Extramedullary Myeloma Research Articles

PULMONARY PARENCHYMAL AND PLEURAL INVOLVEMENT BY MULTIPLE MYELOMA

TOPIC: Disorders of the Pleura TYPE: Fellow Case Reports INTRODUCTION: Extramedullary multiple myeloma (EMM) is an uncommon complication that presents in only 7% of patients with multiple myeloma. Common sites of involvement include the gastrointestinal and central nervous system. Pulmonary infiltration is very rarely seen, accounting for less than 1% of patients with multiple myeloma and is indicative of poor overall short-term survival. Here we present a case of pulmonary multiple myeloma with parenchymal as well as pleural involvement diagnosed via cytology and flow cytometry. CASE PRESENTATION: A 71-year-old female with multiple myeloma presented to oncology clinic noting progressive dyspnea, 15lb weight loss, and night sweats in the preceding month. She was admitted to our hospital where CT of her chest demonstrated diffuse ground glass opacities with central predominance and associated septal thickening, a moderate-sized right pleural effusion, and innumerable lytic lesions. She underwent diagnostic and therapeutic thoracentesis which was exudative with 67% lymphocytosis. Pleural fluid cytology was positive for malignant cells associated with IgG lambda-restricted multiple myeloma, and flow cytometry demonstrated a 48% population of plasmacytoid cells. Bronchoscopy ruled out opportunistic infection and alveolar lavage had only a few nucleated cells with a normal differential. Cytology showed rare malignant cells suspicious for involvement by multiple myeloma. Our patient expired approximately 1 month after this diagnosis despite rapid initiation of chemotherapy. DISCUSSION: Most commonly seen thoracic abnormalities with myeloma are osteolytic lesions, plasmacytomas, and pulmonary infiltrates as a result of infection. Infiltration of plasma cells within the parenchyma or pleural space is rarely seen and considered a poor prognostic factor. In one study of 958 patients with multiple myeloma seen within the thorax, parenchymal myelomatous infiltration and myelomatous effusions were noted in only 24 and 8 patients, respectively. Our patient with advanced disease presented with both parenchymal and pleural infiltration by plasma cells which was readily diagnosed via pleural fluid analysis and alveolar lavage using cytology and flow cytometry. In other instances, diagnosis may be more challenging and require either pleural biopsy or VATS if clinical suspicion remains despite non-diagnostic work-up. CONCLUSIONS: Diffuse pulmonary opacities and pleural effusions due to myelomatous infiltration can be diagnosed via analysis of pleural & alveolar lavage samples using cytology and flow cytometry. This is unfortunately associated with rapid progression and poor overall survival, even despite institution of therapy. REFERENCE #1: Lok R, Golovyan D, Smith J. Multiple myeloma causing interstitial pulmonary infiltrates and soft-tissue plasmacytoma. Respir Med Case Rep. 2018;24:155-157. REFERENCE #2: Kim YJ, Kim SJ, Min K, et al. Multiple myeloma with myelomatous pleural effusion: a case report and review of the literature. Acta Haematol. 2008;120(2):108-111. REFERENCE #3: Kintzer JS, Rosenow EC, Kyle RA. Thoracic and pulmonary abnormalities in multiple myeloma. A review of 958 cases. Arch Intern Med. 1978;138(5):727-730. DISCLOSURES: No relevant relationships by Brandon Jakubowski, source=Web Response Scientific Medical Advisor relationship with Boehringer Ingelheim Please note: May 2021 (one time) Added 04/20/2021 by Corey Kershaw, source=Web Response, value=Consulting fee No relevant relationships by Margaret Kypreos, source=Web Response

P-105: Mass spectrometry and artificial neural networks for discrimination of extramedullary Multiple Myeloma

