Extramedullary Multiple Myeloma Research Articles

Multiple Myeloma

The second most common hematologic malignancy is the clonal proliferation of neoplastic plasma cells within the bone marrow. There is the presence of monoclonal immunoglobulins in the serum and/or urine. This results in anemia, myelosuppression, bone destruction, and clinical consequences of para-proteinemia on kidney function and other organ systems. The disease manifests through the acronym CRAB (hypercalcemia, renal impairment, anemia, and bone lesions). Less frequent manifestations of multiple myeloma are of extramedullary localizations. Myeloma cells can become independent of the bone marrow microenvironment, circulate freely in the blood, and infiltrate organs. This results in a high-risk state characterized by increased proliferation, evasion of apoptosis, and treatment resistance. It can affect any area of tissue. Most commonly it involves the pleura, lymph nodes, chest wall, liver, skin/soft tissue, lungs, CNS, genitourinary system, breast and pancreas. In patients with confirmed multiple myeloma, the diagnosis of extramedullary involvement is typically established by the presence of pathological soft tissue masses using radiological methods such as computed tomography (CT) scan, positron emission tomography/CT (PET/CT), magnetic resonance imaging (MRI), or ultrasound, along with biopsy or physical examination. The molecular mechanisms underlying the development of extramedullary multiple myeloma (EMM) have not been fully defined. Various cytogenetic abnormalities are observed, and some studies have generated genomic sequencing profiles that distinguish EMM from classic multiple myeloma. While plasma cell leukemia (PCL) and central nervous system (CNS) EMM indicate a poor prognosis, outcomes for other manifestations can be highly heterogeneous. Sensitive imaging modalities including PET/CT and MRI (Fig.1) are integral components of diagnosis and response assessment. Patients with extramedullary multiple myeloma (EMM) have a clear survival disadvantage.

Successful Treatment of Refractory Orbital Plasmacytoma with Chimeric Antigen Receptor T Cell Therapy: A Case Report and Review of the Literature.

Orbital plasmacytoma is a rare plasma cell tumor that may arise as an aggressive form of extramedullary multiple myeloma. Treatment modalities include surgical excision, radiation, and chemotherapy. Chimeric antigen receptor T cell therapy is currently reserved for refractory disease. The authors present a case of a 69-year-old woman with an extensive orbital plasmacytoma refractory to multimodal therapy who was treated with idecabtagene vicleucel chimeric antigen receptor T cell therapy. Four days after infusion, the patient exhibited grade 1 cytokine release syndrome, which resolved with tocilizumab. The orbital plasmacytoma significantly decreased in size 1 month after treatment and demonstrated complete serological response and sustained tumor burden reduction at 10-month follow-up. This case highlights the efficacy of chimeric antigen receptor T cell therapy for refractory orbital plasmacytoma and calls attention to potential inflammatory toxicities.

Beyond the marrow: insights from comprehensive next-generation sequencing of extramedullary multiple myeloma tumors

Extramedullary multiple myeloma (EMM) is an aggressive form of multiple myeloma (MM). This study represents the most comprehensive next-generation sequencing analysis of EMM tumors (N = 14) to date, uncovering key molecular features and describing the tumor microenvironment. We observed the co-occurrence of 1q21 gain/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting that these are crucial mutational events in EMM development. We also demonstrated that patients with mutated KRAS and 1q21 gain/amplification at the time of diagnosis have a significantly higher risk of EMM development (HR = 2.4, p = 0.011) using data from a large CoMMpass dataset. We identified downregulation of CXCR4 and enhanced cell proliferation, along with reduced expression of therapeutic targets (CD38, SLAMF7, GPRC5D, FCRH5), potentially explaining diminished efficacy of immunotherapy. Conversely, we identified significantly upregulated EZH2 and CD70 as potential future therapeutic options. For the first time, we report on the tumor microenvironment of EMM, revealing CD8+ T cells and NK cells as predominant immune effector cells using single-cell sequencing. Finally, this is the first longitudinal study in EMM revealing the molecular changes from the time of diagnosis to EMM relapse.

