Ho, Matthew

ABSTRACT Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant precursor to multiple myeloma (MM). While development of end‐organ damage in MM largely reflects increasing clonal burden, emerging evidence indicates that qualitative properties of the monoclonal immunoglobulins in MGUS can be directly pathogenic, leading to serious organ injury independent of disease burden. This has led to the recognition of a broader spectrum of disorders collectively termed monoclonal gammopathy of clinical significance (MGCS). MGCS can be further subclassified based on the organ system involved; for example, monoclonal gammopathy of renal significance specifically refers to monoclonal immunoglobulin‐driven renal injury. Along these lines, we propose monoclonal gammopathy of thrombotic significance (MGTS) as encompassing thrombotic disorders in which there is definitive, mechanistically supported evidence that a monoclonal (M)‐protein associated with a clonal plasma or B‐cell disorder directly contributes to thrombosis. Based on current evidence, monoclonal protein–induced immune thrombocytopenia and thrombosis is the only disorder that meets our criteria for MGTS. Other thrombotic disorders, such as thrombotic microangiopathy and antiphospholipid syndrome, may occur in the setting of a monoclonal protein and have biologically plausible M‐protein‐mediated mechanisms; however, direct evidence implicating the M‐protein in thrombosis is currently lacking. Accordingly, we provisionally classify these disorders as thrombotic syndromes associated with M‐proteins, pending causal validation. We also highlight thrombotic disease associations with multifactorial pathogenesis that should not be classified as MGTS. Broader recognition of MGTS is essential to advance consensus definitions, establish diagnostic criteria, and develop evidence‐based management strategies for this clinically important group of disorders.

Extramedullary multiple myeloma (EMM), defined in this review as soft tissue plasmacytomas resulting from hematogenous spread, is characterized by the ability of MM cells to proliferate outside of the bone marrow microenvironment. It is aggressive, often associated with high-risk cytogenetics and early relapse, and independently portends significantly shorter progression-free and overall survival, even in the era of highly effective immunotherapies. The molecular and microenvironmental factors underlying extramedullary MM dissemination continue to be studied to inform the development of better treatments. In this review, we discuss our current understanding of the biology of EMM, focusing on its distinct molecular and microenvironmental characteristics vis-à-vis MM. We also review the current treatment strategies, acknowledging the paucity of large, randomized studies specific to this population.

Background: Deeper depth of response (DpR) after induction therapy, especially gain of negative minimal residual disease (MRD), has been linked to prolonged survival in multiple myeloma (MM). However, flow-MRD examination focuses on the numbers but not on the biological characteristics of residual plasma cells (PCs). Objectives: To explore whether the genetic features of residual tumor cells affect the survival time of patients with MM. Design: A retrospective cohort study. Methods: We investigated the clonality of cytogenetic abnormalities (CAs) of the residual PCs using interphase fluorescence in situ hybridization (iFISH) in the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). Here, a longitudinal cohort of 269 patients with patient-paired diagnostic and post-induction iFISH results was analyzed. Results: Persistent CAs after induction therapy were detected in about half of the patients (118/269, 43%), and patients with undetectable CAs showed significantly improved survival compared with those with genetically detectable MRD [median progression-free survival (mPFS): 59.7 versus 35.7 months, p < 0.001; median overall survival (mOS): 97.1 versus 68.8 months, p = 0.011]. In addition, different patterns of therapy-induced clonal evolution were observed by comparing the clonal structure of residual PCs with paired baseline samples. Patients who maintained at a high risk during follow-up had the worst survival (mPFS: 30.5 months; mOS: 54.4 months), while those who returned to lower risk or had iFISH− at both time points had the best survival (mPFS: 62.0 months, mOS: not reached). Conclusion: These findings highlighted the prognostic value of genetic testing in residual tumor cells, which may provide a deep understanding of clonal evolution and guide clinical therapeutic strategies.

Abstract The success of chimeric antigen receptor T‐cell (CAR‐T) therapy in hematologic malignancies has realized a longstanding effort toward harnessing the immune system to fight cancer in a truly personalized fashion. Second generation chimeric antigen receptors (CAR) incorporating co‐stimulatory molecules like 4‐1BB or CD28 were able to overcome some of the hindrances with initial CAR constructs resulting in efficacious products. Many second‐generation CAR‐T products have been approved in the treatment of relapsed/refractory hematologic malignancies including multiple myeloma (MM), non‐Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia. However, challenges remain in optimizing the manufacturing, timely access, limiting the toxicity from CAR‐T infusions and improving sustainability of responses derived with CAR‐T therapy. Here, we summarize the clinical trial data leading to approval CAR‐T therapies in MM and NHL, discuss the limitations with current CAR‐T therapy strategies and review emerging strategies for overcoming these limitations.

Abstract 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).

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]

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]

Abstract Multiple myeloma (MM) bone disease is a significant cause of morbidity but there is a paucity of data on the impact of malignant plasma cells on adjacent trabecular bone within the BM. Here, we characterize the proteome of trabecular bone tissue from BM biopsies of 56 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM), newly diagnosed (NDMM), relapsed MM (RMM), and normal controls. Proteins involved in extracellular matrix (ECM) formation and immunity pathways were decreased in SMM and active MM. Among the proteins most decreased were immunoglobulins, type IV collagen, and TIMP3, suggesting increased immunoparesis and decreased ECM remodelling within trabecular bone. Proteins most increased in SMM/MM were APP (enhances osteoclast activity), ENPP1 (enhances bone mineralization), and MZB1 (required for normal plasmablast differentiation). Pathway analyses showed that proteins involved in gamma -carboxylation, a pathway implicated in osteocalcin function, osteoblast differentiation, and normal hematopoiesis, were also overexpressed in SMM/MM. This study is the first comprehensive proteomic atlas of the BM bone proteome in dysproteinemias. We identify new key proteins and pathways for MM bone disease and potentially impaired hematopoiesis, and show for the first time that gamma -carboxylation pathways are increased in the bone tissue of SMM/MM.

Abstract Novel therapies in multiple myeloma (MM) have increased the rates of conventional complete remission (CR) in patients. However, patients in CR can have highly heterogeneous outcomes. Novel and more sensitive methods of assessing residual disease burden after therapy will help prognosticate this group better and, ideally, allow individualized therapy adjustments based on response depth in the future. Here, we review novel bone marrow, peripheral blood, and imaging methods for assessing myeloma burden and discuss the opportunities and limitations of incorporating these in everyday clinical practice.