<h3>Background</h3> Multiple myeloma (MM) is the second most common hematological malignancy of the elderly. The bone marrow is infiltrated by malignant plasma cells. MM may progress into so-called extramedullary disease (EMD). EMD occurs when a subclone of clonal plasma cells migrates out of the bone marrow and infiltrates soft tissues. <h3>Aims</h3> We focused on the analysis of low molecular weight molecules in peripheral blood of 20 MM and 20 EMD patients using MALDI-TOF mass spectrometry to create a diagnostic tool based on prediction by artificial neural network, which should distinguish different groups of diseases. <h3>Methods</h3> Matrix-Assisted Laser Desorption/Ionization Time-of Flight Mass Spectrometry (MALDI-TOF MS) has become an indispensable research tool, which is used for analysis of biomolecules and various organic molecules. Artificial Neural Networks (ANN) are components of artificial intelligence inspired by biological neural networks. Using ANN, we can model complex non-linear systems, as previously published. In our previous study, we recorded mass spectra of MM and healthy donor samples. ANN specifically predicted MM samples with high sensitivity, specificity and accuracy. <h3>Results</h3> The RStudio was used for statistical analysis, where the data were evaluated using Principal Component Analysis (PCA) and Partial least squares discriminant analysis (PSL-DA). Using MALDI-TOF MS, it was possible to distinguish between samples of MM patients and healthy donors, as well as MM and EMD patients. Informative patterns in mass spectra served as inputs for ANN that specifically distinguished between healthy donors and patients. <h3>Conclusion</h3> We demonstrated that using MALDI-TOF MS coupled with ANN is a useful tool that can distinguish between healthy donors and patients. Thus, it can be used as a fast alternative to conventional analyses. This study was supported by grants of the Ministry of Health of the Czech Republic, grant nr. NV18-08-00299, AZV 18-03-00203.

Treatment of extramedullary recurrent multiple myeloma with daretozumab in combination with the DECP regimen: a case report

Treatment of extramedullary recurrent multiple myeloma with daretozumab in combination with the DECP regimen: a case report

Whole-genome optical mapping of bone-marrow myeloma cells reveals association of extramedullary multiple myeloma with chromosome 1 abnormalities

Extramedullary disease (EMM) represents a rare, aggressive and mostly resistant phenotype of multiple myeloma (MM). EMM is frequently associated with high-risk cytogenetics, but their complex genomic architecture is largely unexplored. We used whole-genome optical mapping (Saphyr, Bionano Genomics) to analyse the genomic architecture of CD138+ cells isolated from bone-marrow aspirates from an unselected cohort of newly diagnosed patients with EMM (n = 4) and intramedullary MM (n = 7). Large intrachromosomal rearrangements (> 5 Mbp) within chromosome 1 were detected in all EMM samples. These rearrangements, predominantly deletions with/without inversions, encompassed hundreds of genes and led to changes in the gene copy number on large regions of chromosome 1. Compared with intramedullary MM, EMM was characterised by more deletions (size range of 500 bp–50 kbp) and fewer interchromosomal translocations, and two EMM samples had copy number loss in the 17p13 region. Widespread genomic heterogeneity and novel aberrations in the high-risk IGH/IGK/IGL, 8q24 and 13q14 regions were detected in individual patients but were not specific to EMM/MM. Our pilot study revealed an association of chromosome 1 abnormalities in bone marrow myeloma cells with extramedullary progression. Optical mapping showed the potential for refining the complex genomic architecture in MM and its phenotypes.

Multiple Extramedullary-Bone Related and/or Extramedullary Extraosseous Are Independent Poor Prognostic Factors in Patients With Newly Diagnosed Multiple Myeloma.

