Unusual painful pelvic masses: Extramedullary hematopoiesis with extramedullary multiple myeloma.

The coexistence of extramedullary hematopoiesis and extramedullary multiple myeloma can occur and present as painful pelvic masses. In such a case, normal hematopoietic cells may outnumber clonal plasma cells, posing a diagnostic challenge.

Multifocal Extramedullary Plasmacytoma of the Thyroid With Cervical and Paratracheal Lymph Node Involvement and Progression to Multiple Myeloma.

Extramedullary plasmacytomas without evidence of systemic illness make up less than 5% of all plasma cell neoplasms. The incidence of extramedullary plasmacytoma of the thyroid region is exceedingly rare. This report discusses the case of a 72-year-old male with extramedullary plasmacytoma of the thyroid. The patient underwent a total thyroidectomy for an enlarging right-sided thyroid nodule, and intraoperatively, the plasmacytoma was found to have an extracapsular component with adherence to the regional soft tissue as well as involvement of the right laryngeal nerve and regional lymph nodes. Despite a comprehensive negative workup for multiple myeloma initially, including a bone marrow biopsy and hematologic workup, the disease progressed to multiple myeloma following definitive radiation therapy, as evidenced by the development of hypermetabolic lytic lesions and further pathological examination. The patient's treatment course included systemic chemotherapy and an autologous stem cell transplant, resulting in a favorable treatment response. The progression to multiple myeloma despite established guidelines highlights the need for close observation and the potential for innovative therapeutic strategies to manage this rare entity.

Light Chain Multiple Myeloma Presenting As Secondary Cutaneous Amyloidosis: A Case Report on an Uncommon Systemic Manifestation.

Light chain multiple myeloma presenting as secondary cutaneous amyloidosis is an uncommon systemic manifestation, posing diagnostic challenges. We present a case of an elderly woman with a history of hemorrhoidal disease, who sought medical attention for what she thought was rectal bleeding. Initial examination revealed an ulcerative vulvar lesion. After extensive evaluation by different medical fields, two skin and a bone marrow biopsies, the diagnosis was finally confirmed. This case emphasizes interdisciplinary collaboration, comprehensive evaluation, and awareness of rare multiple myeloma manifestations. It highlights the importance of considering systemic implications even in localized presentations.

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

BACKGROUND: Extramedullary 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. METHODS: Selinexor 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. RESULTS: After 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. CONCLUSIONS: The combination of Selinexor and CT103A exerts preliminary synergistic effect, and can be developed as a promising strategy for relapsed/refractory extramedullary myeloma.

Explosive Disease Progression After Single-Agent B-cell Maturation Antigen-Targeted Treatment in Multiple Myeloma: A Report of Three Cases in Sheikh Shakhbout Medical City.

Patients with "penta-refractory" multiple myeloma (MM) are challenging to treat given the limited treatment options available to them. Belantamab mafodotin is the first B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate approved for the treatment of relapsed/refractory MM (RRMM). In this case report, we reviewed in detail three female patients who were diagnosed with MM international scoring system (ISS)-3 and were heavily pretreated, and refractory to CD38 monoclonal antibodies, two proteasome inhibitors, and two immunomodulatory agents. These patients were started on belantamab mafodotin and experienced rapid and explosive clinical, biochemical, and extramedullary disease progression within a short period of time. All three patients experienced worsening cytopenia, increased transfusion requirement, severe uncontrolled bony pain, recurrent infections, and frequent hospital admissions. Two of them passed away due to disease progression complications within a few months of starting belantamab mafodotin. Although belantamab mafodotin as a single agent was withdrawn from the market after the DREAMM-3 trial failed to achieve its primary endpoint in late RRMM, BCMA-targeted therapy may still be a promising treatment approach, and the role of belantamab mafodotin is yet to be revealed in combination therapy in early RRMM.

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.

A Case of Recurrent Multiple Myeloma as Testicular Plasmacytoma Without Systemic Disease.

Plasma cell neoplasms include various conditions ranging from indolent conditions such as monoclonal gammopathy of undetermined significance (MGUS) to more aggressive forms such as multiple myeloma (MM). The World Health Organization classifies plasmacytomas into two types: solitary osseous plasmacytoma (SOP) and extramedullary plasmacytoma (EMP). Most primary EMPs occur in the upper gastrointestinal tract, head and neck, upper respiratory system, central nervous system, lungs, liver, spleen, and kidneys. However, the occurrence of EMP involving the testis site is quite rare. Given the rarity of testicular plasmacytoma, there is no consensus on the standard of treatment for this diagnosis. Most EMP is radiosensitive, with few localized types responding to surgical intervention. Tumor recurrence and disseminated infiltration are treated with adjuvant chemotherapy after radiation or surgery. Our patient has a unique presentation of an individual who developed recurrent myeloma of the testis 12 years after his initial diagnosis of myeloma.

