Rare Case of a Solitary Bone Plasmacytoma of the Proximal Femur Managed with Surgery and Adjuvant Chemotherapy: A Case Report

Introduction: Solitary plasmacytoma of the bone is a rare neoplasm characterized by proliferation of neoplastic plasma cells in the bone in the absence of systemic involvement. We present a managed case of a 64-year-old male with solitary bone plasmacytoma of the right proximal femur, who presented as a pathological subtrochanteric femur fracture. Case Report: A 64-year-old male presented to our outpatient department with pain in the right hip and restricted range of motion following a trivial trauma. The radiographs showed an osteolytic lesion in the right proximal femur with a right subtrochanteric femur fracture. A magnetic resonance imaging scan revealed a well-defined lesion in the right proximal femur. A 18F-fluorodeoxyglucose positron emission tomography did not show a lesion at any other site suggesting that the lesion was solitary. A serum protein electrophoresis study was normal and the urine was negative for myeloma protein. The patient had a score of 12 as per Mirel’s criteria and hence required operative intervention and fixation. The patient was managed with a thorough mechanical and chemical curettage of the lesion followed by fixation with a proximal femur locking plate and augmentation with fibula and iliac crest bone graft. He was then given a chemotherapy regimen consisting of nine cycles of bortezomib, lenalidomide, and dexamethasone. Conclusion: Solitary bone plasmacytoma is a rare neoplasm of the bone. Early diagnosis and intervention are required to manage it and prevent its progression to multiple myeloma, which is a more aggressive entity and lies at the other end of the spectrum of plasma cell dyscrasias. Management of this lesion requires an active participation of the hematologist and a holistic approach which includes radiotherapy or surgery with possible adjuvant chemotherapy. Keywords: Solitary bone plasmacytoma, subtrochanteric femur fracture, multiple myeloma, bortezomib, lenalidomide, dexamethasone.

Rheumatologic diseases impact the risk of progression of MGUS to overt multiple myeloma

Monoclonal gammopathy of undetermined significance (MGUS), a premalignant condition, is associated with various chronic inflammatory rheumatic diseases (RDs) and is frequently observed as an incidental finding during routine work-up. The association of MGUS and chronic RDs is well established, but the impact of RDs on the risk of transformation into overt multiple myeloma (MM) has not been evaluated so far. MGUS patients diagnosed between January 2000 and August 2016 were identified and screened for concomitant RDs. RDs were grouped into antibody (Ab)-mediated RDs and non-Ab–mediated RDs (polymyalgia rheumatica, large-vessel giant cell arteritis, spondyloarthritis, and gout). Progression to MM was defined as a categorical (yes/no) or continuous time-dependent (time to progression) variable. Of 2935 MGUS patients, 255 (9%) had a concomitant RD. MGUS patients diagnosed with non-Ab–mediated RDs had a doubled risk of progression compared with those without a concomitant RD (hazard ratio, 2.1; 95% CI, 1.1-3.9; P = .02). These data translate into a 5-year risk of progression of 4% in MGUS patients without rheumatologic comorbidity, 10% in those with concomitant non-Ab–mediated RDS, and 2% in those with Ab-mediated RDs. By using the complex risk stratification model that includes myeloma protein (M-protein) concentration, immunoglobulin type, and level of free light chain ratio as variables, patients with non-Ab–mediated RDs (n = 57) had the highest risk for progression (hazard ratio, 6.8; 95% CI, 1.5-30.7; P = .01) compared with patients with Ab-mediated RDs (n = 77). Chronic inflammatory diseases have an impact on the risk of MGUS progressing into overt MM, with a doubled risk of transformation observed in patients with non-Ab–mediated RDs. Future research can elucidate whether comorbidities such as RDs should be included in currently applied prognostic MGUS scores.