BackgroundExtramedullary (EM) lesions are common in multiple myeloma (MM) and are often related to the poor prognosis of MM but are scarcely understood.MethodsIn this retrospective study, the baseline characteristics of 357 newly diagnosed patients with extramedullary multiple myeloma (EMM) and their impact on the prognosis were analyzed. All patients received first-line treatment with bortezomib-based regimen.ResultsThe overall incidence rate of EM was 22.4%, and the detection rate of PET/CT was significantly higher than other imaging methods (P = 0.015). The cohorts consisted of 10 cases of extramedullary extraosseous (EME) and 70 cases of extramedullary-bone related (EMB), including 53 cases with single site involvement (one case with EME) and 27 cases with multiple sites (>1 site) involvement (nine cases with EME). EMM patients had high levels of hemoglobin (Hgb, ≥10 g/dl) and serum lactate dehydrogenase (LDH, >245u/L) and are inclined to early-stage revised international staging system (R-ISS). Compared to patients without EM, those with EMM had worse progression-free survival (PFS) (P = 0.014) and overall survival (OS) (P = 0.032). In addition, patients without EM and those with a single site of EMB had similar PFS and OS, while patients with multiple sites of EMB or EME and multiple sites of EMB with EME had poor PFS and OS. Multivariate analysis confirmed that multiple sites of EMB and/or EME were independent prognostic predictors affecting PFS and OS in newly diagnosed MM patients.ConclusionsThis study suggested that among patients treated with bortezomib-based regimens, multiple sites of EMB and/or EME are independent poor prognostic factors for newly diagnosed MM patients, while a single site of EMB does not affect the survival of newly diagnosed MM patients. Thus, these findings could be used as a reference for the study of EMM patients in the new drug era, but prospective clinical studies are needed to provide evidence-based data for the diagnosis and treatment of EMM.

Incidence and Survival Outcomes Of Extramedullary Myeloma

BackgroundThe survival of patients with multiple myeloma (MM) has considerably improved during the last decade. MM at presentation is mostly limited to the bone marrow, with circulating plasma cells seen in a modest proportion of patients. Organ infiltration or soft tissue involvement by the tumor cells is relatively uncommon at diagnosis; however, several recent reports suggest an increasing number of patients presenting with extramedullary disease at the time of relapse. This could be related to several aspects, especially increased use of more sensitive imaging studies and the newer therapies. We undertook the current study to examine the changes in incidence and potential predisposing causes for development of clinically detected EMD. Patients and MethodsWe retrospectively examined the cohort of 1,051 patients with newly diagnosed MM seen at Mayo Clinic between Jan 2001 and Dec 2010, for their initial evaluation and treatment. Data regarding baseline characteristics, site of EMD, types of therapy and response were extracted from medical records. EMD was defined as a plasmacytoma outside the bone and not contiguous to any bone lesion. Cox proportional hazards model was used to estimate the effect of variables on development of EMD. ResultsThe median age at the diagnosis of MM was 66 years (range, 22-93) with 19% >75 years; 59% were male. The median estimated follow up for the entire cohort was 5.9 years, 492 (47%) were alive at the time of analysis. Over 4139 person years of follow up, 93 patients had an EMD detected (9%), including 32 patients (2.5%) in whom it was found at diagnosis. The median time to detection of EMD among the 61 patients in whom EMD developed after diagnosis, was 26 months (1 mo -10 yrs). The cumulative risk of developing EMD is shown in figure 1A and does not appear to be different between patients seen earlier (2001-2005) vs. (2006-2010), at least during the initial years. The most common sites were skin and soft tissue, lymph nodes, liver/ spleen and pleura/ peritoneum. Twelve patients had a second EMD diagnosed at a median of 5 months from the first EMD. The median OS from diagnosis of MM for the 93 patients with EMD was 3.3 years vs. 5.3 years for the rest; p<0.01. Examining the risk factors associated with development of EMD, an LDH>221 (ULN), PCLI >=3%, bone marrow plasma cell%, presence of high risk FISH abnormalities (Del 17p, t(14;16) and t (14;20) and use of SCT as part of therapy were risk factors for development of EMD. Only, a PCLI >=3 and presence of high-risk FISH increased the risk of developing EMD. [Display omitted] ConclusionExtramedullary disease in multiple myeloma, both present at diagnosis and upon relapse, is associated with poor prognosis. While there is no clear evidence of recent increase in EMD, extended follow-up of patients seen in the recent years may alter that conclusion. Patients presenting with EMD clearly appear to have higher risk disease with more proliferative cells and high-risk cytogenetic abnormalities. Disclosures:No relevant conflicts of interest to declare.

Intratumor Heterogeneity of MIF Expression Correlates With Extramedullary Involvement of Multiple Myeloma.

