Extramedullary Myeloma Research Articles

Initial manifestation of parotid extra-medullary myeloma in an HIV positive patient on anti-retroviral therapy: A case report and review of the literature.

Multiple myeloma is a biologically diverse, malignant disease that involve plasma cells. Multiple myeloma is characterized by the unrestrained proliferation of monoclonal plasma cells within the bone marrow. In the present case report, the case of a human immunodeficiency virus (HIV) positive patient with an initial manifestation of extramedullary myeloma involving the parotid gland is described. The patient had been on antiretrovirals for the last two years. A Medline, Embase, Scopus and Google Scholar search was performed using the key words: ‘Parotid extramedullary myeloma AND HIV’ as part of the literature review. A 46-year-old female presented to our hospital with a 6-month history of a painful mass on the left side of the face, involving the parotid area, with rapid growth in the preceding month. There was associated fever, body pains and difficulty opening the mouth. This resulted in difficulty in mastication and she also reported pain on swallowing. She did not notice any weakness of her face on the left side. She had no complaints regarding her eyes, such as visual disturbances, eye pain, or an inability to close the eye on the affected side. The patient was diagnosed with HIV infection 2 years prior, and had been on highly active antiretroviral therapy (HAART) since the diagnosis. There is no consensus regarding a treatment protocol for HIV positive patients on HAART and multiple myeloma. However, based on the clinical case report and a review of the relevant literature, the treatment should include high doses of a combination of chemotherapeutic agents. Although multiple myeloma is considered incurable, all patients should be started on treatment with the goal of preventing further complications.

Genetic Basis of Extramedullary Plasmablastic Transformation of Multiple Myeloma.

In patients with multiple myeloma, plasmablastic transformation in the bone marrow is rare and associated with poor outcomes. The significance of discordant extramedullary plasmablastic transformation in patients with small, mature clonal plasma cells in the bone marrow has not been well studied. Here, we report the clinicopathologic, cytogenetic, and molecular features of 10 such patients (male/female: 6/4, median age: 65 y, range: 48 to 76 y) with an established diagnosis of multiple myeloma in the bone marrow composed of small, mature plasma cells in parallel with a concurrent or subsequent extramedullary plasmablastic transformation. Eight patients with available survival data showed an overall aggressive clinical course with a median survival of 4.5 months after the diagnosis of extramedullary plasmablastic transformation, despite aggressive treatment and even in patients with low-level bone marrow involvement. Pathologically, the extramedullary plasmablastic myeloma were clonally related to the corresponding bone marrow plasma cells, showed high levels of CMYC and/or P53 expression with a high Ki-67 proliferation index by immunohistochemistry and harbored more complex genomic aberrations including frequent mutations in the RAS pathway and MYC rearrangements compared with their bone marrow counterparts. In summary, although genetic and immunohistochemical studies were not uniformly performed on all cases due to the retrospective nature of this study, our data suggest that discordant extramedullary plasmablastic transformation of multiple myeloma has an aggressive clinical course and is characterized by frequent mutations in the RAS pathway and more complex genomic abnormalities.

Alterations in the Transcriptional Programs of Myeloma Cells and the Microenvironment during Extramedullary Progression Affect Proliferation and Immune Evasion.

In multiple myeloma, extramedullary progression is associated with treatment resistance and a high mortality rate. To understand the molecular mechanisms controlling the devastating progression of myeloma, we applied single-cell RNA-sequencing (RNA-seq) to myeloma in the bone marrow and myelomatous pleural effusions or ascites. Bone marrow or extramedullary myeloma samples were collected from 15 patients and subjected to single-cell RNA-seq. The single-cell transcriptome data of malignant plasma cells and the surrounding immune microenvironment were analyzed. Comparisons of single-cell transcriptomes revealed the systematic activation of proliferation, antigen presentation, proteasomes, glycolysis, and oxidative phosphorylation pathways in extramedullary myeloma cells. The myeloma cells expressed multiple combinations of growth factors and receptors, suggesting autonomous and pleiotropic growth potential at the single-cell level. Comparisons of the tumor microenvironment revealed the presence of cytotoxic T lymphocytes and natural killer (NK) cells in both the bone marrow and extramedullary ascites, demonstrating a gene-expression phenotype indicative of functional compromise. In parallel, isolated myeloma cells persistently expressed class I MHC molecules and upregulated inhibitory molecules for cytotoxic T and NK cells. These data suggest that myeloma cells are equipped with specialized immune evasion mechanisms in cytotoxic microenvironments. Taken together, single-cell transcriptome analysis revealed transcriptional programs associated with aggressive myeloma progression that support autonomous cell proliferation and immune evasion.

