Citations

Abstract Most patients with solitary bone plasmacytomas (SBP) progress to multiple myeloma (MM) after definitive radiation therapy as their primary treatment. Whether the presence of high-risk (HR) cytogenetic abnormalities by fluorescence in situ hybridization (FISH) in the clonal plasma cells, obtained either directly from the diagnostic SBP tissue or the corresponding bone marrow examination at the time of diagnosis, is associated with a shorter time to progression (TTP) to MM is unknown. This study evaluated all patients diagnosed with SBP at the Mayo Clinic from January 2012 to July 2022. The presence of del(17p), t(14;16), t(4;14), or +1q (gain or amplification) by FISH in clonal plasma cells was defined as HR. A total of 114 patients were included in this cohort, and baseline FISH was available for 55 patients (48%), of which 22 were classified as HR (40%). The median TTP to MM for patients with SBP and HR FISH was 8 months (95% confidence interval [CI], 6.3-26) compared with 42 months (95% CI, 25-not reached [NR]) in patients with SBP without HR FISH (P < .001). In a multivariate analysis, only HR FISH was a significant predictor for shorter TTP to MM, independent of minimal marrow involvement and an abnormal serum free light chain ratio at diagnosis. Deletion (17p) and gain 1q abnormalities were the most common FISH abnormalities responsible for the short TTP to MM. Thus, assessing for HR FISH abnormalities in clonal plasma cells derived from either the diagnostic SBP tissue or the staging bone marrow examination of patients with newly diagnosed SBP is feasible and prognostic for a shorter TTP to MM.

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).

AbstractIn this phase 1/2 study, carfilzomib was added to high‐dose melphalan conditioning prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma that had been treated with ≤2 prior lines of therapy. Carfilzomib was escalated at doses of 27, 36, 45, and 56 mg/m2 on days −6, −5, −2, and −1 before ASCT in the phase 1 component of the study. In addition, all the patients received melphalan 100 mg/m2 on days −4 and −3. The primary endpoint of the phase 1 component was to identify the maximum tolerated dose, and the primary endpoint of the phase 2 component was the rates of complete response (≥CR) at 1 year after ASCT. The phase 1 dose escalation cohort included 14 patients, and 35 patients were included in the phase 2 cohort. The maximum tested dose was 56 mg/m2 (MTD). The median time from diagnosis to study enrollment was 5.8 (range 3.4–88.4) months, and 16% of patients had obtained a ≥CR prior to ASCT. The best response within 1 year after ASCT was a ≥ CR rate in 22% for the entire cohort, and 22% for patients treated at the MTD. The ≥VGPR rates improved from 41% before ASCT to 77% by 1 year after ASCT. One patient had a grade 3 renal adverse event, and renal function returned to baseline with supportive care. The rate of grade 3–4 cardiovascular toxicity was 16%. The addition of carfilzomib to melphalan conditioning was safe and resulted in deep responses after ASCT.

Abstract Introduction: Cytokines are protein factors that regulate diverse cellular processes. The malignant progression of immunoglobulin M monoclonal gammopathy of undetermined significance (IgM-MGUS) to Waldenstrom macroglobulinemia (WM) is in part cytokine mediated, and we have previously shown IL-6 mediates IgM secretion in WM via the JAK/STAT pathway. Cytokine signaling can be epigenetically modulated by micro-RNAs (miRs). We aimed to identify the role of miRs in the regulation of inflammatory cytokine pathways between these diseases. Methods: Bone marrow samples of patients with IgM-MGUS (n=7) and WM (n=25) were prospectively collected and sorted for CD19+ and/or CD138+ malignant cells. Total RNA extraction and sequencing were performed, miR and mRNA profiling was conducted, and differential expression was calculated between WM and IgM-MGUS using a log2 fold change (FC)>0.5 and ←0.5, false discovery rate<0.05. Experimental differentially expressed miR-mRNA pairing was performed, and pairs were filtered for correlated expression (i.e., upregulated miR/downregulated mRNA, and vice-versa). Filtered pairs were analyzed using the Ingenuity Pathway Analysis to identify pathways between WM and IgM-MGUS with absolute activation Z-score ≥1. Results: We identified 34 differentially expressed miRs experimentally targeting 1132 mRNAs. Pathway analysis showed overall miR-based inactivation of inflammatory cytokine signaling pathways in WM compared to IgM-MGUS, especially of the interleukin (IL) family: IL-2, IL-6, IL-8, IL-9, IL-15, and IL-17. Underlying multiple pathways was upregulation of miRs-146a, 150, 194, all targets of Signal Transducer and Activator of Transcription 1 (STAT1), observed to be downregulated. Of relevance, miR-146a has been previously shown to be an inhibitor of inflammatory cytokines, including IL-6. Next, we observed upregulation of miR-142 which targets phosphoinositide-3-kinase regulatory subunit 6 (PIK3R6), observed to be downregulated. Both the STAT and PIK3 families are important cytokine signal transducers, and we have previously shown the PI3k-AKT-IkB-p65 pathway induces expression of IL-6 via a GLI2-mediated mechanism. We additionally observed granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling to be inactivated in WM. Here, miR-19b and miR-30e were upregulated, both target CSF 2 receptor subunit beta (CSF2RB), found to be downregulated. CSF2RB is the common receptor subunit of GM-CSF, IL-3, and IL-5. Conclusion: Our study identifies multiple cytokines pathways involved in inflammation and the tumor microenvironment to be potentially inactivated by differentially expressed miRs in WM compared to IgM-MGUS. Downregulation of these pathways and targeting of the STAT and PIK3 family indicates a possible miR-based negative feedback loop to down-modulate inflammatory cytokine signaling in WM. Citation Format: Karan Chohan, Jonas Paludo, Surendra Dasari, Jithma P. Abeykoon, Prashant Kapoor, Esteban Braggio, Michelle K. Manske, Aneel Paulus, Craig B. Reeder, Sikander Ailawadhi, Asher A. Chanan-Khan, Robert A. Kyle, Morie A. Gertz, Anne J. Novak, Stephen M. Ansell. Micro-RNA induced inactivation of inflammatory cytokine signaling pathways in Waldenstrom macroglobulinemia compared to IgM-MGUS. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3811.

Abstract Patients with multiple myeloma (MM) who do not respond to initial therapy have worse outcomes than primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not yet been studied. We reviewed patients with MM treated with triplet/quadruplet therapy at our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. We identified 1127 patients, of whom 1086 were evaluated for hematologic responses after 4 to 6 cycles. Of these, 93.3% (1013) had evidence of response, whereas 6.7% (73) had primary refractory disease. With a median overall survival (OS) of 51.3 months, patients with primary refractory disease had an increased risk of shorter survival in univariable and multivariable analyses (hazard ratio [HR], 3.5 [95% confidence interval (CI), 2.5-4.9]; HR, 4.3 [95% CI, 2.6-6.9], respectively). In the subgroup analysis of patients with primary refractory disease, those who received second-line autologous stem cell transplantation (ASCT) had increased second progression-free survival (20.9 vs 8.1 months; P < .01) and second OS (74.7 vs 31.3 months; P = .02) compared with patients who did not. We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population.