Macrophage migration inhibitory factor (MIF) has been shown to promote disease progression in many malignancies, including multiple myeloma (MM). We previously reported that MIF regulates MM bone marrow homing and knockdown of MIF favors the extramedullary myeloma formation in mice. Here, based on MIF immunostaining of myeloma cells in paired intramedullary and extramedullary biopsies from 17 patients, we found lower MIF intensity in extramedullary MM (EMM) versus intramedullary MM (IMM). Flow cytometry and histology analysis in xenograft models showed a portion of inoculated human MM cells lost their MIF expression (MIFLow) in vivo. Of note, IMM had dominantly MIFHigh cells, while EMM showed a significantly increased ratio of MIFLow cells. Furthermore, we harvested the extramedullary human MM cells from a mouse and generated single-cell transcriptomic data. The developmental trajectories of MM cells from the MIFHigh to MIFLow state were indicated. The MIFHigh cells featured higher proliferation. The MIFLow ones were more quiescent and harbored abundant ribosomal protein genes. Our findings identified in vivo differential regulation of MIF expression in MM and suggested a potential pathogenic role of MIF in the extramedullary spread of disease.

MET-PET and NGS Targeted Sequencing Guides Precision Medicine in a CNS Relapsed MM Patient

IntroductionCentral nervous system (CNS) involvement is an extremely rare manifestation of extramedullary multiple myeloma (MM), diagnosed in less than 1% of MM patients (pts). It is considered an ultimate high-risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases.CaseAn 81y old male pt. with κ light chain MM on serum and urine, osteolytic lesions and bone marrow involvement in 2015, was referred to our institution. He presented with a CNS MM relapse in June 2017 after prior successful 1st line Bortezomib-based treatment. Cranial MRI confirmed multiple supra- und infratentoral lesions infiltrating the brain. His cerebrospinal fluid (CSF) demonstrated a high load of clonal plasma cells (PMCs) and κ free light chains (FLC), however, the disease was largely absent within the bone marrow of the patient.The use of positron emission tomography (PET) with 18F-2‘-deoxy-2‘-fluorodeoxyglucose (FDG) in MM has been strengthened by the recent publication of the updated imaging guidelines by the IMWG (Cavo et al., Lancet Oncol, 2017). Standard FDG based CNS imaging resolution, however, is impacted by the increased baseline glucose metabolism background of the brain. Therefore, we used radiolabeled 11C-methionine (MET) - that we recently identified as a sensitive imaging tracer in MM and in fact, high metabolic activity could be detected supra- and infratentorial as well as in the right femur and the clivus (Lapa et al., Theranostics, 2016).The pt. received 3 courses of an intrathecal triple therapy (Cytarabin, MTX, Dexamethasone) leading to a significant reduction of PMC-burden in the CSF. In addition, age adjusted systemic Thiotepa/Cytarabin-based therapy was applied, but had to be discontinued after one course of treatment as grade 4 neutropenia occurred with life-threatening septicemia.In parallel, we analyzed CD138+ cells obtained from BM and the CFS using customized next generation targeted sequencing (Ion torrent platform). The M3P (v 3.0) gene selection includes most commonly mutated MM genes, actionable drug targets and genes being associated with drug resistance. Average sequencing depth increased 700X and spatial MM heterogeneity was detected, as the CFS cells harbored a clonal BRAFV600E mutation, which was absent in the germline control and the bone marrow based CD138+ cells.We have initiated targeted therapy using the combination of Dabrafenib/Trametinib, known to be effective in BRAFV600E mutant melanoma brain metastases (Davies MA et al., Lancet Oncol, 2017); responses will be followed by combined cMRI and MET-PET imaging and results will be displayed at the meeting.Conclusion:This is an example of spatial genomic heterogeneity in MM and the first report of a patient with an isolated brain based BRAFV600E mutated MM tumor. This patient with otherwise very limited perspective leverages from innovative diagnostics including MET PET and targeted genome sequencing, demonstrating their clinical utility as they provide the basis for precision medicine concepts to be applied in this MM patient. [Display omitted] DisclosuresStewart:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Consultancy.

