Bilateral Testicular Plasmacytoma Preceding Multiple Myeloma with Extramedullary Renal Involvement: A Case Report

Correlation among DCE‐MRI measurements of bone marrow angiogenesis, microvessel density, and extramedullary disease in patients with multiple myeloma

Multiple myeloma (MM) is a malignant plasma cell disorder characterized by clonal proliferation of plasma cells in the bone marrow. It accounts for approximately 1% of all cancers and about 10% of hematologic malignancies. Diagnosing MM in low-resource settings presents unique challenges dueto restricted access to advanced diagnostic modalities. A 49-year-old male presented to the emergency department with a four-day history of hematemesis and melena. He reported progressive weight loss along with severe chest wall and back pain. On physical examination, he appeared lethargic and anemic,with hepatomegaly and localized tenderness over the chest wall and spine. Initial clinical diagnosis was upper gastrointestinal bleeding, possibly related to underlying liver cirrhosis. Laboratory investigations revealed severe normocytic normochromic anemia (hemoglobin: 6.0 g/dL), and rouleaux formation onperipheral blood smear. Serum urea and creatinine were markedly elevated (108 mg/dL and 7.18 mg/dL, respectively), along with hypercalcemia (1.76 mmol/L). Urinalysis demonstrated +2 proteinuria and granular casts. Chest X-ray revealed multiple geographic lytic lesions involving the clavicle, scapulae, and ribs. Renalultrasonography indicated chronic kidney disease. Based on the presence of all four CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) criteria and rouleaux formation, multiple myeloma was strongly suspected. The patient was managed supportively with red blood cell transfusions and symptomatictreatment. Definitive diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy-proven plasmacytoma plus evidence of one or more myelomadefining events, bone marrow plasmacytosis, and a free light chain ratio >100. Bone marrow and serum electrophoresis analysis are often not available inlow-resource settings. Referral to a tertiary center with appropriate resources was suggested, but was not feasible due to financial constraints. This case illustrates that in low-resource settings, clinical vigilance combined with basic investigations can support a presumptive diagnosis of multiple myeloma andguide appropriate referral.

Novel therapies for multiple myeloma.

Extramedullary disease in multiple myeloma in the era of novel agents.

Single-cell transcriptomics reveals proliferative, immune-evasive, and bone marrow–independent transcriptional programs in extramedullary multiple myeloma.

Comprehensive Characterization of the Bone Marrow Microenvironment Transcriptional Remodeling in the Progression from MGUS to Smoldering and Multiple Myeloma

The Immune Microenvironment in Multiple Myeloma Progression at a Single-cell Level.

Composition and Fitness of T and NK Cells in Extramedullary Myeloma Tumor Microenvironment

Reduced CXCR4 expression is associated with extramedullary disease in a mouse model of myeloma and predicts poor survival in multiple myeloma patients treated with bortezomib

P-077: Bone marrow microenvironment analysis of exosomal microRNAs in multiple myeloma, extramedullary disease and plasma cell leukemia

Age 40 Years and Under Does Not Confer Superior Prognosis in Patients with Multiple Myeloma Undergoing Upfront Autologous Stem Cell Transmplant

Multiple myeloma (MM) is hematologic malignancy characterized by the accumulation of malignant plasma cells in the bone marrow. The annual incidence of newly diagnosed MM cases in the United States is 3 to 4 per 100,000 people and accounts for approximately 1% of all malignant diseases (Jemal et al., 2011). MM is diagnosed at an advanced stage in 95% of patients and the median age at diagnosis is 65 years. It is a progressive malignancy that begins with monoclonal gammopathy of undetermined significance (MGUS), progresses to asymptomatic or smoldering myeloma and then symptomatic MM. MGUS is a disorder that exhibits clonal proliferation of plasma cells and can eventually evolve into MM or other Bcell disorders (Landgren et al., 2011). Clinically, patients with symptomatic myeloma have 10% or more malignant plasma cells in bone marrow, abnormal levels of serum free light chain, osteolytic bone disease, and show damage to other tissues or organs. Smoldering myeloma has the same plasma cell and M-protein characteristics of symptomatic but lacks evidence of organ damage. A rare type of MM, nonsecretory myeloma, has no detectable Mprotein and accounts for only 1-5% of MM cases. Solitary plasmacytoma is a plasma cell neoplasm that has a single bone or extramedullary lesion (Mendenhall et al., 2003). MM is characterized by significant heterogeneity at the molecular level (Herve et al., 2011) and the bone marrow microenvironment plays an active role in supporting tumor growth, angiogenesis, bone disease, and drug resistance (Anderson and Carrasco, 2011). The disease initially responds to alkylating agents, corticosteroids, and thalidomide but eventually becomes refractory (Sirohi and Powles, 2004). High dose melphalan combined with peripheral blood stem cell transplant has improved the response rate in myeloma patients, but is not curative (Fassas and Tricot, 2001). To date, MM remains uniformly fatal with a median survival of approximately 50 months after diagnosis.