Anti-BCMA CAR T-Cell Therapy in Relapsed or Refractory Multiple Myeloma with Extramedullary Disease and Plasma Cell Leukemia

Background: Extramedullary myeloma (EMM) and primary plasma cell leukemia (pPCL) remains a treatment challenge even in the era of new drugs. The prognosis of EMM is inferior, and the median overall survival of patients who experience an extramedullary relapse is < 6 months. Chimeric antigen receptor (CAR)- B-cell maturation antigen (BCMA) has the potential for the treatment of EMM and PCL. Methods: Between February 22, 2017 and June 25, 2018, twenty-eight R/R MM patients (including fourteen EMM patients) and 2 pPCL patients received median dose of 11.2 × 106 CAR+ cells/kg (range, 5.4 – 25.0 × 106 CAR+ cells/kg). Patients had a median of 4 (range, 3 – 11) prior lines of therapy, including a proteasome inhibitor and/or an immunomodulatory agent. A lymphodepleting chemotherapy with cyclophosphamide 20mg/kg and fludarabine 25 mg/m2 daily on days -4 to -2 was administered before infusion of CAR-BCMA T cells on day 0. Findings: Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 96.7% of the patients), lymphopenia (in 100%), anemia (in 76.7%), and thrombocytopenia (in 80.0%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 16.7% and 3.3% of the patients, respectively. The objective response rate (ORR) was 90%, and the complete response (CR) rate was 43.3%. One of 2 primary Plasma cell leukemia achieved CR, and another achieved a very good partial response (VGPR). With a median follow-up of 385 days, relapse occurred in nine of the 13 patients who had a CR. The median progression-free survival (PFS) and overall survivals (OS) were 158 days and 427 days. The median OS of patients with EMM/PCL was 243 days. Interpretation: CAR-BCMA T cell treatment is safe and effective in heavily treated R/R Multiple Myeloma with Extramedullary disease. Trial Registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn. Number, ChiCTR OPC16009113). Funding Statement: This work is supported by the funding from the Key Program of the National Natural Science Foundation of China (81830008 and 81630006, to Dr. J.Z.), the Clinical research program of Huazhong University of Science and Technology affiliated Tongji Hospital (2019YBKY016, to Dr. J.Z.), the National Natural Science Foundation of China (81873452, to Dr. C.L.;81670152, to Dr. L.H.; 81600120, to Dr. N.W.). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: This study was conducted in compliance with the Declaration of Helsinki. The study protocol was approved by the institutional review board of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.

Fto Promotes Extramedullary Progression of Multiple Myeloma By Regulation of HSF1 through m6a RNA Methylation

Introduction :Extramedullary myeloma (EMM), defined by the presence of clonal cells outside the bone marrow, has extraordinarily heterogeneous biological and clinical features and is associated with an adverse prognosis. Recent studies have shown the upregulation of heat shock transcription factor 1 (HSF1) in EMM (Heimberger et al, Brit J Haematol 2013), but little is known about its role and mechanisms underlying the regulation. There is growing evidence that dysregulation of N6-methyladenosine (m6A) RNA methylation plays an important role in tumor invasion and metastasis (Pan et al, J Hematol Oncol 2018) and the m6A RNA modifications are involved in the heat shock response. This study was designed to reveal that the fat mass and obesity-associate protein (FTO), as a major m6A demethylase, plays a critical oncogenic role in extramedullary metastasis in multiple myeloma (MM) through regulating HSF1 and heat shock proteins (HSPs). Methods and results: Using transcriptome sequencing, we determined that FTO was significantly upregulated in plasma cells (PCs) from EMM and MM patients, compared to healthy donors. We then evaluated the expression levels of FTO and HSF1 in plasma cells (PCs) from EMM patients by qRT-PCR and western blot analysis. The results verified that FTO and HSF1 were markedly upregulated in PCs from newly diagnosed MM patients compared to healthy donors, and it was further upregulated in PCs from patients with EMM. And the expression levels of FTO was positively correlated with HSF1. Measured by colorimetric assay, we found that m6A RNA methylation level of EMM patients was lower than the level of MM and healthy donors, which was consistent with the expression of FTO in EMM patients. Importantly, enforced expression or knockdown expression of FTO via lentivirus transfection, dramatically influenced the proliferation, migration and invasion in MM cells. m6A RNA methylation has been reported to been associated with heat shock response (Zhou et al, Nature 2015). We therefore examined whether FTO can regulate HSF1 in EMM. Enforced expression of FTO dramatically elevated the level of HSF1 and HSPs in MM.1R and RPMI8226 cells, while inhibition of FTO reduced the level of HSF1 and HSPs. Through m6A sequencing and RNA sequencing, we confirmed that HSF1 was a novel target of FTO. Indeed, the demethylase FTO could positively regulate the expression of HSF1 at both the mRNA and protein levels in MM cells. In addition, knockdown of HSF1 by siRNA markedly reduced the ability of migration and invasion of MM cells overexpressing FTO. Thus, these results suggest that HSF1 is a key target gene of demethylase FTO in EMM. Moreover, pharmacological inhibitors of FTO, MA and MA2, could significantly enhance the effect of bortezomib in MM cells. Recent studies have suggested that for m6A modification to exert its biological functions, it must first be recognized by m6A reader proteins. Here, we evaluated whether demethylase FTO could regulate the level of HSF1 via YTHDF2, a crucial m6A reader protein. We confirmed with colorimetric assay that overexpression of FTO could reduce m6A levels in MM cells, and knockdown of FTO could enhance the m6A levels. Using RNA immuno-precipitation sequence (RIP-seq), we identified direct binding between the 3' end of the HSF1 transcript and the m6A reader protein YTHDF2. Consistently, we showed that silencing of YTHDF2 with siRNA strongly promoted HSF1 expression in MM cells with knockdown of FTO. In addition, by RNA stability analysis, we found that the YTHDF2 could regulate the expression of HSF1 through affecting the stability of HSF1. Next, we evaluated whether FTO could regulate extramedullary metastasis of MM in vivo. NCG mice were injected via tail vein with RPMI-8226-luc cells to establish EMM xenografts. Mice were assessed by in vivo bioluminescent imaging and PET-CT. The results showed that combined treatment with MA2 plus bortezomib could remarkably reduce the extramedullary metastasis in MM. Conclusions: Our datas reveal that FTO is frequently up-regulated in EMM and contributes to MM progression. FTO promotes HSF1 expression through inhibiting the degradation effect of YTHDF2 by reducing m6A levels in these mRNA transcripts. Therefore, FTO-YTHDF2-HSF1 regulatory axis may potentially be applied in EMM treatment. Disclosures No relevant conflicts of interest to declare.