Clinical Outcomes of Extramedullary Multiple Myeloma in the Era of Novel Agents

Introduction: Extramedullary multiple myeloma (EMM) is defined as presence of plasma cell infiltration outside of the bone marrow. EMM is predictive of adverse prognosis and should be treated as high-risk multiple myeloma (MM). Optimal treatment strategy is not well defined due to lack of prospective therapeutic studies in this patient population.Methods: We performed a single-center, retrospective chart review of patients with EMM with soft tissue involvement at the time of initial diagnosis with MM.Results: Patients with soft tissue EMM diagnosed between 2015-2016 were identified (n=10). The median age of patients was 62.4 years. Seventy percent of patients were males. Eighty percent of patients had standard risk, and 20% had high-risk chromosomal abnormalities by FISH, defined as the presence of 17p deletion, t(4;14), t(14;16), or t(14;20). Of note, 80% of the patients (8/10) were found to have chromosome 1 abnormalities. Gain of 1q was seen in 50% of patients; the rest were found to harbor gain of 1p, t(1:1), and t(1q21). Based on ISS staging, 10% of patients had stage I, 40% stage II, and 50% stage III disease. Paraspinal, mediastinal and retroperitoneal soft tissue involvement were the most common sites of EMM, followed by liver, cutaneous and pulmonary sites. Half of the patients had more than 3 sites of EMM. Median time of follow-up was 12.5 months.All patients had received initial induction therapy with triplet combination regimen: 50% were treated with bortezomib/lenalidomide/dexamethasone (VRD), and 50% with cyclophosphamide/bortezomib/dexamethasone (CyBorD). Patients had received a median 4 lines of therapy. Among the patients reviewed, none achieved CR, 60% achieved VGPR and 40% achieved only PR as best response to therapy after the course of induction. Thus, overall response rate with front line triplet induction was 100%, but the responses were extremely short-lived. With the median follow-up of 12.5 months, 80% of patients developed rapid progression of disease (PD), with median PFS of 6 months. At a median follow-up of 12.5 months OS was only 50% (5/10).Five patients received daratumumab-based combination during the course of progression of disease (PD). Median PFS while on daratumumab-containing regimen was 3 months. All patients were deemed potentially transplant-eligible at diagnosis and 40% of them were transplanted. However 60% of patients were unable to move forward with autologous SCT due to rapid and aggressive PD.Conclusions: Our results indicate that the presence of soft tissue EMM at the time of diagnosis portends an exceedingly poor prognosis, short duration of PFS and a very limited OS even in the era of novel therapies. Despite the advent of monoclonal antibodies, the prognosis remains grim in this sub-group. There may be an association between chromosome 1 abnormalities and soft tissue EMM. Further research efforts are required to define optimal therapeutic regimen for this subset of myeloma patients. DisclosuresNo relevant conflicts of interest to declare.

Extramedullary multiple myeloma patient-derived orthotopic xenograft with a highly altered genome: combined molecular and therapeutic studies.

ABSTRACTExtramedullary multiple myeloma (EMM) has an overall survival of 6 months and occurs in 20% of multiple myeloma (MM) patients. Genetic and epigenetic mechanisms involved in EMM and the therapeutic role of new agents for MM are not well established. Besides, well-characterized preclinical models for EMM are not available. Herein, a patient-derived orthotopic xenograft (PDOX) was generated from a patient with an aggressive EMM to study in-depth genetic and epigenetic events, and drug responses related to extramedullary disease. A fresh punch of an extramedullary cutaneous lesion was orthotopically implanted in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ(NSG) mouse. The PDOX mimicked histologic and phenotypic features of the tumor of the patient. Cytogenetic studies revealed a hyperploid genome with multiple genetic poor-prognosis alterations. Copy number alterations (CNAs) were detected in all chromosomes. The IGH translocation t(14;16)(q32;q23)IGH/MAF was already observed at the medullary stage and a new one, t(10;14)(p?11-12;q32), was observed only with extramedullary disease and could be eventually related to EMM progression in this case. Exome sequencing showed 24 high impact single nucleotide variants and 180 indels. From the genes involved, only TP53 was previously described as a driver in MM. A rather balanced proportion of hyper/hypomethylated sites different to previously reported widespread hypomethylation in MM was also observed. Treatment with lenalidomide, dexamethasone and carfilzomib showed a tumor weight reduction of 90% versus non-treated tumors, whereas treatment with the anti-CD38 antibody daratumumab showed a reduction of 46%. The generation of PDOX from a small EMM biopsy allowed us to investigate in depth the molecular events associated with extramedullary disease in combination with drug testing.