Incidental diagnosis of a rare pancreatic plasmacytoma with plasmablastic features.

Multiple myeloma is a plasma cell neoplasm that accounts for 10% of all hematologic malignancies, characterized by malignant proliferation of monoclonal plasma cells in the bone marrow. It predominantly affects men 60 to 70 years of age. Plasmacytoma is a discrete mass of neoplastic monoclonal plasma cells that may be osseous or extramedullary. Though extramedullary plasmacytomas are uncommon, they can involve any tissue or organ. Only a few cases of pancreatic involvement have been reported. We report a case of a 78-year-old woman with a long-standing history of multiple myeloma noted to have pancreatic tail involvement with plasmacytoma with plasmablastic features. Multiple myeloma with plasmablastic transformation has a poor prognosis; hence, a multidisciplinary team approach is crucial to identify and initiate appropriate management in these cases.

When Two Worlds Collide: A Rare Case of Multiple Myeloma With Extramedullary Plasmacytoma.

In this case report, we discuss the presentation, diagnosis, and management of a 67-year-old gentleman with stage II multiple myeloma with concurrent biopsy-proven bone plasmacytoma and why it is important to understand the molecular intricacies of these disorders. We emphasize the critical role of radiology in identifying, characterizing, and managing these lesions. Furthermore, we shed light on the critical differentiation between solitary extramedullary plasmacytoma and multiple myeloma and discuss treatment modalities for both conditions.

Analysis of High-Risk Extramedullary Relapse Factors in Newly Diagnosed MM Patients.

Extramedullary relapse of multiple myeloma (MM) is often resistant to existing treatments, and has an extremely poor prognosis, but our understanding of extramedullary relapse is still limited. The incidence, clinical characteristics, impact on the prognosis of extramedullary relapse, and the risk factors for extramedullary relapse in NDMM patients were analyzed. Among the 471 NDMM patients, a total of 267 patients had disease relapse during follow-up, including 64 (24.0%) patients with extramedullary relapse. Extramedullary relapse was more common in patients with younger age, IgD subtype, elevated LDH, extensive osteolytic lesions, extramedullary involvement, and spleen enlargement at the time of MM diagnosis. Survival analysis showed that extramedullary relapse patients had significantly worse median OS than patients with relapse but without extramedullary involvement (30.8 months vs. 53.6 months, p = 0.012). Multivariate analysis confirmed that elevated LDH (OR = 2.09, p = 0.023), >2 osteolytic lesions (OR = 3.70, p < 0.001), extramedullary involvement (OR = 3.48, p < 0.001) and spleen enlargement (OR = 2.27, p = 0.011) at the time of MM diagnosis were independent risk factors for extramedullary relapse in NDMM patients. Each of the above four factors was assigned a value of 1 to form the extramedullary relapse prediction score, and the 3-year extramedullary relapse rates of patients in the 0−2 and 3−4 score groups were 9.0 % and 76.7 %, respectively. This study suggested that extramedullary relapse was associated with poor clinical characteristics and poor prognosis in NDMM patients. The extramedullary relapse prediction score model composed of LDH, osteolytic lesions, extramedullary involvement and spleen enlargement has a better ability to predict extramedullary relapse than the existing ISS and R-ISS stages.

A prognostic model for patients with primary extramedullary multiple myeloma.

Background: Extramedullary disease is a manifestation of multiple myeloma, the prognosis of which remains poor even in the era of novel drugs. Therefore, we aimed to develop a predictive model for patients with primary extramedullary multiple myeloma (EMM). Methods: Clinical and laboratory data of patients diagnosed with primary EMM between July 2007 and July 2021 were collected and analyzed. Univariate and least absolute shrinkage and selection operation Cox regression analyses (LASSO) were used to select prognostic factors for overall survival (OS) to establish a nomogram prognostic model. The performance of the model was evaluated using concordance index which was internally validated by bootstraps with 1,000 resample, area under the curve (AUCs), and calibration curves. Results: 217 patients were included in this retrospective study. Patients with EMM had a higher rate of belonging to the male sex, age >50 years, advanced Durie-Salmon stage III, hypercalcemia, and low hemoglobin level. Compared with patients with bone-related extramedullary disease, those with extraosseous-related extramedullary disease had a higher frequency of advanced Durie-Salmon stage III, lower rate of hypercalcemia, and elevated prothrombin time. The OS and progression-free survival (PFS) of patients with bone-related extramedullary disease were significantly higher than those of patients with extraosseous-related extramedullary disease. After the univariate and LASSO analyses, six prognostic factors, including performance status, number of extramedullary involved sites, ß2-microglobulin, lactate dehydrogenase, monocyte-lymphocyte ratio, and prothrombin time, were integrated to establish a nomogram. The model showed robust discrimination with a concordance index (C-index) of 0.775 (95% confidence interval [CI], 0.713-0.836), internally validated with the corrected C-index of 0.756, and excellent performance in time-dependent AUCs compared with other staging systems. The AUCs for 1-, 3-, and 5-year OS were 0.814, 0.744, and 0.832, respectively. The calibration curves exhibited good consistency between the observed and nomogram-predicted OS. The 5-year OS of patients in the high-risk group (23.3%; 95% CI, 13.9%-39.3%) was much worse than that in the low-risk group (73.0%; 95% CI, 62.5%-85.4%; p < 0.001). Conclusion: The nomogram predictive model based on six clinical variables showed good prognostic performance and could better predict individual survival in patients with EMM.