Incidence and Outcomes of Extramedullary Myeloma in a South Australian Hospital

Introduction The overall incidence of extramedullary myeloma ranged from 6% to 30% 1-3 in reported literatures. The mechanism of extramedullary myeloma is poorly understood with some authors suggesting an increased incidence of extramedullary relapses post autologous or allogenic stem cell transplants 4. For our case series, we aim to compare the incidences, frequency of aberrant cytogenetic abnormalities and outcomes of extramedullary myeloma with current reported literature. Method We examined data from the myeloma database in the Royal Adelaide Hospital, South Australia, of patients presenting for treatment from June 2009 to June 2019. Patients with biopsy-proven extramedullary myelomas involving skin, organ or central nervous system, were selected. We looked at paraprotein subtype, cytogenetic abnormalities at diagnosis, sites of involvement, treatment details including autologous and allogenic stem cell transplants. Results A total of 743 patients presenting with myeloma from June 2009 to June 2019 were isolated. From these, a total of 47 (6%) patients with extramedullary disease were reported. Thirteen patients (3%) presented with extramedullary disease at diagnosis, while 34 patients (5%) presented with extramedullary disease at relapse. The most common involved paraprotein were IgG and IgA with an incidence of 38% each. Patients with excess lambda light chains (15%) formed the next most common subtype. Two patients had non-secretory myeloma. Majority of the patients (28%) did not have any cytogenetic abnormality as detected by conventional karyotype or FISH studies. The most common cytogenetic abnormality was +1q (15%), followed by hyperdiploidy (13%). Two patients did not undergo diagnostic bone marrow biopsies and 4 patients did not have cytogenetic and FISH analysis on their diagnostic bone marrow samples. The most common sites of EM disease are soft tissue plasmacytomas with an overall incidence of 46%; followed by major organ involvement at 31% and central nervous system involvement at 19%. Bortezomib-based therapy was the most common upfront treatment in 7 patients (54%) followed by immunomodulator (IMiD) based treatment with 4 patients (31%) being treated in this regime. A total of 7 patients underwent an autologous stem cell transplant with melphalan conditioning post induction therapy and 4 patients received maintenance therapy with an IMiD post transplant. Of the 13 patients who had extramedullary disease at diagnosis, 2 patients passed away due to progressive disease while 10 patients at this time of analysis are still alive. 1 patient was lost to follow up. Of the 47 patients with extramedullary disease, a total of 7 patients received an allogenic stem cell transplant as salvage therapy. Five patients received a salvage allogenic stem cell transplant and subsequently only had extramedullary disease manifestation post transplant. Of these patients, 2 patients passed away from progressive disease, 2 passed away of causes unrelated to disease, with one surviving patient. Of the remainder 2 patients, salvage allogenic stem cell transplant were only undertaken post diagnosis of relapsed extramedullary disease. Conclusions The overall incidence of extramedullary myeloma in our institution at 6% is slightly less than published case series in current literature 1-3. In this small case series, most patients did not have a cytogenetic abnormality detected at diagnosis while of the patients with cytogenetic abnormalities, the most common was +1q. This presents a different view with current literature suggesting high risk cytogenetic abnormalities such as del17p, del13q are more common in extramedullary myeloma 5,6. We did not routinely perform a bone marrow biopsy at relapse, nor were karyotype and FISH analysis analysed on biopsies from extramedullary sites. Extramedullary myeloma disease remains a heterogenous disease. Regardless of the presence of extramedullary disease, current Australian guidelines recommend induction therapy with a bortezomib-based therapy followed by high dose melphalan consolidation and autologous stem cell transplant in eligible patients. There are new novel agents available which may be used for treatment of relapsed disease however their efficacy in extramedullary disease is yet to be determined. Disclosures Yong: Celgene: Honoraria; Janssen: Other: other ; Amgen: Honoraria.