Rare case of plasmablastic myeloma diagnosed on lung biopsy

Plasmablastic myeloma is a rare variant of multiple myeloma characterised by neoplastic proliferation of single clone of plasma cells producing monoclonal immunoglobulins. A 60-year-old man presented to hospital with a 6-week history of chest pain, back pain, leg weakness and numbness. Imaging revealed a 75 mm left lobular lung mass with chest wall invasion, metastatic bony and soft-tissue deposits and spinal cord compression at T5 level. Lung biopsy, for suspected metastatic lung cancer, surprisingly showed features of plasmablastic myeloma. Protein electrophoresis demonstrated 2 g/L of IgG lambda paraproteinaemia and an increase in lambda light chains with reduced kappa/lambda ratio of 0.01. Bone marrow biopsy did not show evidence of infiltration by disease. The patient received radiotherapy to the spine; responded to third-line chemotherapy and received autologous stem cell transplant. This case adds to the rare causes of lung mass and is the first reported case of plasmablastic myeloma diagnosed on lung biopsy.

Renal Expression of Light Chain Binding Proteins

Overproduction of human light chains (LCs) and immunoglobulins can result in various forms of renal disease such as cast nephropathy, monoclonal immunoglobulin deposition disease, LC proximal tubulopathy, AL amyloidosis, and crystal storing histiocytosis. This is caused by cellular uptake of LCs and overwhelmed intracellular transport and degradation in patients with high urine LC concentrations. LC kappa and lambda purification was evaluated by sodium dodecyl sulfate gel electrophoresis. LC and myeloma protein binding to immobilized renal proteins was measured by enzyme-linked immunosorbent assay (ELISA). The human protein microarray (HuProt™) was screened with purified kappa and lambda LC. Identified LC partners were subsequently analyzed in silico for renal expression sites using protein databases, Human Protein Atlas, UniProt, and Bgee. Binding of urinary LCs and immunoglobulins to immobilized whole renal proteins from 22 patients with myeloma or plasma cell dyscrasia was shown by ELISA. Forty lambda and 23 kappa interaction partners were identified from HuProt™ array screens, of which 21 were shared interactors. Among the total of 42 interactors, 12 represented cell surface proteins. Lambda binding signals were approximately 40% higher than kappa signals. LC interaction with renal cells and disease-causing pathologies are more complex than previously thought. It involves an extended spectrum of proteins expressed throughout the nephron, and their identification has been enabled by recently developed methods of protein analysis such as protein microarray screening. Further biochemical studies on interacting proteins are warranted to elucidate their clinical relevance.

Peripheral retinal leakage in POEMS syndrome

Background POEMS (polyneuropathy, organomegaly, endocrinopathy, myeloma protein, skin changes) syndrome is a rare blood disorder with multi-system involvement. The cause is unknown. It is marked by elevated plasma cells, platelets, & VEGF (vascular endothelial growth factor) levels. 52% of patients develop optic disc edema which may be vision threatening but the exact etiology of optic disc edema is uncertain. We report a rare finding of peripheral retinal leakage in POEMS syndrome. Case presentation A 60 year-old female with POEMS syndrome presented with bilateral blurred vision. Fundi showed grade 3 disc edema OU. Lumbar puncture showed normal opening pressure. CSF analysis showed elevated proteins with no cells. MRI brain and MR Venogram head were unremarkable. Wide field fluorescein angiography demonstrated multifocal tiny vascular leakage and significant anterior temporal leakage. Conclusion The authors hypothesize the disc edema in POEMS syndrome may be caused by increased vascular permeability at the optic disc secondary to increased VEGF (vascular endothelial growth factor) levels. Though disc leakage is a well-documented finding in fundus fluorescein imaging, peripheral retinal leakage in POEMS syndrome is not reported.

Efficacy and Safety of Regimens Used for the Treatment of POEMS Syndrome- a Systematic Review

