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Extramedullary involvement (or extramedullary disease, EMD) represents an aggressive form of multiple myeloma (MM), characterized by the ability of a clone and/or subclone to thrive and grow independent of the bone marrow microenvironment. Several different definitions of EMD have been used in the published literature. We advocate that true EMD is restricted to soft-tissue plasmacytomas that arise due to hematogenous spread and have no contact with bony structures. Typical sites of EMD vary according to the phase of MM. At diagnosis, EMD is typically found in skin and soft tissues; at relapse, typical sites involved include liver, kidneys, lymph nodes, central nervous system (CNS), breast, pleura, and pericardium. The reported incidence of EMD varies considerably, and differences in diagnostic approach between studies are likely to contribute to this variability. In patients with newly diagnosed MM, the reported incidence ranges from 0.5% to 4.8%, while in relapsed/refractory MM the reported incidence is 3.4 to 14%. Available data demonstrate that the prognosis is poor, and considerably worse than for MM without soft-tissue plasmacytomas. Among patients with plasmacytomas, those with EMD have poorer outcomes than those with paraskeletal involvement. CNS involvement is rare, but prognosis is even more dismal than for EMD in other locations, particularly if there is leptomeningeal involvement. Available data on treatment outcomes for EMD are derived almost entirely from retrospective studies. Some agents and combinations have shown a degree of efficacy but, as would be expected, this is less than in MM patients with no extramedullary involvement. The paucity of prospective studies makes it difficult to justify strong recommendations for any treatment approach. Prospective data from patients with clearly defined EMD are important for the optimal evaluation of treatment outcomes., (© 2022. The Author(s).)

In this review, two types of soft-tissue involvement in multiple myeloma are defined: (i) extramedullary (EMD) with haematogenous spread involving only soft tissues and (ii) paraskeletal (PS) with tumour masses arising from skeletal lesions. The incidence of EMD and PS plasmacytomas at diagnosis ranges from 1·7% to 4·5% and 7% to 34·4% respectively. EMD disease is often associated with high-risk cytogenetics, resistance to therapy and worse prognosis than in PS involvement. In patients with PS involvement a proteasome inhibitor-based regimen may be the best option followed by autologous stem cell transplantation (ASCT) in transplant eligible patients. In patients with EMD disease who are not eligible for ASCT, a proteasome inhibitor-based regimen such as lenalidomide-bortezomib-dexamethasone (RVD) may be the best option, while for those eligible for high-dose therapy a myeloma/lymphoma-like regimen such as bortezomib, thalidomide and dexamethasone (VTD)-RVD/cisplatin, doxorubicin, cyclophosphamide and etoposide (PACE) followed by SCT should be considered. In both EMD and PS disease at relapse many strategies have been tried, but this remains a high-unmet need population., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

In addition to randomized clinical trials, consideration of Real-World Evidence is necessary for mirroring clinical reality. However, processing such evidence for large numbers of patients often requires considerable time and effort. This is particularly true for rare tumor diseases such as multiple myeloma (MM) or for adverse effects that occur even more rarely. In such cases, artificial intelligence is able to efficiently detect patients with rare conditions. One of these rare adverse events, and the most discussed, following bone protective treatment in MM is medication-related osteonecrosis of the jaw (MRONJ). The association of bone protective treatment to MM outcome has been intensively studied. However, the impact of MRONJ resulting from such treatment on MM prognosis and outcome is poorly understood. In this retrospective study, we therefore investigated the long-term effects of MRONJ. We used natural language processing (NLP) to screen individual data of 2389 MM patients to find 50 out of 52 patients with MRONJ matching our inclusion criteria. To further improve data quality, we then performed propensity score matching. In comparison to MM patients without MRONJ, we found a significantly longer overall survival (median 126 vs. 86 months) despite slightly worse clinical features. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Copyright comment corrected publication 2021 Dear Editor, The Chinese colleagues from Wuhan reported for the first time the novel coronavirus (COVID-19), which caused severe acute respiratory syndrome [[1]]. The patient No. 7 who was receiving the frontline therapy with VTD also had an elevated procalcitonin value (30.05 ng/ml), suggesting an additional bacterial infection, and, despite maximal medical care, this patient died due to acute respiratory failure. Importantly, MM patients with COVID-19 infection need close monitoring for severe COVID-19-related complications, and early intervention may be life-saving for the patients [[11]]. [Extracted from the article]

