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Multiple myeloma (MM) is a plasma cell dyscrasia characterized by production of abnormal levels of a monoclonal immunoglobulin or plasma cell deposition that leads to end organ destruction. The disease remains incurable despite advances in combination treatments with classes of medications that include proteosome inhibitors, immunomodulating agents, monoclonal antibodies, small molecule inhibitors, alkylating agents, T-cell-based immunotherapies, and others. Checkpoint inhibitors (CKP-I), though showing robust efficacy in solid tumor and lymphoma, have had limited success as single agents in the treatment of MM. Furthermore, early FDA holds on trials involving CKP-I in myeloma led to diminished enrollment and data on its potential use. Nevertheless, clearer understanding of the mechanisms of immune dysregulation and unique bone marrow biology in the pathophysiology of MM have opened the opportunity for future uses of CKP-I in multiple myeloma. Herein we provide a comprehensive review of the immunologic basis of multiple myeloma, preclinical and published data from trials utilizing CKP-I in MM patients, and future targets in CKP-I development that may provide promising opportunities in the treatment of MM.

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Hematoxylin and eosin staining is widely used for routine histopathological analysis under light microscopic examination to determine alterations of tissue architecture and cellular components in animal studies. Aside from hematoxylin/eosin staining, periodic acid Schiff (PAS) staining is used to detect polysaccharides and carbohydrate-rich macromolecules, and is essential in immunological fields for evaluation of glomerular lesions of kidneys in autoimmune animals. Since erythrocytes are not stained by PAS, this stain is also helpful for identifying changes in immune cells in the red pulp of the spleen, which is filled with erythrocytes. This article describes a protocol to detect Mott cells, bizarre plasma cells containing immunoglobulin inclusion bodies (Russell bodies) in the cytoplasm. The protocol can be used for formalin-fixed, paraffin-embedded tissue sections, frozen tissue sections, tissue-touch preparations, blood films, and cytocentrifuged cell smears. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Detection of Mott cells by PAS staining in formalin-fixed, paraffin-embedded tissue sections Basic Protocol 2: Detection of Mott cells by PAS staining in frozen tissue sections, touch preparations, blood films, and cytocentrifuged cell smears.

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Objective: To explore the prognostic factors of primary plasma cell leukemia (pPCL) in the era of novel agents. Methods: The clinical data of 66 patients with pPCL treated at the Department of Haematology, Beijing Chao-Yang Hospital, Capital Medical University from 2011 to 2022 were retrospectively collected to analyze their prognostic factors. Results: Among the 66 patients with pPCL, the median age was 59 (range: 29-79) years. The median overall survival (OS) duration was 19.0 (95% CI 10.4-27.6) months, and the median progression-free survival (PFS) duration was 11.0 (95% CI 6.5-15.6) months. The median OS and PFS were significantly longer in patients with the best post-treatment response of very good partial remission (VGPR) or better than in patients with a response of partial remission (PR) or worse (median OS: 33.0 months vs 6.0 months, P<0.001; median PFS: 16.0 months vs 3.0 months, P<0.001). OS was significantly longer in patients who underwent autologous hematopoietic stem cell transplantation than in those who did not undergo transplantation (49.0 months vs 6.0 months, P=0.002), and there was a trend toward a longer PFS in patients who underwent transplantation than in those who did not undergo transplantation (19.0 months vs 8.0 months, P=0.299). The median OS and PFS were significantly longer in patients who received maintenance therapy than in those who did not receive maintenance therapy (median OS: 56.0 months vs 4.0 months, P<0.001; median PFS: 20.0 months vs 2.0 months, P<0.001). Multivariate analysis showed that hypercalcemia was an independent risk factor (HR=3.204, 95% CI 1.068-9.610, P=0.038) for patients with pPCL, while receiving maintenance therapy (HR=0.075, 95% CI 0.022-0.253, P<0.001) and post-treatment response of VGPR or better (HR=0.175, 95% CI 0.048-0.638, P=0.008) were independent protective factors for patients with pPCL. Conclusions: In the era of novel agents, hypercalcemia, receiving maintenance therapy, and post-treatment response of VGPR or better are independent prognostic factors for pPCL.