KD-PACE Salvage Therapy for Aggressive Relapsed Refractory Multiple Myeloma, Plasma Cell Leukemia and Extramedullary Myeloma

BackgroundPatients with advanced/aggressive multiple myeloma have limited treatment options to achieve rapid disease control. In eligible patients, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide is often used. However, many patients are refractory to or have toxicities from bortezomib and there is a need for bridging therapy. We have used a modified regimen incorporating the second-generation proteasome inhibitor carfilzomib (carfilzomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide [KD-PACE]) instead of bortezomib for relapsed/refractory multiple myeloma. Patients and MethodsThis 2-center retrospective study included consecutive patients receiving KD-PACE for relapsed or refractory multiple myeloma, plasma cell leukemia, or extramedullary myeloma. The primary outcome was the feasibility of KD-PACE as a bridging therapy to a more definitive treatment option. ResultsFifty-two patients were included. The median age was 57 years, and 67% were male. Thirty-one patients were bridged with KD-PACE to autologous hematopoietic stem cell transplant (29%), allogenic hematopoietic stem cell transplant (27%), or a clinical trial (12%). Patients bridged to autologous hematopoietic stem cell transplant, allogenic hematopoietic stem cell transplant, or a clinical trial had a superior progression-free survival (8.3 months vs 2.3 months in the nonbridged group; P < .001) and overall survival (median, 16.7 months vs 4.3 months in the nonbridged group; P < .001). No unexpected toxicities occurred from the treatment regimen. ConclusionKD-PACE is a promising treatment option for select patients with advanced/aggressive forms of myeloma requiring rapid disease control before a more definitive salvage therapy such as auto/allotransplantation or a clinical trial.

Immature Plasma Cell Myeloma Mimics Metastatic Renal Cell Carcinoma on 18F-PSMA-1007 PET/CT Due to Endothelial PSMA-Expression.

We present a 71-year-old female patient who underwent 18F-PSMA-1007 PET/CT for suspected metastatic renal cell carcinoma (RCC), as RCC also shows high PSMA-expression in tumor neovascularization. 18F-PSMA-1007 PET/CT showed a high PSMA-avidity in the renal tumor, enlarged intra-abdominal and mediastinal lymph nodes. Moreover, PSMA-positive pleural, pulmonal and osseous lesions were found. However, histopathology revealed an immature plasma cell myeloma with an endothelial PSMA-expression of the neovasculature. This case illustrates the increased PSMA-avidity in multiple myeloma and highlights PSMA as a potential theragnostic target in multiple myeloma. For clinical routine, lymphatic diseases such as extramedullary myeloma should be considered as differential diagnosis in PSMA-avid renal masses on PET/CT.

Treatment of two cases of extramedullary infiltration multiple myeloma with BCMA CAR-T cells

Treatment of two cases of extramedullary infiltration multiple myeloma with BCMA CAR-T cells

Elotuzumab for the treatment of extramedullary myeloma: a retrospective analysis of clinical efficacy and SLAMF7 expression patterns

Extramedullary disease (EMD) represents a high-risk state of multiple myeloma (MM) associated with poor prognosis. While most anti-myeloma therapeutics demonstrate limited efficacy in this setting, some studies exploring the utility of chimeric antigen receptor (CAR)-modified T cells reported promising results. We have recently designed SLAMF7-directed CAR T cells for the treatment of MM. SLAMF7 is a transmembrane receptor expressed on myeloma cells that plays a role in myeloma cell homing to the bone marrow. Currently, the only approved anti-SLAMF7 therapeutic is the monoclonal antibody elotuzumab, but its efficacy in EMD has not been investigated thoroughly. Thus, we retrospectively analyzed the efficacy of elotuzumab-based combination therapy in a cohort of 15 patients with EMD. Moreover, since the presence of the target antigen is an indispensable prerequisite for effective targeted therapy, we investigated the SLAMF7 expression on extramedullary located tumor cells before and after treatment. We observed limited efficacy of elotuzumab-based combination therapies, with an overall response rate of 40% and a progression-free and overall survival of 3.8 and 12.9 months, respectively. Before treatment initiation, all available EMD tissue specimens (n = 3) demonstrated a strong and consistent SLAMF7 surface expression by immunohistochemistry. Furthermore, to investigate a potential antigen reduction under therapeutic selection pressure, we analyzed samples of de novo EMD (n = 3) outgrown during elotuzumab treatment. Again, immunohistochemistry documented strong and consistent SLAMF7 expression in all samples. In aggregate, our data point towards a retained expression of SLAMF7 in EMD and encourage the development of more potent SLAMF7-directed immunotherapies, such as CAR T cells.