Primary multifocal extramedullary multiple myeloma with a rare cytogentic abnormality

Primary multifocal extramedullary multiple myeloma with a rare cytogentic abnormality

Doxorubicin-loaded PEG-CdTe QDs conjugated with anti-CXCR4 mAbs: a novel delivery system for extramedullary multiple myeloma treatment

Extramedullary multiple myeloma (EMM) is defined as the presence of plasma cells outside the bone marrow of multiple myeloma patients, and its prognosis is poor. High-dose chemotherapy with autologous stem cell transplantation, as a good option on early lines of therapy, has retained the survival benefit of youny EMM patients, but is intolerant for the majority of old patients because of drug cytotoxicity. To essentially address the intolerance above, we designed a CXCR4-PEG-CdTe-DOX (where CXCR4: chemokine receptor 4; PEG-CdTe: polyethylene glycol-modified cadmium telluride; DOX:doxorubicin) nanoplatform. First, CXCR4 is highly expressed in extramedullary plasma cells. Second, PEG-CdTe a drug carrier that controls drug release, can reduce adverse reactions, prolong drug (e.g, DOX) circulation time in the body, and form a targeting carrier after connecting antibodies. In vitro experiments showed CXCR4-PEG-CdTe-DOX facilitated intracellular drug accumulation through active CXCR4 targeting and released DOX into the microenvironment in a pH-controlled manner, enhancing the therapeutic efficacy and apoptosis rate of myeloma cells (U266). Therefore, targeted chemotherapy mediated by CXCR4-PEG-CdTe-DOX is a promising option for EMM treatment.Graphical abstractFigure 1 Action mechanism of drug delivery pathway: CXCR4-PEG-CdTe-DOX nanocomplex can be targeted and close to MM cell membranes, effectively transport DOX into MM cells, and promote MM cell apoptosis.

Ophthalmoplegia Associated With Extramedullary Multiple Myeloma: Case Series From a Tertiary Cancer Center.

Multiple myeloma (MM) is a malignant disorder of plasma cells that results in tumor cells replacing the bone marrow. In extramedullary MM (EMM), however, tumor cells proliferate outside the bone marrow. EMM may produce ophthalmoplegia through direct invasion of the superior orbital fissure, cavernous sinus, and/or sphenoidal sinus. Several mechanisms have been proposed including cranial nerve palsies, direct infiltration of bone, extraocular muscle metastasis, myelomatous meningitis, and parenchymal or paraneoplastic effects. We retrospectively reviewed the medical records of 7 patients at MD Anderson Cancer Center who suffered from ophthalmoplegia secondary to extramedullary MM between 2019 and 2021. We collected information regarding the symptoms, signs, radiographic and laboratory findings, management, complications, and prognosis of these patients throughout their disease course. Skull base MRI revealed 4 patients with ophthalmoplegias secondary to superior orbital fissure invasion, 2 patients with ophthalmoplegias secondary to cavernous sinus invasion, and 1 patient with ophthalmoplegia secondary to sphenoid sinus invasion. This is a case series describing 7 patients with ophthalmoplegias secondary to EMM. Our article is unique because of the size of the included cohort, which is large when compared with most English language publications detailing such ophthalmoplegias.

Immune checkpoint receptors and their ligands on CD8 T cells and myeloma cells in extramedullary multiple myeloma

Immune checkpoint receptors and their ligands on CD8 T cells and myeloma cells in extramedullary multiple myeloma

Unicentric Retrospective Analysis of 130 Patients with Extramedullary Multiple Myeloma (EMM)

