Citations

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 Glomerulonephritis (GN) is a diverse group of immune-mediated disorders. Currently, GN is classified largely by histological patterns that are difficult to understand and teach, and most importantly, do not indicate treatment choices. Indeed, altered systemic immunity is the primary pathogenic process and the key therapeutic target in GN. Here, we apply a conceptual framework of immune-mediated disorders to GN guided by immunopathogenesis and hence immunophenotyping: (i) infection-related GN require pathogen identification and control; (ii) autoimmunity-related GN, defined by presence of autoantibodies and (iii) alloimmunity-related GN in transplant recipients both require the suppression of adaptive immunity in lymphoid organs and bone marrow; (iv) autoinflammation-related GN, e.g. inborn errors of immunity diagnosed by genetic testing, requires suppression of single cytokine or complement pathways; and (v) Monoclonal gammopathy-related GN requires B or plasma cell clone-directed therapy. A new GN classification should include disease category, immunological activity to tailor the use of the increasing number of immunomodulatory drugs, and chronicity to trigger standard chronic kidney disease care including the evolving spectrum of cardio-renoprotective drugs. Certain biomarkers allow diagnosis and the assessment of immunological activity and disease chronicity without kidney biopsy. The use of these five GN categories and a therapy-focused GN classification is likely to overcome some of the existing hurdles in GN research, management and teaching by reflecting disease pathogenesis and guiding the therapeutic approach.

Key Points Urinary TIMP2×IGFBP7 (uTIMP2×IGFBP7) concentrations experienced a rapid and sustained decline after high-dose methotrexate (MTX) exposure. uTIMP2×IGFBP7 kinetics and concentrations after high-dose MTX exposure demonstrated no utility in predicting AKI.

AbstractWaldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10‐year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960–1977, n = 12), Group 2 (1978–1995, n = 48), and Group 3 (1996–2013, n = 74). Among young patients, there was no disease‐specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5–23), 16 years (95% CI 14–22), and 15 years (95% CI 10‐NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years‐of‐life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age‐ and sex‐matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.

Abstract Lenalidomide‐containing (R) triplet and quadruplet regimens are the standard of care for multiple myeloma (MM) and have been shown to increase the risk of thrombosis. The association between thromboembolism (TE) and survival in the novel multidrug era is not yet delineated. In this study, we evaluated the incidence of TE during the first year of MM diagnosis, its association with the type of induction regimen, and its impact on overall survival. We studied 672 newly diagnosed MM (NDMM) patients who received a triplet or quadruplet lenalidomide‐based induction at the Mayo Clinic, Rochester. TE was diagnosed in 83 patients (12.4%). Of these, 56 (8.3%) had a deep venous thrombosis (DVT), 23 (3.4%) had a pulmonary embolism (PE) with or without the DVT, and 4 (0.6%) patients had a stroke. Carfilzomib‐Rd (KRd) had the highest risk of TE (21.1%, 18/85), followed by quadruplets (11.1%, 5/45), bortezomib‐Rd (9.6%, 51/531), and 0/11 (0%), treated with other lenalidomide‐containing regimens. The difference in TE risk between KRd and the other regimens was statistically significant (OR = 2.6, p < .01). Nine patients developed a TE before being exposed to any treatment. Survival was significantly lower among patients that developed a TE (66 vs. 133 months, p < .01). The association of TE with reduced survival demonstrated in univariate analysis (HR = 2.2, 95% CI = 1.6–3.3) was maintained in the multivariable analysis adjusted for high‐risk interphase fluorescence in situ hybridization (FISH), sex, age, receipt of an upfront transplant, the response at induction, and the International Staging System (ISS) (HR = 2.61, CI = 1.74–3.9). We conclude that TE is an important aspect of MM management, and effective management is especially relevant in the novel treatment era.

Abstract POEMS syndrome is a rare paraneoplastic syndrome and therapies are directed against plasma cells that produce the proteins that cause this syndrome. Novel therapies are widely used in multiple myeloma aiming for plasma cell eradication. However, data on their use in POEMS syndrome are lacking. In this case series, we provide the Mayo Clinic experience in treating 16 patients with relapsed POEMS syndrome with novel agents (daratumumab, carfilzomib, pomalidomide, and elotuzumab). The patients were treated with a doublet including dexamethasone (N = 5) (31%) or in various combinations with other agents: DRd (N = 6), DC(V)d (N = 3), KRd (N = 3), KPd (N = 1), DP(V)d (N = 5), and EloRd (N = 1). The outcomes with novel agent therapies were favorable. Overall, twelve patients treated with daratumumab-based therapies (86%) and five patients treated with carfilzomib-based therapies (83%) responded to therapy. Among patients treated with daratumumab based therapies (N = 14), 9 patients achieved CR/VGPRH, 7 patients achieved CRV, and 5 patients achieved CRP. Among patients treated with carfilzomib-based therapies (N = 6), 3 patients achieved CR/VGPRH, and one achieved PRH. At a median follow-up of 38 months since starting of the novel agent (IQR 24–57), 15 of the patients (93%) are still alive, and the median TTNT was not reached. None of the patients discontinued therapy due to adverse events and no deaths occurred on therapy. Novel therapies were safe with 7 events of hospitalization due to pneumonia (4 in daratumumab-based therapies and 3 on carfilzomib-based therapies), and 4 patients were hospitalized due to volume overload. Three patients experienced infusion-related reactions (IRR) to the first dose of IV daratumumab. The response rate to novel agents was high, and the responses were deep. Novel agent therapies were safe, and no death case occurred on therapy. Future studies are needed to clarify the optimal sequence of novel agents and the best combination.