Introduction: POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy/edema, myeloma protein, skin changes) is a rare disorder associated with plasma cell neoplasia where an overproduction of proinflammatory cytokines such as vascular endothelial growth factor (VEGF) upregulates vasculogenesis and increases vascular permeability resulting in multiple symptoms of the disease e.g. edema and hemangioma. Although the limited-stage disease can be treated with radiotherapy, treatment for the more advanced disease remains unclear. Here we offer a systematic review of the efficacy and safety of treatment regimens used to treat POEMS syndrome in the adult population. Methods: Databases i.e. PubMed, Embase, Web of Science, and clinicaltrials.gov were searched since inception through May 15th, 2020, following the PRISMA guidelines. Out of 421 studies, 8 articles (5 prospective clinical trials, and 3 retrospective studies) were included. Phase I clinical trials, abstracts, case reports, case series, and review articles were excluded. Results: A total of 171 patients (21-79 years of age) were evaluated in 8 clinical studies. Immunomodulator Based Regimens: In the 5 clinical studies (N=96) where lenalidomide (Len) plus dexamethasone (Dex) were used, the hematological (heme) complete response (CR) ranged from 20% to 46%. Heme CR was defined as the absence of monoclonal immunoglobulins in serum or urine. VEGF CR defined as normalization of serum VEGF levels ranged from 35% to 80%. Neurological response defined as the improvement in the overall neuropathy limitations scale (ONLS) by at least one score ranged from 0% to 95%. These studies reported 2-3 year progression-free survival (PFS) and overall survival (OS) of 59% to 92% and 90% to 100%, respectively. In the study by Suichi et al. (N=5), VEGF CR was reported to be 80%. However, no neurological improvement was seen in these patients. Proteasome Inhibitor Based Regimens: In the study by He et al. (N=20) bortezomib in combination with cyclophosphamide and Dex yielded heme, VEGF, and neurological responses in 76%, 88%, and 95% of the patients, respectively. No grade ≥3 treatment-related adverse effects (TRAE) were seen. Conventional Chemotherapy Based Regimens: In the phase II trial conducted by Misawa et al. (N=25) the reduction in serum VEGF levels, as well as clinical response as measured by improvement in muscle strength, was higher in the thalidomide arm as compared to the placebo arm. Grade ≥3 TRAE reported in the treatment arm were cardiac arrest, heart failure, and dehydration in 1 (8%) patient each. In the study by Li et al. (N=31) melphalan (Mel) in combination with Dex achieved heme, VEGF, and neurological response rates of 81%, 100%, and 100%, respectively. Twenty percent of the patients experienced grade ≥3 TRAE. Conclusion: Immunomodulator and chemotherapy based regimens appear to have a reasonable safety and efficacy profile. Lenalidomide and melphalan based therapies were most effective. Proteasome inhibitors based regimens yielded efficacious results without significant toxicity. More studies with existing and newer combinations with autologous stem cell transplantation are warranted. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Development of novel methods for non-canonical myeloma protein analysis with an innovative adaptation of immunofixation electrophoresis, native top-down mass spectrometry, and middle-down de novo sequencing

ObjectivesMultiple myeloma (MM) is a malignant plasma cell neoplasm, requiring the integration of clinical examination, laboratory and radiological investigations for diagnosis. Detection and isotypic identification of the monoclonal protein(s) and measurement of other relevant biomarkers in serum and urine are pivotal analyses. However, occasionally this approach fails to characterize complex protein signatures. Here we describe the development and application of next generation mass spectrometry (MS) techniques, and a novel adaptation of immunofixation, to interrogate non-canonical monoclonal immunoproteins.MethodsImmunoprecipitation immunofixation (IP-IFE) was performed on a Sebia Hydrasys Scan2. Middle-down de novo sequencing and native MS were performed with multiple instruments (21T FT-ICR, Q Exactive HF, Orbitrap Fusion Lumos, and Orbitrap Eclipse). Post-acquisition data analysis was performed using Xcalibur Qual Browser, ProSight Lite, and TDValidator.ResultsWe adapted a novel variation of immunofixation electrophoresis (IFE) with an antibody-specific immunosubtraction step, providing insight into the clonal signature of gamma-zone monoclonal immunoglobulin (M-protein) species. We developed and applied advanced mass spectrometric techniques such as middle-down de novo sequencing to attain in-depth characterization of the primary sequence of an M-protein. Quaternary structures of M-proteins were elucidated by native MS, revealing a previously unprecedented non-covalently associated hetero-tetrameric immunoglobulin.ConclusionsNext generation proteomic solutions offer great potential for characterizing complex protein structures and may eventually replace current electrophoretic approaches for the identification and quantification of M-proteins. They can also contribute to greater understanding of MM pathogenesis, enabling classification of patients into new subtypes, improved risk stratification and the potential to inform decisions on future personalized treatment modalities.