CONCLUSION Despite the development of new agents and the widespread use of hematopoietic cell transplantation (HCT), the prognosis of patients (pts) with multiple myeloma and extramedullary involvement (EMM) is rather unfavorable. Until now, there are no generally accepted standards for diagnosis and treatment of EMM. We performed a retrospective analysis of 130 pts with EMM treated at Klinikum Chemnitz between 2007 and 2022. Various demographic and clinical factors were recorded in a database and evaluated for their impact on response and survival. The data cut point was July 2022, and for follow-up a minimum of 3 months was required. One hundred and thirty pts (89 men, 41 women) with EMM at a median age of 68 years (range, 37-87 years) were included. In 78 pts extramedullary involvement was detected at the time of initial diagnosis (primary EMM), and in the remaining 52 pts a secondary EMM was diagnosed at the time of relapse (n=38) or refractory disease (n=14). In approximately two-thirds of pts EMM manifested exclusively in the paraskeleton (n=84), while roughly one-third of pts showed an extramedullary organ involvement (n=25), or both (n=21). Cytogenetic data were available in 125 pts, with 39 pts classified as high-risk EMM (including del17p in 11 pts). ISS could be evaluated in only 56 pts, of whom 22 pts had ISS III. Elevated serum LDH levels were observed in almost half of the pts (n=63) at the time of EMM diagnosis. Treatment regimens included mainly proteasome inhibitors (n=106), immunomodulatory drugs (n=74) and CD38 antibodies (n=42). Fifty-five pts (42.3%) received autologous (n=44), allogeneic (n=8) or autologous-allogeneic HCT (n=3). Serologic response to treatment (at least PR) according to IMWG criteria was 63.8% (83/130) and imaging response was 56.9% (74/130). With a median follow-up of 84.2 months, median progression-free survival was 10.3 months and median overall survival was 23.8 months. In univariate analysis for PFS and OS, we found significantly worse outcomes in patients with secondary EMM (vs. primary EMM), EMM with organ manifestation (vs. paraskeletal EMM only), ISS III (vs. ISS I +II), and elevated serum LDH (vs. not elevated). Furthermore, pts with del17p had significantly shorter PFS, while detection of ampl1q32 (n=14) was associated with significantly worse OS. For other tested factors [lambda light chain involvement, t(14;16), dupl1q21 or tripl1q21, EMM diagnosis 2007-2013 vs. 2014-2022] we found no negative effects on PFS or OS. Multivariate Cox regression analysis confirmed secondary EMM as an independent negative factor for PFS (HR 3.62, p<0.0001) and OS (HR 2.95, p<0.0001), whereas detection of del17p was only associated with unfavorable PFS (HR 2.02, p=0.03). Our data show that the prognosis of pts with EMM remains poor. Despite the introduction of many innovative agents, outcomes have not improved significantly since 2013. There is an urgent need for diagnostic/therapeutic guidelines of EMM as well as risk-adapted therapeutic strategies (using modern immunotherapies and cell therapies).

A novel two-step administration of XPO-1 inhibitor may enhance the effect of anti-BCMA CAR-T in relapsed/refractory extramedullary multiple myeloma

BackgroundExtramedullary disease usually implies a dismal outcome in relapsed/refractory multiple myeloma patients, and requires novel treatment approaches. We designed a trial using Selinexor, a nuclear export protein 1 inhibitor, together with anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell product CT103A to treat these patients, and describe the first two cases in this report.MethodsSelinexor was administered with a novel two-step schedule in bridging therapy and in maintenance. The clinical responses and adverse events were recorded after CAR-T infusion and Selinexor administration. In vitro analysis of the influence of Selinexor on CAR-T cell function was performed using myeloma cell lines.ResultsAfter infusion, both patients achieved stringent complete remission (sCR), and were maintained in sCR at data-cutoff, with survival over 13 and 10 months, respectively. Neither immune effector cell-associated neurotoxicity syndrome nor over grade 2 cytokine release syndrome was observed. Meanwhile, the patients showed good tolerance to the combination. In addition, we demonstrated that low dose of Selinexor could upregulate the expression of BCMA on plasma cell lines and subsequently enhance the function of CAR-T cell in vitro.ConclusionsThe combination of Selinexor and CT103A exerts preliminary synergistic effect, and can be developed as a promising strategy for relapsed/refractory extramedullary myeloma.

CD38 expression by plasma cells in extramedullary multiple myeloma.

Not available.