The Transmembrane Receptor Roundabout 1 (ROBO1) Is Necessary for Multiple Myeloma Proliferation and Homing to the Bone Marrow Niche

Introduction Multiple myeloma (MM) is characterized by dissemination and accumulation of plasma cells in the bone marrow (BM), which promotes tumor cell growth and therapy resistance. ROBO1 is a conserved transmembrane receptor of the Ig superfamily with no intrinsic catalytic activity, and its role in MM pathogenesis is unknown. Material and Methods We first analyzed ROBO1 expression via western blot and/or immunohistochemistry (IHC). Gene expression profiling in a cohort of 170 newly diagnosed MM patients (IFM170) was used to compare ROBO1 expression across primary MM and BM stroma cells (BMSC), and normal BM plasma cells (PC). We used short hairpin RNA (shRNA) for stable ROBO1 knock down (KD) and CRISPR-Cas9 for ROBO1 knock out (KO). For protein structure-function and rescue studies, ROBO1 KO MM cells were transduced with a lentiviral vector expressing either full-length (FL) or truncated ROBO1 mutants devoid of extracellular (Cyt) or intracellular domain (DeltaCyt), including patient-derived truncating mutations, with a C-terminus triple FLAG tag. FLAG immunoprecipitation (IP) followed by mass spectrometry or western blotting and immunofluorescence (IF) were used to identify ROBO1 interacting partners and ROBO1 cellular localization. We used a hydrogel encapsulation system to study proliferation in a 3D system. To study extramedullary and intramedullary MM growth in vivo, WT and ROBO1 KO OPM2 were injected either subcutaneously (plasmacytoma model) or intra-medullary in femoral bones of donor mice which were then implanted subcutaneously in recipient SCID mice (µ-SCID model). PET-CT was used to assess tumor volume. Mouse tumors were retrieved for IHC and RNA extraction followed by RNA sequencing. To study dissemination and homing, KO and FL addback OPM2 cells were injected intravenously in SCID mice. Femurs and plasmacytoma were retrieved at endpoint for IHC. Results ROBO1 is highly expressed in human MM cell lines and primary MM cells with highest expression in cells carrying the high risk t(4;14) cytogenetic and low/absent expression in normal PC. Of human cancer cell lines, ROBO1 expression was limited to late B cell lineage; and ROBO1 KD was selectively cytotoxic against MM, but not other hematologic cancers. ROBO1 KO significantly decreases proliferation in a 3D culture system and tumor growth in extramedullary (mean tumor volume KO versus WT plasmacytoma: 457 versus 1323 mm3, p value= 0.02) and intramedullary (mean tumor volume KO versus WT: 823 versus 2684 mm3, p value= 0.001) murine models of human MM. ROBO1 KO MM cells show decreased adhesion to BM endothelial and BMSC, which is fully rescued by FL ROBO1 addback. To address whether ROBO1 loss alters dissemination/homing of MM cells in vivo, we injected mice intravenously with ROBO KO or FL addback OPM2 cells. While ROBO1 KO resulted in a modest, non-statistically significant prolongation in mouse OS (90 versus 75 days, respectively, p value 0.2), the pattern of disease was strikingly different. As expected, ROBO1 FL mice developed hindlimb paralysis with extensive BM infiltration with MM. Importantly, ROBO1 KO mice demonstrated reduced BM infiltration and developed solitary plasmacytoma. We next showed that ROBO1 C-terminus domain is necessary and sufficient to rescue ROBO1 KO proliferative defect while expression of ROBO1 truncations, including patient-derived frameshift mutations, acted as dominant negative. IP showed avid interaction of ROBO1 with ABL1. Interestingly, we showed that the cytosolic domain of ROBO1 undergoes cleavage and translocates to the nucleus, where its function is now being studied. Conclusions We show that ROBO1 is necessary for MM homing to the BM niche and for MM growth within and outside the BM space. ROBO1 cytosolic domain undergoes proteolytic cleavage and translocates to the nucleus and is necessary and sufficient to rescue ROBO1 KO defective proliferation. Based on our data, we propose a dual model for ROBO1 in MM: the full transmembrane receptor is involved in regulating adhesion, dissemination and homing of MM cells within the BM niche; the cleaved intracellular C-terminus domain participates in transcriptional regulation, promoting MM proliferation. These data suggest that ROBO1 C-terminus may be a novel molecular target in MM. Disclosures Roccaro: Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Associazione Italiana per al Ricerca sul Cancro (AIRC): Research Funding; Associazione Italiana per al Ricerca sul Cancro (AIRC): Research Funding; European Hematology Association: Research Funding; Transcan2-ERANET: Research Funding; European Hematology Association: Research Funding; AstraZeneca: Research Funding; Transcan2-ERANET: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding. Ghobrial:Takeda: Consultancy; Sanofi: Consultancy; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Anderson:Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