Background: Substantial advances in our understanding of the biology of the incurable plasma cell (PC) malignancy multiple myeloma (MM) came from the study of the bone marrow (BM) microenvironment (BMME). Our previous work disclosed an essential role for autophagy in sustaining MM cell proliferation and survival. However, the control exerted on PC autophagy by the BMME and its pathophysiological significance are virtually unknown. Experimental design: We integrated ex vivo multiplexed phosphoprotein cell signaling analyses of primary MM and BMME cells, metabolomic profiling of patient-derived BM and peripheral plasma, and in vitro studies on human MM cell lines. Primary CD138+ MM and BMME CD138- cells were isolated from BM aspirates obtained from 35 clinically characterized MM patients and 60 proteins - representative of autophagy, cell survival, proliferation, protein degradation and translation pathways - were analyzed by Reverse Phase Protein Arrays (RPPA).Comprehensive metabolomics profiling was achieved by ultra-high performance liquid and gas chromatography followed by mass spectrometry (UHPLC/GC-MS) on ad hoc-collected B and peripheral plasma samples from patients at different disease stages (30 MGUS, 17 smoldering MM, 16 MM) and age-matched healthy donors (29). For in vitro studies, human MM lines were exposed to amino acid (AA) depletion and selected responses evaluated by quantitative RT-PCR and immunoblotting analyses. Results: First, RPPA revealed that patients with the most aggressive clinical presentation (refractoriness, short time to progression and active bone disease) displayed higher activity of the PI3K/AKT/mTOR pathway associated to higher expression of the autophagic proteins ATG5, LC3B and p62. In search for extrinsic stimuli capable of raising both mTOR and autophagic activity, we recapitulated such expression pattern in MM cells through selective starvation of tryptophan (Trp) and arginine (Arg), two AA endowed with distinctive immune regulatory activity. When exposed to Trp-free or Arg-free medium, human MM cell lines activated GCN2-mediated responses, increasing mTOR, p-S6RP, CHOP, p62 and Blimp-1 and immunoglobulin secretion; conversely, stable lentiviral p62 silencing reduced Blimp-1 and caused the in vitro extinction of MM cell lines within 10 days of culture. UHPLC/GC-MS metabolomics analysis of plasma samples revealed a progressively and significantly lower concentration of Trp and Arg associated with disease evolution and shorter progression-free survival. Conclusion: Taken together, our findings disclose a novel extrinsic circuit whereby reduced concentration of the essential immunoregulatory AA Trp and Arg sustains PC cell fitness and survival. Attesting to pathophysiologic relevance, this mechanism appears coopted by MM as a component of its vicious BMME. Note: This abstract was not presented at the meeting. Citation Format: Alessandra Romano, Floriana Cremasco, Antonella Chiechi, Francesca Paradiso, Enrico Milan, Francesca Fontana, Jose M. Manteiga, Francesco Di Raimondo, Alexander I. Spira, Amy Van Meter, Emanuel Chip Petricoin, Virginia Espina, Lance A. Liotta, Simone Cenci. Multiplexed phosphoprotein cell signaling analysis in multiple myeloma reveals a pro-survival pathway elicited by amino-acid starvation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5413. doi:10.1158/1538-7445.AM2017-5413

New Diagnostic Criteria for Multiple Myeloma

Lenalidomide: A double-edged sword for concomitant multiple myeloma and post-essential thrombocythemia myelofibrosis.