Massive gingival involvement due to extramedullary multiple myeloma progression

Massive gingival involvement due to extramedullary multiple myeloma progression

P-069 Liquid biopsy monitoring is more sensitive than alternative techniques in extramedullary multiple myeloma

P-069 Liquid biopsy monitoring is more sensitive than alternative techniques in extramedullary multiple myeloma

P-344 Multiomics profiling of extramedullary multiple myeloma tumors and their microenvironment

P-344 Multiomics profiling of extramedullary multiple myeloma tumors and their microenvironment

Proteomic and Metabolomic Analysis of Bone Marrow and Plasma from Patients with Extramedullary Multiple Myeloma Identifies Distinct Protein and Metabolite Signatures.

Multiple myeloma (MM) is an incurable haematological malignancy of plasma cells in the bone marrow. In rare cases, an aggressive form of MM called extramedullary multiple myeloma (EMM) develops, where myeloma cells enter the bloodstream and colonise distal organs or soft tissues. This variant is associated with refractoriness to conventional therapies and a short overall survival. The molecular mechanisms associated with EMM are not yet fully understood. Here, we analysed the proteome of bone marrow mononuclear cells and blood plasma from eight patients (one serial sample) with EMM and eight patients without extramedullary spread. The patients with EMM had a significantly reduced overall survival with a median survival of 19 months. Label-free mass spectrometry revealed 225 proteins with a significant differential abundance between bone marrow mononuclear cells (BMNCs) isolated from patients with MM and EMM. This plasma proteomics analysis identified 22 proteins with a significant differential abundance. Three proteins, namely vascular cell adhesion molecule 1 (VCAM1), pigment epithelium derived factor (PEDF), and hepatocyte growth factor activator (HGFA), were verified as the promising markers of EMM, with the combined protein panel showing excellent accuracy in distinguishing EMM patients from MM patients. Metabolomic analysis revealed a distinct metabolite signature in EMM patient plasma compared to MM patient plasma. The results provide much needed insight into the phenotypic profile of EMM and in identifying promising plasma-derived markers of EMM that may inform novel drug development strategies.

Genetic Abnormalities in Extramedullary Multiple Myeloma.

Extramedullary multiple myeloma (or extramedullary disease, EMD) is an aggressive form of multiple myeloma (MM) that occurs when malignant plasma cells become independent of the bone marrow microenvironment. This may occur alongside MM diagnosis or in later stages of relapse and confers an extremely poor prognosis. In the era of novel agents and anti-myeloma therapies, the incidence of EMD is increasing, making this a more prevalent and challenging cohort of patients. Therefore, understanding the underlying mechanisms of bone marrow escape and EMD driver events is increasingly urgent. The role of genomics in MM has been studied extensively; however, much less is known about the genetic background of EMD. Recently there has been an increased focus on driver events for the establishment of distant EMD sites. Generally, high-risk cytogenetic abnormalities and gene signatures are associated with EMD, alongside mutations in RAS signalling pathways. More recently, changes in epigenetic regulation have also been documented, specifically the hypermethylation of DNA promoter regions. Therefore, the focus of this review is to summarize and discuss what is currently known about the genetic background of EMD in MM.

Natural history, predictors of development of extramedullary disease, and treatment outcomes for patients with extramedullary multiple myeloma.