KD-PACE salvage therapy for aggressive relapsed multiple myeloma

The non-cross-resistant combination VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide) incorporating novel and traditional anti-MM drugs has been evaluated for relapsed and/or refractory myeloma (RRMM) or aggressive clinical situations such as plasma cell leukemia (PCL) or extramedullary myeloma (EMM). However, in the modern era, many patients are already refractory to bortezomib when this therapy is utilized. Outcomes from incorporation of carfilzomib (KD-PACE) instead of bortezomib as salvage therapy for relapsed aggressive MM are described.

Initial extramedullary myeloma impacts overall survival via affecting post progression survival

Initial extramedullary myeloma impacts overall survival via affecting post progression survival

Research progress on treatment of extramedullary myeloma

Extramedullary myeloma (EMM) refers to the presence of clonal plasma cells outside the bone marrow in a patient with multiple myeloma (MM). The development of novel agents and hematopoietic stem cell transplantation (HSCT) significantly extend the survival of patients with MM, but none of the current treatments can completely overcome the adverse prognosis of EMM, and the prognosis of EMM is still poor. It is important to understand the current status of EMM treatments and explore new therapies to improve the prognosis of EMM. This article summarizes the recent advances in the treatment of EMM, including chemotherapy, HSCT, cellular immunotherapy and molecular targeted therapy. Key words: Multiple myeloma; Antineoplastic combined chemotherapy protocols; Hematopoietic stem cell transplantation; Molecular targeted therapy; Extramedullary myeloma; Chimeric antigen receptor-based immunotherapy

Clinical effects of CD45 on the prognosis of extramedullary myeloma relapse.

The incidence of extramedullary relapse (EMR) arising during the clinical course of multiple myeloma (MM) has increased in recent years. Therefore, we herein investigated the effects of immunophenotyping on the prognosis of MM patients with EMR. We conducted a retrospective review on data collected from MM patients with EMR between January 2007 and December 2018 at the Japanese Red Cross Society Wakayama Medical Center. Patient characteristics at the diagnosis of EMR, the prognostic significance of immunophenotyping and other factors were evaluated. Extramedullary relapse was detected in 55 of 231 patients (23.8%). At the diagnosis of EMR, CD45, the leucocyte common antigen, was detected in 54.5% of cases. CD45 negativity in bone marrow correlated with thrombocytopenia and higher serum LDH levels. Moreover, high-risk cytogenetics was more frequently observed in CD45- than in CD45+patients. A univariate analysis showed that overall survival (OS) was significantly shorter in CD45- than in CD45+patients. Thrombocytopenia, higher serum LDH levels and high-risk cytogenesis were also associated with shorter OS. A multivariate analysis confirmed that CD45 negativity, higher serum LDH levels and high-risk cytogenesis were independent adverse prognostic factors for OS. A Kaplan-Meier analysis revealed the potential of CD45- as a prognostic factor in patients with EMR and that it correlated with shorter survival. The present results showed that the expression of CD45 in the neoplastic plasma cells of MM patients with EMR was associated with patient prognosis independent of other prognostic factors. The establishment of a treatment strategy for EMR patients with CD45- MM cells is needed to improve poor outcomes.