Summary: Gain of chromosome 1q21 and the gene expression‐based GEP70 risk score are established prognostic markers for newly diagnosed Multiple Myeloma (MM) patients. Here we addressed the prognostic impact of these two markers in 81 relapsed/refractory (RR) MM patients treated with the CD38‐antibody daratumumab. Fluorescence in situ hybridization for 1q21 was performed at initial presentation, while the GEP70 score was determined at initial presentation and prior to daratumumab treatment. While the GEP70 at initial presentation showed a trend for inferior survival, the GEP70 collected prior to daratumumab treatment was significantly associated with poor outcome (P < 0·05). The worst outcome was seen for patients who were positive for gain(1q) and classified as GEP70 high risk prior to daratumumab [progression‐free (PFS) and overall survival (OS) of 0·3 years (95% CI: 0·15–1·4 years) and 0·8 years (95% CI: 0·5–1·9 years) respectively], while the median PFS and OS were not reached by patients without gain(1q) and GEP70 low‐risk status. In conclusion, gain(1q) and the GEP70 are powerful prognostic markers for RR MM patients treated with daratumumab, and patients classified as high risk according to these markers experience shorter treatment response. [ABSTRACT FROM AUTHOR]

Simple Summary: Extramedullary disease can occur either in multiple myeloma at the initial diagnosis or relapse or as primary extramedullary plasmocytoma/solitary osseous plasmocytoma. The exact molecular mechanisms underlying extramedullary spread of clonal plasma cells are not fully understood. The aim of our study was to assess further insights into clinical and biological characteristics of different types of extramedullary plasma cell disorders. We show that expression profiles of molecules involved in homing and cytogenetic abnormalities differ between various types of plasma cell dyscrasias, indicating the contrasting biology of these diseases. Background: Extramedullary plasma cell (PC) disorders may occur as extramedullary disease in multiple myeloma (MM-EMD) or as primary extramedullary plasmocytoma (pEMP)/solitary osseous plasmocytoma (SOP). In this study, we aimed to obtain insights into the molecular mechanisms of extramedullary spread of clonal PC. Methods: Clinical and biological characteristics of 87 patients with MM-EMD (n = 49), pEMP/SOP (n = 20) and classical MM (n = 18) were analyzed by using immunohistochemistry (CXCR4, CD31, CD44 and CD81 staining) and cytoplasmic immunoglobulin staining combined with fluorescence in situ hybridization (cIg-FISH). Results: High expression of CD44, a cell-surface glycoprotein involved in cell-cell interactions, was significantly enriched in MM-EMD (90%) vs. pEMP/SOP (27%) or classical MM (33%) (p < 0.001). In addition, 1q21 amplification by clonal PC occurred at a similar frequency of MM-EMD (33%), pEMP/SOP (57%) and classical MM (44%). Conversely, del(17p13), t(4;14) and t(14;16) were completely absent in pEMP/SOP. Besides this, 1q21 amplification was identified in 64% of not paraskeletal samples from MM-EMD or pEMP compared to 9% of SOP or paraskeletal MM-EMD/pEMP and 44% of classical MM samples, respectively (p = 0.02). Conclusion: Expression of molecules involved in homing and cytogenetic aberrations differ between MM with or without EMD and pEMP/SOP. [ABSTRACT FROM AUTHOR]

Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40–80) years. Twenty (44%) and 25 (56%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59%. Extramedullary response was evaluable in 33 patients, nine (27%) of them achieved partial remission (PR) (ORR = 27%). In 15 (33%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95% CI, 3.5–6.5) and ten (95% CI, 7.5–12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS (p = 0.004) and OS (p = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients. [ABSTRACT FROM AUTHOR]

Purpose: We tested a novel multi-parametric (mp) whole body (WB)-MRI evaluation algorithm for medullary lesions in comparison to positron emission tomography (PET) radiotracers 18F-fluorodeoxyglucose (18F-FDG) and 11C-methionine (11C-MET).Methods and Materials: This retrospective single-center study included 44 MM patients, who received both 18F-FDG-PET and WB-MRI within ten days. MRI classified focal lesions as vital when showing 1) significant diffusion-restriction, 2) a fat fraction (FF) less than 20 % and 3) homogenous hypointensity on T2-weighted images. On a lesion-by-lesion level the findings were compared to 18F-FDG PET by using a 5-point scoring system (analogous to the Deauville score [DS]). In 24/44 (55 %) patients additional comparison to 11C-MET PET was available.Results: Among two radiologists, an excellent inter-observer reliability for mpWB-MRI in a total of 84 medullary lesions was observed (ICC = 1, k = 1, p <.01). 16/17 (94.1 %) MRI-classified vital lesions had a DS of 4 or 5 on either 18F-FDG-PET or 11C-MET-PET. MRI-rated non-vital lesions correlated with PET-based DS ≤ 3. When results of mpWB-MRI were compared to 18F-FDG, a fair inter-observer agreement was recorded (ICC = 0.52, k = 0.53, p <.01), while for 11C-MET, an excellent concordance rate was achieved (ICC = 0.81, k = 0.79, p <.01).Conclusion: The proposed mpWB-MRI interpretation algorithm allowed to assess tumor activity of myeloma lesions with high inter-observer reproducibility. We observed a substantial concordance between the mpWB-MRI classification of lesions and PET assessment based on a semi-automatically calculated 5-point scoring system analogous to the Deauville scores. [ABSTRACT FROM AUTHOR]