Extramedullary multiple myeloma (EMM) can present either at initial diagnosis (de novo) or at disease relapse (secondary) and confers an aggressive clinical course. Limited data exist for choosing the optimal therapy for EMM and this remains an area of unmet clinical need. After excluding paraskeletal multiple myeloma and primary plasma cell leukemia, we identified 204 (68%) patients with secondary EMM and 95 (32%) with de novo EMM between January 01, 2000 and 31 December, 2021. The median overall survival (OS) was 0.7 (95% CI: 0.6-0.9) years for secondary EMM and 3.6 (95%CI: 2.4-5.6) years for de novo EMM. The median progression-free survival (PFS) with initial therapy was 2.9 months (95% CI: 2.4-3.2 months) for secondary EMM and 12.9 months (95% CI: 6.7-18 months) for de novo EMM. Patients with secondary EMM treated with CAR-T therapy (n = 20) achieved a partial response (PR) or better in 75% with a median PFS of 4.9 months (3.1 months-not reached; NR). Patients with EMM treated with bispecific antibodies (n = 12) achieved a ≥ PR in 33%, with a median PFS of 2.9 months (95%CI: 2.2 months-NR). In a matched cohort, multivariate logistic regression analysis demonstrated younger age at diagnosis, 1q duplication, and t(4;14) at diagnosis of MM to be independent predictors of development of secondary EMM. Presence of EMM was independently associated with inferior OS in the matched cohorts for both de novo (HR 2.9 [95% CI: 1.6-5.4], p = .0007) and secondary EMM (HR 1.5 [95% CI: 1.1-2], p = .001).

Massive gingival involvement due to extramedullary multiple myeloma progression

Massive gingival involvement due to extramedullary multiple myeloma progression

Identification of evolutionary mechanisms of myelomatous effusion by single-cell RNA sequencing

AbstractMyelomatous effusion (ME) is a rare manifestation of extramedullary multiple myeloma (MM) with limited therapeutic options and poor outcomes. The molecular mechanisms underlying ME are incompletely understood. We profiled transcriptomes of bone marrow, peripheral blood (PB), and pleural effusion/ascites from 3 patients with ME using single-cell RNA sequencing analysis. We found that ME contained a higher percentage of cytotoxic T cells, whereas PB contained a higher proportion of naive T cells. Malignant cells varied within and between sites and patients in their expression of signatures. We identified a gene module highly expressed in intramedullary and extramedullary plasma cell clusters and defined cell clusters expressing this gene set as extramedullary-initiating cells (EMICs). This gene set was associated with increased cellular proliferation, involved in p53 signaling, and related to poor prognosis in MM. The transcriptional regulators E2F1, YY1, and SMAD1 were activated in EMICs. Leukocyte immunoglobulin–like receptor subfamily B4 (LILRB4) was upregulated in extramedullary EMICs. We confirmed that LILRB4 promoted MM cell migration in vitro. This study provided insight into the evolutionary mechanisms of ME and defined EMICs and LILRB4 associated with extramedullary development.

Treatment patterns for extramedullary multiple myeloma and outcomes with CAR-T therapy and bispecific antibodies.

8022 Background: Extramedullary Multiple Myeloma (EMM) is an aggressive entity with a dismal prognosis. Immune effector therapies (IETs), including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific T-cell engaging antibodies (BsAb), have demonstrated excellent efficacy in relapsed/refractory MM with limited data for efficacy in EMM. Here, we report the treatment outcomes for patients with EMM. Methods: We identified 299 patients with EMM diagnosed between 01/01/2000 and 12/31/2021 after excluding solitary plasmacytomas, paraskeletal MM and primary plasma cell leukemia. The IMWG criteria were used for response definition. Results: Of the 299 patients, 204 (68%) patients had secondary EMM (sEMM) and 95 (32%) patients had primary EMM (pEMM). For sEMM (n=204), the median progression free survival (PFS) with initial therapy was 2.9 (95% CI: 2.4-3.2) months. Initial treatment strategies for sEMM were heterogenous and demonstrated in the table; 44% patients achieved ≥partial response (PR) with initial treatment for sEMM. The median PFS in patients with ≥PR was 5.8 (95%CI: 4.5-6.9) months vs 1.8 (95%CI: 1.4-2; p <0.0001) months for <PR. For patients with pEMM (n=95), the median PFS was 12.9 (95% CI: 6.7-18) months; the median PFS was 17.4 (95%CI: 12.9-25.4) months for patients with ≥PR versus 1 month (95%CI: 0.8-2) in patients with <PR. Thirty patients (all sEMM and triple class refractory) were treated with IET after development of EMM: 18 with BCMA-directed CAR-T, 10 with BsAbs, and 2 with both CAR-T and BsAbs. In patients receiving CAR-T therapy, 75% (15/20) achieved ≥PR with 40% (n=8) achieving MRD negative (by flowcytometry) complete response. Fifteen (75%) patients receiving CAR-T had progressive disease (PD); 7 with systemic and EMM PD and 4 patients each with isolated EMM or systemic PD. The median PFS for patients treated with CAR-T was 4.9 months [3.1- not reached (NR)]. Among patients achieving a ≥PR with CAR-T, the median PFS was 5.8 (95%CI: 4.7-NR) months vs 1.4 months [(95%CI: 0.8-NR), p<0.001] for <PR. Among patients treated with BsAbs (10-BCMA, 1 each against FcRH5 and GPRC5D), 33% (4/12) achieved a ≥PR. Ten (83%) patients had PD on BsAb; 8 with both EMM and systemic PD and 1 patient each with isolated EMM or PD. The median PFS with BsAb was 2.9 months (95%CI: 2.2-NR). Conclusions: Patients with EMM continue to have dismal outcomes with conventional therapies. High response rates were noted with CAR-T therapy, but these tend to be short-lived. [Table: see text]