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BACKGROUND: Plasma cell leukemia (PCL) is a rare monoclonal gammopathy, associated with short survival. Because of its very low incidence, only a few cohorts have been reported and thus, information on this disease is scarce. The goal of this study was to better understand the clinical features, prognostic factors, and efficacy of modern treatments in both primary PCL (pPCL) and secondary PCL (sPCL). METHODS: We performed a retrospective, multicenter study of patients diagnosed with PCL, defined as circulating plasma cells ≥20% of total leukocytes and/or ≥2 × 109/L. RESULTS: We identified 99 eligible PCL patients, of whom 33 were pPCL and 66 were sPCL. The median progression-free survival (PFS) to frontline treatment and overall survival (OS) were, respectively, 4.8 (95% CI, 0.4-9.2) and 18.3 months (95% CI, 0.0-39.0) for pPCL and 0.8 (95% CI, 0.5-1.1) and 1.2 months (95% CI, 0.9-1.5) for sPCL (both p < 0.001). We observed no improvement in OS over time (2005-2012 vs. 2013-2020, p = 0.629 for pPCL and p = 0.329 for sPCL). Finally, our data suggested that sPCL originates from a high-risk multiple myeloma (MM) population with a short OS (median 30.2 months), early relapse after stem cell transplant (median 11.9 months) and a high proportion of patients with multiple cytogenetic abnormalities (36% with ≥2 abnormalities). CONCLUSIONS: This study is one of the largest PCL cohorts reported. We are also the first to investigate characteristics of MM before its transformation into sPCL and demonstrate that high-risk biologic features already present at the time of MM diagnosis. Moreover, our data highlights the lack of improvement in PCL survival in recent years and the urgent need for better treatment options.

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Primary or light-chain (AL) (lambda) amyloidosis is a rare systemic disorder that is characterized by the misfolding of autologous proteins and the extracellular deposition of abnormally folded proteins composed of immunoglobulin light chains, often caused by plasma cell dyscrasias. We present a unique case of a 57-year-old female with multiple comorbidities, including extensive smoking history and chronic kidney disease, who was incidentally discovered to have a left upper lobe lung nodule on a chest X-ray prompted by complaints of shortness of breath. The patient underwent biopsy of the lung nodule, and by utilizing the gold standard diagnostic technique of a Congo red stain, positive test results confirmed the diagnosis of AL amyloidosis. However, additional investigations, including bone marrow and fat pad biopsies, were negative for plasma cell dyscrasias. The patient subsequently underwent a wedge resection of the nodule, and a follow-up positron emission tomography-computed tomography (PET-CT) scan showed only post-surgical changes in the left upper lobe of the lung without evidence of disease progression or systemic involvement. Given the asymptomatic and multisystem symptomology of most cases, treatment options for AL amyloidosis are individualized. This case discusses pulmonary nodular AL amyloidosis and highlights the diagnostic and treatment options for this disorder.

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Plasma cell-rich acute rejection (PCAR), a relatively rare subtype of acute allograft rejection, is usually associated with a significantly lower treatment response rate and a higher graft failure rate. PCAR is characterized by the presence of more than 10% of plasma cells out of all graft infiltrating cells, with approximately 40%-60% of PCAR resulting in graft failure within a year. Currently, there is no gold standard for the effective treatment of PCAR. This case report demonstrates the potential treatment effect of bortezomib in PCAR. A 37-year-old woman with reflux nephropathy received a kidney transplant from a brain-dead kidney donor. The patient presented with an acute kidney injury with a serum creatinine level over 4 mg/dL 4 months after the surgery. The allograft biopsy showed acute T cell-mediated rejection (TCMR), Grade IIA, plasma cell-rich variant. There were diffuse polyclonal plasma cells infiltrating the renal parenchyma with marked tubulitis and focal endarteritis. She received a methylprednisolone pulse of 500 mg daily x3, followed by thymoglobulin (rATG) at 4.2 mg/kg. However, a repeated biopsy after 2 months showed persistent plasma cells infiltrate with increased interstitial fibrosis with tubular atrophy. Then, the patient was given one cycle of bortezomib with a total of four subcutaneous injections and continued immunosuppressants of tacrolimus, mycophenolate mofetil, and prednisone. Following the treatment, the patient's serum creatinine level trended down to 2 mg/dL, and a second repeat biopsy after 4 months showed a significant treatment effect with complete resolution of interstitial inflammation and decreased chronicity. Bortezomib is a proteasome inhibitor that prevents cell proliferation by inducing apoptosis in plasma cells and has shown great promise as a therapeutic agent for multiple myeloma. Our case suggests that bortezomib can also be used as a potential therapeutic intervention for patients with PCAR.