A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma

AbstractB-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies have shown efficacy in relapsed/refractory multiple myeloma (RRMM). Because the non-human originated antigen-targeting domain may limit clinical efficacy, we developed a fully human BCMA-specific CAR, CT103A, and report its safety and efficacy in a phase 1 trial. Eighteen consecutive patients with RRMM, including 4 with prior murine BCMA CAR exposures, were enrolled. CT103A was administered at 1, 3, and 6 × 106 CAR-positive T cells/kg in the dose-escalation phase, and 1 × 106 CAR-positive T cells/kg in the expansion cohort. The overall response rate was 100%, with 72.2% of the patients achieving complete response or stringent complete response. For the 4 murine BCMA CAR–exposed patients, 3 achieved stringent complete response, and 1 achieved a very good partial response. At 1 year, the progression-free survival rate was 58.3% for all cohorts and 79.1% for the patients without extramedullary myeloma. Hematologic toxicities were the most common adverse events; 70.6% of the patients experienced grade 1 or 2 cytokine release syndromes. No immune effector cell–associated neurotoxicity syndrome was observed. To the cutoff date, CAR transgenes were detectable in 77.8% of the patients. The median CAR transgene persistence was 307.5 days. Only 1 patient was positive for the anti-drug antibody. Altogether, CT103A is safe and highly active in patients with RRMM and can be developed as a promising therapy for RRMM. Patients who relapsed from prior murine BCMA CAR T-cell therapy may still benefit from CT103A. This trial was registered at http://www.chictr.org.cn as #ChiCTR1800018137.

Research progress on treatment of extramedullary multiple myeloma

ABSTRACT Objectives: Extramedullary multiple myeloma (EMM) is a relatively less frequent subentity of multiple myeloma (MM) and is generally considered to be a poor prognostic factor. Novel agents and hematopoietic stem cell transplantation (HSCT) have led to a significant improvement in the progression-free survival and overall survival of patients with MM, but outcomes of EMM remain dismal. Little is known regarding the role of novel therapies in this setting. This review summarizes the current available data regarding the roles of proteasome inhibitors, immunomodulators, monoclonal antibodies, chimeric antigen receptor (CAR)-T cell therapy and HSCT in EMM. Methods: A systematic literature review through PubMed was conducted to summarize the published evidence on the therapeutic developments of novel agents and HSCT in EMM. Literature sources published in English were searched, using the terms multiple myeloma, extramedullary and treatment. Results: Long-term outcomes of EMM patients remain dismal despite the utilization of novel agents and HSCT. The standard therapy of EMM has not been established. EMM should be managed as high-risk disease and treated accordingly. Discussion and conclusion: This review will provide an insight on the current and emerging treatment strategies as well as their efficacy in EMM. Further subgroup analyses in large prospective trials focusing on EMM is needed to help optimize the therapy.

Clinical features of the disease course in patients with solitary plasmacytoma and extramedullary multiple myeloma