Clinical characteristics, markers of adverse prognosis, and predictors of development of extramedullary multiple myeloma.

8043 Background: Extramedullary Multiple Myeloma (EMM) has an aggressive clinical course and can present at diagnosis [primary EMM, (pEMM)] or relapse [secondary EMM, (sEMM)]. Here, we report clinical characteristics and outcomes of EMM, and predictive factors for the development of sEMM. Methods: We identified 299 patients with biopsy-proven EMM between 01/01/2000 and 12/31/2021. Patients with solitary plasmacytomas, paraskeletal MM and primary plasma cell leukemia were excluded. A 1:1 matched pair analysis (matched for year of diagnosis of MM for comparable follow-up and treatment eras) was performed to compare clinical characteristics and outcomes for patients with and without sEMM. Results: The median follow-up from the diagnosis of MM was 11.5 years (95%CI: 9.3-14.8). Of 299 patients, 204 (68%) patients had sEMM and 95 (32%) had pEMM, with largely comparable baseline characteristics (Table). The median overall survival (OS) from the diagnosis of sEMM was 0.7 (95% CI: 0.6-0.9) years compared to 3.6 (95%CI: 2.4-5.6) years for pEMM (p<0.0001). For sEMM, mutlvariable analysis (MVA) for OS identified visceral organ involvement (eg. liver, lung/pleura, brain, pancreas, etc.) to be associated with inferior OS [HR 1.6 (95% CI: 1.1-2.4), p=0.01]; high-risk cytogenetics (HR-CTG), ISS-3 stage, and age did not impact OS from sEMM. For pEMM, HR-CTG [HR 2.3 (95% CI 1.1 -4.8), p=0.03] and ISS-3 stage [HR 3.1 (95% CI 1.5-6.7), p=0.003] were associated with inferior OS on MVA whereas visceral EMM or age did not impact OS from pEMM. On univariate analysis, patients with sEMM were younger (median age 58.7 vs 61 years, p=0.006), had a higher proportion of 1q duplication (32% vs 17%, p=0.001), t(4;14) [16% vs 9%, p=0.047] and elevated LDH (30% vs 19%, p=0.04), compared to the matched cohort of patients without sEMM. On MVA, younger age at diagnosis, t(4;14) and 1q duplication at diagnosis of MM were independent predictors of development of sEMM. The median OS from diagnosis of MM was 5.4 years (95%CI: 4.1-6.2) for patients with sEMM versus 7.5 years (95% CI: 6.4-10.1; p <0.001) for the matched cohort. Secondary EMM was an independent poor prognostic marker for OS from the diagnosis of MM [HR 1.6 (95%CI: 1.2-2.1); p=0.004] in addition to age, ISS3 disease and HR-CTG. Conclusions: Outcomes of patients with EMM, especially sEMM, remain dismal. Patients with sEMM have higher rates of 1q duplication and t(4;14) at diagnosis of MM and carried an independent adverse prognosis in a matched cohort. [Table: see text]