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ABO discrepancies in plasma cell myeloma (PCM) present unique challenges in blood typing tests and transfusion management. We present the case of a 51-year-old male with PCM who exhibited discrepancies between forward and reverse blood grouping. Further investigation revealed that the patient's blood type was a variant of blood group B. While type III discrepancies, typically characterized by elevated globulin levels causing false-positive reactions in both forward and reverse blood grouping, are common in multiple myeloma, our case differed due to the loss of B antigens secondary to the malignant condition. This caused a discrepancy in forward blood grouping. The rarity of ABO discrepancies in multiple myeloma underscores the importance of thorough evaluation. Awareness of potential antigen alterations in such patients is crucial to ensure safe transfusion practices.

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BACKGROUND: Loss-of-function mutations of ZBTB24 cause immunodeficiency, centromeric instability, and facial anomalies syndrome 2 (ICF2). ICF2 is a rare autosomal recessive disorder with immunological defects in serum antibodies and circulating memory B cells, resulting in recurrent and sometimes fatal respiratory and gastrointestinal infections. The genotype-phenotype correlation in patients with ICF2 indicates an essential role of ZBTB24 in the terminal differentiation of B cells. METHODS: We used the clustered regularly interspaced short palindromic repeats (CRISPER)/Cas9 technology to generate B cell specific Zbtb24-deficient mice and verified the deletion specificity and efficiency by quantitative polymerase chain reaction (Q-PCR) and western blotting analyses in fluorescence-activated cell sorting (FACS)-sorted cells. The development, phenotype of B cells and in vivo responses to T cell dependent or independent antigens post immunization were analyzed by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Adoptive transfer experiment in combination with in vitro cultures of FACS-purified B cells and RNA-Seq analysis were utilized to specifically determine the impact of Zbtb24 on B cell biology as well as the underlying mechanisms. RESULTS: Zbtb24 is dispensable for B cell development and maintenance in naive mice. Surprisingly, B cell specific deletion of Zbtb24 does not evidently compromise germinal center reactions and the resulting primary and secondary antibody responses induced by T cell dependent antigens (TD-Ags), but significantly inhibits T cell independent antigen-elicited antibody productions in vivo. At the cellular level, Zbtb24-deficiency specifically impedes the plasma cell differentiation of B1 cells without impairing their survival, activation and proliferation in vitro. Mechanistically, Zbtb24-ablation attenuates heme biosynthesis partially through mTORC1 in B1 cells, and addition of exogenous hemin abrogates the differentiation defects of Zbtb24-null B1 cells. CONCLUSIONS: Zbtb24 seems to regulate antibody responses against TD-Ags B cell extrinsically, but it specifically promotes the plasma cell differentiation of B1 cells via heme synthesis in mice. Our study also suggests that defected B1 functions contribute to recurrent infections in patients with ICF2.

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The quantitation of plasma cells in bone marrow (BM) is crucial for diagnosing and classifying plasma cell neoplasms. Various methods, including Romanowsky-stained BM aspirates (BMA), immunohistochemistry, flow cytometry, and radiological imaging, have been explored. However, challenges such as patchy infiltration and sample haemodilution can impact the reliability of BM plasma cell percentage estimates. Bone marrow plasma cell percentage varies across methods, with immunohistochemically stained biopsies consistently yielding higher values than Romanowsky-stained BMA or flow cytometry alone. CD138 or MUM1 immunohistochemistry and artificial intelligence image analysis on whole-slide images are emerging as promising tools for accurate plasma cell identification and quantification. Radiological imaging, particularly with advanced technologies like dual-energy computed tomography and radiomics, shows potential for multiple myeloma diagnosis, although standardisation remains a challenge. Molecular techniques, such as allele-specific oligonucleotide quantitative polymerase chain reaction and next-generation sequencing, offer insights into clonality and measurable residual disease. While no consensus exists on a gold standard method for BM plasma cell quantitation, CD138-stained biopsies are favoured for accurate estimation and play a pivotal role in diagnosing and assessing multiple myeloma treatment responses. Combining multiple methods, such as BMA, BM biopsy, and flow cytometry, enhances accuracy of diagnosis and classification of plasma cell neoplasms. The quest for a gold standard requires ongoing research and collaboration to refine existing methods. Furthermore, the rise of digital pathology is anticipated to reshape laboratory medicine and the role of pathologists in the digital era. What this study adds: This article adds a comprehensive review and comparison of different methods for plasma cell estimation in the bone marrow, highlighting their strengths and limitations. The goal is to contribute valuable insights that can guide the selection of optimal techniques for accurate plasma cell estimation.