The Utility of Non-Invasive Liquid Biopsy for Mutational Analysis and Minimal Residual Disease Assessment in Extramedullary Multiple Myeloma

Liquid biopsy is a promising technique for tumor genetic profiling and evaluating disease progression. Recent advances in circulating tumor DNA (ctDNA) research highlight its utility in solid tumors and hematological diseases. Extramedullary multiple myeloma (EMM) is an advanced type of multiple myeloma, defined by the presence of clonal plasma cells outside of the bone marrow. The potential of ctDNA to reveal the holistic genomic landscape of EMM is of great interest. Moreover, the mutational concordance between ctDNA and extramedullary plasmacytoma biopsies requires further investigation. In this study, using time-matched extramedullary plasmacytoma biopsies, bone marrow aspirates, and plasma samples from eight EMM patients, we conducted deep sequencing targeting the coding regions of 22 multiple myeloma-related genes. Sequencing results were further verified using droplet digital PCR. Gene mutations in mitogen-activated protein kinase pathways were identified in all 8 tissue biopsies and 7/8 (87.5%) time-matched plasma samples. The ctDNA to tissue biopsy concordance and bone marrow aspirate to tissue biopsy concordance were 0.873 (P = 8.66e−7) and 0.621 (P = 0.109), respectively. In conclusion, our results suggest that ctDNA can be a reliable surrogate for extramedullary plasmacytoma biopsy to characterize the genomic landscape and track disease progression, particularly when extramedullary plasmacytomas are inaccessible. Funding Statement: This work was supported in part by the National Science Foundation for Young Scientists of China (No. 81700160), National Natural Science Foundation of China (General Program, No. 81873452), National Natural Science Foundation of China (Key Program, No. 81630006). Declaration of Interests: The authors stated: No relevant conflicts of interest to declare. Ethics Approval Statement: This study was approved by Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The approval file number is TJ-IRB20180813.

PB2140 IMPACT OF EXTRAMEDULLARY DISEASE IN THE OUTCOMES OF MEXICAN PATIENTS WITH MULTIPLE MYELOMA

Background:Extramedullary myeloma (EMM) is the synchronous presence of clonal plasma cells (CPC) at bone marrow and distant sites. Its frequency is reported among 6‐20% of multiple myeloma (MM) patients and manifest as bone‐dependent plasmocitoma (BP) or tissue‐dependent plasmocitoma (TP). Previous reports state a more aggressive clinical course, whether at diagnosis or relapse. There is no data regarding the clinical course and prognosis in Mexican patients with EMM.Aims:To analyze and describe the impact of EMM on overall survival (OS) and progression free survival (PFS) of Mexican patients diagnosed and treated at monoclonal gammapathies clinic of our institution.MethodsRetrospective analysis including &gt;18 year‐old patients with MM diagnosis according to IMWG criteria. EMM was defined as presence of CPC corroborated by immunohistochemistry in BP or TP or demonstration of a synchronous tumor by imaging method and no accessible to biopsy.Results:A total of 199 patients were included. Sixty‐three patients had EMM (31.8%), 45 cases (71.4%) presented at diagnosis and 18 (28.6%) at progression. Forty‐eight cases (76.2%) were diagnosed by biopsy and 15 (23.8%) by imaging. Fifty‐four percent (n = 34) cases presented BP and 46% (n = 29) TP. Most frequently involved sites were abdomen (34.5%), thorax (27.6%) and lymph nodes (13.8%) in TP and spine (50%), chest wall (26.3%) and head/neck (13.2%) in BP. EMM was associated with lower comorbidity rate and higher renal failure. Population characteristics are shown in Table 1. Mean PFS and OS was 22.9 and 43.7 months, respectively. EMM at any time of disease resulted on lower PFS and OS (p = 0.03, p = 0.04), while TP showed lower OS (p &lt; 0.01). A higher ECOG PS and lower deep response was associated with worse PFS (HR 1.05‐2.60 (p = 0.03) and HR 0.20‐0.38 (p &lt; 0.01), respectively) while ISS and lower deep response resulted on worse OS (HR 1.0‐2.2 (p = 0.02) and HR 0.37‐0.73 (p &lt; 0.01)) at multivariate regression.Summary/Conclusion:A higher EMM rate was found in the studied population. EMM was associated to higher renal failure and low incidence of comorbidities, as shorter PFS and OS, particularly in TP. Identification of this high risk myeloma population allows an attempt for more intensive treatment with intention to improve prognosis.image