Multiple Myeloma With Retroperitoneal Extramedullary Plasmacytoma Causing Renal Failure and Obstructive Shock From Inferior Vena Cava Compression: A Case Report.

Multiple myeloma (MM) is a hematologic malignancy of plasma cells. It can lead to multiorgan involvement and thus may present with various clinical manifestations, the most common being hypercalcemia, renal impairment, anemia, and bone involvement. Extramedullary multiple myeloma (EM) with soft tissue plasmacytoma (plasma cell tumor of soft tissue outside of the bone marrow) is an uncommon finding in patients with MM, which, when present, is clinically symptomatic based on the location of the tumor. An EM in the retroperitoneum is an infrequent presentation with only a few reported cases. We present a 56-year-old male with a history of retroperitoneal EM near the renal pelvis causing renal failure, presenting with obstructive shock from inferior vena cava (IVC) compression. Perirenal retroperitoneal plasmacytoma causing acute renal failure has been previously reported. A retroperitoneal EM plasmacytoma compressing the IVC precipitating obstructive shock is a unique finding that has yet to be mentioned in the literature. This report hopes to highlight the consideration of EM in patients with MM with obstructive symptoms, particularly in patients such as ours, who had a history of EM in the past. In addition, it shows the utility of bedside point-of-care ultrasound (POCUS) in the intensive care unit. After seeing persistently collapsed IVC on POCUS despite aggressive fluid management with worsening lower extremity edema and ascites, a presumptive diagnosis was made and later confirmed with magnetic resonance imaging (MRI). Although IVC stenting was planned initially, it was deferred due to fear of stent migration after chemotherapy. He was initially stabilized with vasopressors and treated with chemotherapy with cyclophosphamide and dexamethasone, which resolved hypotension. Timely intervention allowed vasopressors to be tapered, and he was subsequently discharged with outpatient chemotherapy.

Phase II trial of daratumumab with DCEP in relapsed/refractory multiple myeloma patients with extramedullary disease.

Extramedullary multiple myeloma (EMD) is an aggressive subentity of multiple myeloma (MM) with poor prognosis. As more innovative therapeutic approaches are needed for the treatment of MM with EMD, we conducted this multicenter, non-randomized phase II trial of daratumumab in combination with dexamethasone, cyclophosphamide, etoposide and cisplatin (DARA-DCEP). A total of 32 patients (median age 59, range 35-73) were treated with DARA-DCEP. Based on the best response during the study, the complete remission (CR) rate was 35.5% and overall response rate (ORR) 67.7%. During the median follow-up of 11 months, the median progression-free survival (PFS) was 5 months and median overall survival (OS) 10 months. There were 7 long-term responders whose median PFS was not reached. The most common grade ≥ 3 hematologic AE was thrombocytopenia. The most common non-hematologic AE was nausea (22.6%), followed by dyspepsia, diarrhea and stomatitis (all 12.9%). Grade ≥ 3 daratumumab infusion-related reaction was noted in 9.7% of the patients. Except for the planned 30% dose adjustment in cycle 1, only 2 patients required DCEP dose reduction. This is one of the very few prospective trials focusing on EMD and we successfully laid grounds for implementing immunochemotherapy in MM treatment.

Efficacy and follow-up of humanized anti-BCMA CAR-T cell therapy in relapsed/refractory multiple myeloma patients with extramedullary-extraosseous, extramedullary-bone related, and without extramedullary disease.

The prognosis of patients with multiple myeloma (MM) with extramedullary disease (EMD) remains poor. A high overall response rate (ORR) has been reported following anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell therapy in relapsed/refractory (R/R) patients with MM; however, data on patients with EMD remain limited. Herein, we compared and analyzed the efficacy and long-term follow-up of anti-BCMA CAR-T cell therapy in R/R MM patients with extramedullary-extraosseous (EM-E), extramedullary-bone related (EM-B), and without extramedullary disease. No difference in the ORR was observed between the three groups. The long-term efficacy of anti-BCMA CAR-T cell therapy in the EM-E group was worse than that in patients without EMD and with EM-B. In the EM-E group, disease progression was the reappearance of extramedullary lesions without an increase in the MM cell percentage or M protein level. Although no difference in the proportion of CAR-T cells was detected among the three groups, the EM-E group might exhibit a relatively high grade of cytokine release syndrome following anti-BCMA CAR-T therapy. Interleukin-6 levels in the without EMD group were lower than those in the EM-E and EM-B groups. However, given the small number of cases in the three groups, statistical analysis was not performed.(ChiCTR1800017051 and ChiCTR2000033925).