Objective: to study the clinical laboratory features of the course of solitary plasmacytoma (SP) and extramedullary multiple myeloma (EMM).Material and methods. The study included 42 people (22 patients newly diagnosed with EMM and 20 patients diagnosed with SP of various localization). The results were evaluated after 3 years of the study. The median age in the SP group was 61.5 years, in the EMM group — 65 years.Results. A comparative analysis of the SP and EMM groups in terms of the clinical and laboratory parameters has found no statistical differences in the distribution of immunochemical variants. Significant differences were found in the frequency of determination of the abnormal ratio of immunoglobulin light chains (p = 0.046).In EMM, extramedullary lesions were the most common for patients with multiple lytic bone lesions of the skeleton. SP was the most frequently detected in lesions of the peripheral skeletal bones and vertebral bodies.Clinically, EMM was characterized by a more aggressive course if additional factors of an unfavorable prognosis (translocations, mutations) or unfavorable immunophenotypic markers (a combination of signs — expression of markers CD56 &gt; 20 % and CD95 &lt; 20 %) were identified or if the disease had been diagnosed at a young age.The presence of even a minimal number of tumor or aberrant plasma cells in the bone marrow of SP patients, an abnormal ratio of immunoglobulin light chains, paraprotein detected in blood serum or urine were all poor prognostic factors.Conclusion. The clinical course of SP and EMM combined with a young age, the presence of translocations or mutations, unfavorable immunophenotypic markers, is characterized by an increased frequency of progression or the development of resistance to the performed therapy.

Daratumumab efficacy in extramedullary orbital myeloma.

Daratumumab is very efficacious in multiple myeloma. Few reports are present about efficacy in extramedullary myeloma. We report here daratumumab efficacy in extramedullary ocular myeloma in a young 46‐year‐old man diagnosed 3 years earlier and relapse refractory to five previous lines of therapy.

S2095 Gastric Extramedullary Plasmacytoma Presenting as a Solitary Gastric Mass

INTRODUCTION: Extramedullary plasmacytomas (EMP) are a subcategory of plasma cell neoplasm that involves organs outside the bone marrow. We report a case of an aggressive extramedullary myeloma invading the stomach. CASE DESCRIPTION/METHODS: An 84 year old lady with PMHx of DM, hypothyroidism, HTN and GERD presented to the ED with abdominal pain, nausea and vomiting for 2 days. Patient was found to be anemic with Hgb of 10.7 g/dL, hematocrit 32.4%. Patient’s electrolytes and renal function tests were within normal limits. Imaging (US) of the abdomen showed gallbladder calculus with positive murphy’s sign and no pericholecystic fluid. A CT scan of the abdomen and pelvis showed a large hiatal hernia with suspicion of cholelithiasis. A HIDA scan showed no evidence of cystic duct obstruction or distal biliary obstruction. After cholecystitis was ruled out GI was consulted and a EGD was planned for intractable abdominal pain with intermittent vomiting. During the EGD findings [Figure 1] were noted for a 4 cm non-bleeding, non-ulcerated mass on a very large stalk that appeared to be blocking the pylorus. The pylorus was normal appearing once past the mass. The polyp was partially resected. A small polyp was resected but the larger polyp was not able to be removed due to getting stuck at the cricopharyngeus so it remained in the stomach. Biopsy findings were noted predominantly of well-differentiated plasma cells with some of the cells extending to the mucosa. The immunohistochemical stains were positive for CD138, CD 79 [Figure 2] and showed a low Ki-67 proliferation index of < 5%. The neoplastic cells were lambda light chain restricted [Figure 3]. Rare plasma cells are positive for kappa. They were negative for PAX5, CD20, CD56, c-KIT, cyclin D1 and pankeratin. CD3 highlights background T-cells. Based on the findings a plasmacytoma or secondary involvement by multiple myeloma was favored. DISCUSSION: Plasmacytoma can be primary or secondary with secondary form more common. The most commonly involved sites are the liver, spleen, and lymph nodes. The prevalence of GI system involvement was found to be 0.9% in a recent systematic review done with 2,584 Multiple myeloma (MM) patients. This is associated with a poor survival of less than seven months from diagnosis. [1] Favorable outcomes in cases of EMP have been linked to tumor size < 4 cm, age < 50 years, patients with head and neck EMP, and serum M protein negativity. [2]. We have described a rare case of gastric plasmacytoma without symptoms of MM.Figure 1.: EGD finding of a mass obstructing the pylorus, injected with epinephrine and clamped before excision.Figure 2.: Cells stained with CD79A.Figure 3.: Monoclonal population lambda +.

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

Purpose 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. Experimental design 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. Results 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. Conclusions 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.