PB2187 SURGICAL TREATMENT OF BONE DISEASE IN MULTIPLE MYELOMA PATIENTS

Background:The definition of bone disease in multiple myeloma bone disease (MMBD) includes a wide range of clinical symptoms as well as anatomical changes. These include bone pain, osteoporosis, osteolytic lesions, pathological fractures, spinal cord and nerve root compression and extramedullary myeloma tumors. One of the most common symptoms reported by multiple myeloma (MM) patients with bone disease is pain. It is particularly severe in the case of localization of lesions in the spine and caused by compression fracture of the vertebral body. In the case of patients with MM, MMBD is most often related to the spine and about 11‐24% of patients have spinal cord compression. This is one of the most dangerous complications of MMBD. In each case, it requires special attention, and sometimes rapid surgical intervention.Aims:Determination of the neurosurgical treatment possibilities of patients with multiple myeloma, depending on reported complaints and neurological symptoms resulting from damage to the nervous system.MethodsRetrospective analysis of MM patients hospitalized in the Department of Neurosurgery and Pediatric Neurosurgery of the Medical University of Lublin in 2005‐2017 included 27 people: 12 (44%) women and 15 (56%) men aged 47‐82 (average 62 years). In each case, the clinical condition was assessed according to the Karnofsky performance status scale, the neurological status and medical imaging (computed tomography, magnetic resonance) were performed. In the majority of patients (25/93%) the diagnosis of MM was made on the basis of histopathological examination of the material collected during the surgery. In three cases, a plasmocytoma solitare was found.Results:Bone pain and neurological symptoms resulting from damage of the central nervous system were the main reason for hospitalization and the main indication for surgical procedures in patients with MM. The most frequently performed procedure was laminectomy (15/56%), and more rarely (7/26%), spinal stabilization was performed in the event of instability risk. Myeloma changes occurred mainly in the spine. In 4 cases, the intracranial location was observed (two times the cranial bone tumor buckling to its interior causing pressure to right and left parietal lobe, sphenoid sinus tumor and temporal bone petrous pyramid tumor). One patient was diagnosed with an orbital wall tumor. Among the entire study group there was only one postoperative complication observed (facial nerve paresis), which concerned the patient after the removal of a large temporal bone pyramid tumor. In 20 (74%) patients, improvement was stated, stabilization of neurological status in comparison with the period before surgery was found in 7 patients (26%). There was no deterioration of condition in any patient. In two cases, due to earlier diagnosis of MM, chemotherapy preceded hospitalization at the Neurosurgery Department. In 25 (93%) patients further postoperative treatment was used: chemotherapy (24/89%), radiotherapy (9/33%) or autologous hematopoietic stem cell transplantation (8/30%).Summary/Conclusion:Surgical treatment is one of the elements of a holistic therapeutic plan in which chemotherapy plays the most important role. Its goal is not radical treatment of MM, but a significant reduction of pain and often serious neurological complications. Although at the present time there is no irrefutable evidence that surgery affects the extension of overall survival, undoubtedly it often significantly improves its quality.

Research progresses in the pathogenesis of multiple myeloma with extramedullary disease

Multiple myeloma (MM) is a plasma cell malignant disease which is characterized by unlimited proliferation of monoclonal plasma cells and multiple infiltration of the bone marrow. Extramedullary myeloma (EMM) is found in some MM patients with extramedullary disease (EMD) at the initial diagnosis or during treatment. Particularly the hematogenous EMM has great heterogeneity and possesses poor prognosis in clinical applications. In general, the mechanism of EMM is closely related to cytogenetic abnormalities, the changes of the adhesion molecules, chemokine receptors, abnormal cytokine expression and exosomes etc. in bone marrow microenvironment. The authors focuses on the pathogenesis of EMM, in order to explore the causes of EMM heterogeneity. Key words: Multiple myeloma; Neoplasm metastasis; Plasmacytoma; Extramedullary myeloma; Hematogenous metastasis; Pathogenesis

Dyscrasies plasmocytaires : formes rares et atypiques

Plasma cell dyscrasias, other than classical symptomatic multiple myeloma, can take very various clinical presentations. AL amyloidosis, monoclonal immunoglobulin deposition disease or monoclonal gammopathy of clinical significance look like indolent diseases : a small clone of plasma cells produces low amounts of monoclonal immunoglobulins that deeply damage some organs, especially kidney, skin or heart. On the other hand, extramedullary myeloma disease or plasma cell leukemia are highly aggressive diseases related to the spread of tumor cells outside of the bone marrow. Prognostic of these presentations remains appalling, even with the introduction of new promising treatments. For these unusual forms, the best strategy remains unclear but often relies to the eradication of clonal plasma cells, using classical chemotherapy (alkylating agents), but also proteasome inhibitors, immunomodulatory drugs, and more recently monoclonal antibodies.

A Case Report of Extramedullary Myeloma Mimicking Lymphoma with Extensive Abdominal Involvement

A Case Report of Extramedullary Myeloma Mimicking Lymphoma with Extensive Abdominal Involvement

Incidence of Extramedullary Myeloma in Multiple Myeloma Patients

Incidence of Extramedullary Myeloma in Multiple Myeloma Patients

Clinical and biological characteristics of myeloma patients influence response to elotuzumab combination therapy.

