosis of multiple myeloma (MM). This study aimed to evaluate the association between T-cell clonality, immune response, and clinical outcomes in patients with plasma cell dyscrasias using next-generation sequencing of the TCR β chain (TCRB). TCRB sequencing was performed on peripheral blood samples from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma (MM). Healthy individuals served as controls. No significant differences in TCR repertoire diversity were observed between healthy individuals and those with MGUS, SMM or MM after adjusting for age. Furthermore, TCR diversity did not correlate with treatment response in newly diagnosed MM or SMM patients. However, machine learning analysis revealed distinct TCR clusters differentially abundant between healthy individuals and those with plasma cell dyscrasias, exhibiting different amino acid properties. These findings suggest that shared T-cell receptor specificities among patients with plasma cell dyscrasias reflect underlying differences in antigen recognition and underscore the need for further studies to unravel the functional and clinical significance of these distinct immune signatures.