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Diseases in which cutaneous plasma cell infiltrates predominate are rare and usually of unknown etiology, including those that transition from benign to malignant, such as cutaneous plasmacytosis, multicentric Castleman disease, and extramedullary plasmacytoma. These diseases may present as purplish, reddish-brown cutaneous plaques or nodules. Here, we report an exceptional case of lichen planus (LP) in which the patient had classic histopathological features, but the infiltrating inflammatory cells were plasma cells with restricted light chain expression. The patient presented with severe rashes, including purplish-red plaques and nodules, erythema, and erosions in the palmoplantar area, verrucous hyperplasia of the oral mucosa, and anonychia of the toes. These findings suggest a possible role of plasma cells with restricted light chain expression in the LP. Clinicians should closely follow patients for changes in their rash, perform repeat biopsies if necessary, and regularly conduct multisystemic evaluations.

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This commentary highlights a need for comprehensive measures of structural racism tailored to cancer health disparities, in particular Black-White disparities in multiple myeloma (MM). Recent political and social calls and advances in the ability to quantitate structural racism have led to rapidly growing research on the health consequences of structural racism. However, to date, most studies have used unidimensional measures of structural racism that do not capture cumulative influences or enable the identification of factors most responsible for driving disparities. Furthermore, measures may not reflect aspects of structural racism most relevant to underlying disease processes and risks. This study proposes a multifaceted approach to measuring structural racism relevant to MM that includes comprehensive, disease- and at-risk population-tailored social and environmental data and biomarkers of susceptibility and progression related to underlying biological changes associated with structural racism. Such novel measures of structural racism may improve the ability to assess the influence of structural racism on cancer health disparities, which may advance understanding of disease etiology and differences observed by racialized groups.

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BACKGROUND: Plasma cell myeloma (PCM) is characterized by hypercalcemia, renal impairment, anemia, and bone destruction. While pleural effusion, ascites, abdominal pain, and bloody stool are common manifestations of lung disease or gastrointestinal disorders, they are rarely observed in patients with PCM. CASE SUMMARY: A 66-year-old woman presented with complaints of recurrent chest tightness, wheezing, and abdominal bloating accompanied by bloody stools. Computed tomography revealed pleural effusion and ascites. Pleural effusion tests showed inflammation, but the T-cell spot test and carcinoembryonic antigen were negative. Endoscopy showed colonic mucosal edema with ulcer formation and local intestinal lumen stenosis. Echocardiography revealed enlarged atria and reduced left ventricular systolic function. The diagnosis remained unclear. Further testing revealed elevated blood light chain lambda and urine immunoglobulin levels. Blood immunofixation electrophoresis was positive for immunoglobulin G lambda type. Smear cytology of the bone marrow showed a high proportion of plasma cells, accounting for about 4.5%. Histopathological examination of the bone marrow suggested PCM. Flow cytometry showed abnormal plasma cells with strong expression of CD38, CD138, cLambda, CD28, CD200, and CD117. Fluorescence in situ hybridization gene testing of the bone marrow suggested 1q21 gene amplification, but cytogenetic testing showed no clonal abnormalities. Colonic mucosa and bone marrow biopsy tissues were negative for Highman Congo red staining. The patient was finally diagnosed with PCM. CONCLUSION: A diagnosis of PCM should be considered in older patients with pleural effusion, ascites, and multi-organ injury.