Based on ELOQUENT-2, combination therapy with the monoclonal antibody elotuzumab was approved for relapsed/refractory multiple myeloma in the US and Europe. However, outside clinical trials, the optimal integration of elotuzumab into the sequence of treatment lines remains to be determined. Therefore, we analyzed safety and efficacy of elotuzumab/immunomodulatory drug combinations in a real-life cohort of 33 patients from our institution. The most frequent grade 3/4 adverse event was lymphopenia which did not increase the incidence of viral reactivations. After a median of four prior treatment lines, an overall response rate of 60% and a median progression-free survival (PFS) of 8 months were observed. The presence of cytogenetic high-risk status had no impact on PFS while low disease burden and high numbers of natural killer (NK)-cells at treatment initiation were associated with longer PFS. We observed an extramedullary relapse in three patients, associated with reduced expression of the elotuzumab target antigen SLAMF7 on extramedullary myeloma cells in one patient. Thus, biomarkers like disease burden, NK-cell count and SLAMF7 expression on myeloma cells may help to define myeloma patients with high likelihood to respond to elotuzumab treatment. Prospective trials investigating these biomarkers in larger patient cohorts are highly warranted.

Cases of Extra- Medullary Myeloma Presenting As Liver Infiltrates: A Single Community Hospital Experience

Introduction:Multiple Myeloma (MM) accounts for 13% of all hematologic malignancies. Plasma cells (PC) proliferation is mainly restricted to the bone marrow (BM) in most of the patients. Extramedullary myeloma (EMM) is defined by the PCs outside the bone marrow. The prevalence of EMM in myeloma patients has been reported at 7 to 15 percent in newly diagnosed patients and from 6 to 20 percent in relapsed setting. Patients with EMM have poor prognosis with a median overall survival of < 6 months. This abstract presents two cases of MM with initial presentation as a liver infiltrate.Cases:Case one: 74-year-old female presented with epigastric pain. Physical exam was unremarkable. Labs showed Hemoglobin (Hb) 8.3 g/dL, Creatinine (Cr) 2.0 mg/Dl and normal liver function test. Ultrasound showed multiple hypoechoic liver nodules. Biopsy of the liver nodule confirmed plasma cells. Her kappa/lambda ratio 3338, Lactate dehydrogenase (LDH) 423 IU/L, beta2 microglobulin was 9 mg/L. Serum and urine immunofixation(IFE) both confirmed a monoclonal kappa light chain clone. Skeletal survey was negative. BM biopsy showed 30 % kappa clonal plasma cells. Fluorescence in situ hybridization was positive for hyperdiploidy of chromosomes 7, 9, 11, 14, and 17 with partial deletion of IgH gene. Treatment with CyBorD (weekly dexamethasone 20 mg, bortezomib 1.3 mg/m2, and cyclophosphamide 300mg/m2) was started. After 6 months therapy, patient achieved partial response. Then her regimen was switched from CyBorD to VRD (Revlimid 10 mg, bortezomib 1.3 mg/m2 and dexamethasone 40 mg) because of severe side effect. She achieved a good partial response.Case two: 57-year-old male presented with right upper quadrant abdominal pain. Physical exam showed diffuse tenderness but no rigidity or guarding. Initial labs showed Hb 8.4g/dL, Cr 1. 7 mg/dL, total bilirubin of 3 mg/ dl, alanine aminotransferase 81 U/ l and aspartate aminotransferase 98 U/ l. CT abdomen pelvis showed metastatic disease to omental implants, splenomegaly and an enlarged liver. Patient underwent surgery in which it was noticed that omentum was adhered to stomach wall whose wedge resection showed plasma cells infiltrate. Liver biopsy also showed diffuse myeloma infiltration. His kappa /lambda ratio 0.0029, LDH 2187 IU/ L, beta 2 microglobulin was 8 mg/L. Serum electrophoresis showed M spike 3. 8 g with IFE confirmed IgG lambda band. Skeletal survey showed several osteolytic lesions in iliac bone. BM biopsy showed hypercellularity with 90 % plasma cells. Patient was started on CyBorD regimen. Repeat labs after first cycle was significant for rising free lambda light chain making us refer the patient to a University Hospital for further treatments. He was recently started on VDT- PACE ( bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide).Conclusion:EMM with liver metastasis as initial presentation is rare. Since the low incidence of EMM there are no specific treatment guidelines. There are no clear prognostication factors for EMM. Patients are treated in same way as MM. The current initial treatment relies on whether the patient is a transplant candidate or not.Our first patient showed a good response to treatment. However the second patient had primary refractory disease. Given his young age more intensive chemotherapy like VDT-PACE is a good choice If necessary, should be followed by a autologous transplantation or even allogenic transplantation and/ or involving CAR T- cell therapy.A better understanding of how myeloma cells grow and thrive, as well as the biology of extramedullary tumors, is needed in order to develop better strategies for the treatment of EMM in future. DisclosuresNo relevant conflicts of interest to declare.