Metachronous Bilateral Testicular Plasmacytoma After an Initial Soft Tissue, Extramedullary Plasmacytoma.

Testicular plasmacytoma is a rare extramedullary manifestation of plasma cell dyscrasia. We report a case of a 53-year-old man who presented with a metachronous testicular lesion originating from a soft tissue plasmacytoma of the oral cavity. He underwent radical orchiectomy and a year later, presented with testicular plasmacytoma in the contralateral testis. He received induction chemotherapy, autologous stem cell transplantation with high dose melphalan and maintenance with lenalidomide, as he refused orchiectomy and achieved complete remission. However, six months post-transplant, he relapsed with localized disease in his testis, received second-line chemotherapy, after refusing orchiectomy and still remains in partial remission and alive.

Central nervous system involvement in Multiple Myeloma-Diagnosis, treatment and outcome: A case report.

Multiple Myeloma is a clonal proliferation of plasma cells with bone marrow as the primary site of occurrence. Extramedullary multiple myeloma is uncommonly seen either at presentation or later during the course of the disease. Central nervous system involvement by multiple myeloma is an extremely rare entity with a dismal outcome. This case report focuses on a 45-year-old male who presented with bone aches. Investigation findings leading to the diagnosis included elevated calcium levels, lytic lesions on radiological examination and clonal plasma cells in bone marrow biopsy. During his treatment, the patient was given chemotherapy regimens containing Lenalidomide, Bortezomib, Cyclophosamide, and Prednisolone. Thereafter, he developed neurological complications (CNS myelomatosis), which resulted in his demise. The clinical presentation, diagnosis, treatment and outcome of this rare condition is detailed below.

Cutaneous Multiple Myeloma.

Multiple myeloma is a plasma cell dyscrasia characterized by abnormal bone marrow clonal plasma cells, histological confirmation of plasmacytoma, monoclonal protein in serum or urine, and evidence of end-organ damage. Organ involvement in multiple myeloma manifests as CRAB (hyperCalcemia, Renal insufficiency, Anemia, lytic Bone lesions). Cutaneous complications in multiple myeloma have been reported in many different phenotypes such as cryoglobulinemia rash, bruising, amyloid deposition, and squamous cell carcinoma. However, cutaneous metastasis of multiple myeloma is very rare with fewer than 100 cases described in the literature so far. Here, we present a case of biopsy-confirmed primary cutaneous multiple myeloma. Our case has other less common features of multiple myeloma such as renal amyloidosis and a coexisting malignant melanoma. This case report describes a unique presentation of multiple myeloma to understand the disease better.

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

BACKGROUND: Extramedullary (EM) lesions are common in multiple myeloma (MM) and are often related to the poor prognosis of MM but are scarcely understood. METHODS: In 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. RESULTS: The 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. CONCLUSIONS: This 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.

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.

Successful Treatment of Relapsed/Refractory Extramedullary Multiple Myeloma With Anti-BCMA CAR-T Cell Therapy Followed by Haploidentical Hematopoietic Stem Cell Transplantation: A Case Report and a Review of the Contemporary Literature.

Extramedullary multiple myeloma (EMM) is an aggressive sub-entity of multiple myeloma (MM). Despite an excellent improvement in survival for most patients with MM over recent decades, the overall survival (OS) of patients with EMM was usually not longer than 3 years. Standard treatment for patients with EMM has not been established, and their management is particularly challenging. We presented a heavily pretreated young patient with relapsed EMM and refractoriness to a proteasome inhibitor (PI; bortezomib), a next-generation PI (ixazomib), immunomodulatory drugs (IMiDs; lenalidomide), autologous hematopoietic stem cell transplantation (ASCT), and monoclonal antibody (directed against CD38: daratumumab) and indicated that myeloablative haploidentical hematopoietic stem cell transplantation (haploidentical-HSCT) as a salvage treatment of relapse after a chimeric antigen receptor (CAR)-T cell therapy that targeted B-cell maturation antigen (BCMA) (NCT04650724) is feasible. Taken together of the contemporary literature, the promising results on the effect of anti-BCMA CAR-T cell therapy and allogeneic HSCT might present a proof-of-principle for patients with EMM, and therefore, patients with the disease need to be included in future studies.