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The diagnosis of multiple myeloma (MM) is made based on the presence of either marrow clonal plasma cells > 10% or an extramedullary or bony plasmacytoma confirmed by biopsy. Additionally, at least one of the SLiM (sixty years, light chain ratio, magnetic resonance imaging)-CRAB (calcium elevation, renal insufficiency, anemia, and bone lesions) myeloma-defining events must be present. MM typically presents with symptoms such as fatigue due to anemia, kidney failure, hypercalcemia, and bone pain. It is uncommon, though, for MM to manifest as a single bone mass. We report the case of a 65-year-old male who did not fit the criteria for solitary bone plasmacytoma and presented with an unusual sternal tumor. The patient was diagnosed with MM despite not having any of the traditional symptoms such as low back pain, weight loss, anemia, or hypercalcemia. The diagnosis was based on a bone marrow examination, which showed 50% plasma cells. Radiation therapy and systemic chemotherapy were then used to treat him. The patient's symptoms, radiological findings, and biopsy results are described in detail, emphasizing the difficulty and intricacy of correctly diagnosing this uncommon manifestation of MM. This case highlights the need for a comprehensive and multidisciplinary strategy to diagnose and treat atypical presentations of MM, making sure that all possible diagnostic pathways are investigated in order to achieve accurate and timely diagnosis and treatment.

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The two primary types of non-puerperal mastitis (NPM) are granulomatous lobular mastitis (GLM) and plasma cell mastitis (PCM). Existing research indicates that immune inflammatory response is considered to be the core of the pathogenesis of GLM and PCM, and both innate and adaptive immune responses play an important role in the pathophysiology of PCM and GLM. However, the regulatory balance between various immune cells in these diseases is still unclear. Consequently, we present a comprehensive summary of the immune-related variables and recent advances in GLM and PCM.

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Plasma cell mucositis (PCM) is a rare inflammatory condition affecting the oral tissues, often triggered by allergens or inflammation. Autism spectrum disorder (ASD), a neurodevelopmental condition, poses unique challenges in oral care and hygiene due to behavioral and sensory issues. These conditions have not previously been reported in concert but may share risk factors including through the development of inflammation. We present a case of severe PCM in a 23-year-old male with ASD, illustrating diagnostic complexities and management strategies. The patient presented with widespread and severe lesions, raising the possibility of underlying causes. After multiple interventions, including topical steroids and trigger avoidance, the patient achieved near-complete resolution of the oral lesions. Immunohistochemical and serological investigations suggested an underlying monoclonal gammopathy, warranting hematological evaluation. Our case shows how PCM and ASD can affect each other, highlighting the importance of understanding how these conditions interact, and the need for tailored approaches to oral health in this population. Further research is needed to elucidate any pathophysiological or risk-based link between ASD and inflammatory oral conditions and to refine management strategies for PCM in patients with neurodevelopmental disorders.

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Inflammatory myofibroblastic tumors are rare tumors that have been described in virtually all organs. Even though they are extremely rare in the esophagus, several cases have been described in the literature. Surgical resection has been the therapeutic modality used in most of those cases. In this report, we describe a case of inflammatory myofibroblastic tumor that was successfully managed endoscopically for the first time with the endoscopic submucosal dissection technique.

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Plasma cell neoplasms (PCN) have infrequently been reported in patients with myelodysplastic syndrome (MDS) and even more rarely in those with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN). We report the clinicopathologic features of 26 patients with bone marrow myelodysplasia accompanied by PCN, including 21 patients with MDS and 5 with MDS/MPN. The clinicopathologic features of the MDS/MPN-PCN were compared to those of the MDS-PCN group and 68 cases of MDS/MPN without PCN, respectively. The MDS/MPN-PCN group was notable for increased reticulin fibrosis > grade 1 when compared to both the MDS/MPN (p = 0.007) and MDS-PCN (p = 0.02) groups. MDS/MPN-PCN was associated with worse overall survival when compared with MDS-PCN (p = 0.03) and but not with MDS/MPN. Notably, hemoglobin level <8 g/dl (p = 0.008), and IDH2 somatic mutation (p = 0.003) were independent predictors of poor overall survival in all patients with MDS/MPN. Analysis of larger cohorts is required to confirm these associations and provide an insight into the pathogenesis.