Faculty Bibliography

Background: Therapeutic advances in multiple myeloma (MM) have greatly improved the rate and depth of response. Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that has synergistic activity with carfilzomib (K) and dexamethasone (d), and is currently under investigation as a targeted therapy in relapsed/refractory (R/R) MM. Using next-generation sequencing (NGS) and ¹⁸F-Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT), we aimed to comprehensively evaluate minimal residual disease (MRD) in R/R MM patients (pts) treated with VenKd.
Method(s): In this phase 2, dose-escalation study (NCT02899052), R/R MM (1 - 3 prior lines of therapy and no prior K exposure) pts received VenKd: Ven 400 mg/day + K 27 mg/m2 d1,2,8,9,15,16 + d 40 mg d1,8,15,22 (Cohort 1), same regimen but with Ven 800 mg/day (Cohort 2), Ven 800 mg/day + K 70 mg/m2 d1,8,15 + d 40 mg d1,8,15, 22 (Cohort 3/expansion cohort), or Ven 800 mg + K 56 mg/m2 d1,2,8,9,15,16 + d 40 mg d1,2,8,9,15,16,22,23 (Cohort 4). The following biomarker analyses were performed by central laboratory assessments of CD138-enriched bone marrow mononuclear cells collected at baseline: BCL2 gene expression by quantitative PCR and cytogenetic abnormalities by interphase fluorescence in situ hybridization. MRD assessments by NGS (clonoSEQ) were performed on bone marrow aspirates at cycle 3 day 1 in pts achieving VGPR or better, time of suspected CR/sCR, and 6- and 12-months post confirmation of CR/sCR with negativity determined at <10^-5 threshold. FDG-PET/CT imaging was performed on a subset of pts at baseline, cycle 3 day 1, and confirmation of CR or sCR, which corresponded to the bone marrow MRD evaluations by NGS. Lesions assessed by PET/CT were guided by standard of care imaging (i.e., x-ray, CT), and FDG-uptake was measured by maximum standardized uptake value. Pts were excluded from subsequent FDG-PET imaging based on proximity of evaluable lesions to anticipated areas of high normal FDG uptake (e.g., brain), or PET negative based on baseline FDG-PET imaging. MRD negativity (NGS and/or Imaging) was evaluated in the ITT population and key biomarker-defined subgroups (t(11;14) and BCL2^high). Pts with missing or indeterminate assessments were considered MRD positive. Correlation with PFS, DOR, OS, and patient-reported outcomes (e.g., physical functioning, pain scores, fatigue) will be presented.
Result(s): As of 14 Feb 2020, 49 pts were enrolled (4 in cohort 1, 3 in cohort 2, 7 in cohort 4 and 35 in cohort 3 + expansion). Pts had received a median of 2 (1-3) prior lines of therapy, 96% were exposed to PI (57% refractory), 90% exposed to IMiD (71% refractory), and 86% exposed to PI + IMiD (45% double refractory). Median age was 60 years (37 - 79), 61% had ISS II/III disease, 27% had t(11;14), and 45% were BCL2^high. Of note, 8 out of the 22 (36.4%) BCL2^high pts were t(11;14) positive. Overall response rate (ORR) was 80% (>=PR), including 65% >= VGPR and 41% >=CR (Table 1). Among t(11;14) pts, ORR was 92%, >= VGPR 85%, and >=CR 54%; while among BCL2^high pts ORR was 86%, >= VGPR 77%, and >=CR 41%. Of the 19 pts assessed for MRD by NGS, 15 (79%) had clonotypes identified at baseline. Of these 15 pts, 6 (40%) achieved MRD negativity (<10^-5) by NGS in the bone marrow after VenKd treatment. Of the 12 pts who participated in the FDG-PET sub-study, 10 (83%) were FDG-PET positive at baseline, and 8 (67%) completed post-treatment FDG-PET imaging. Of these 8 pts, 3 (38%) achieved complete metabolic response (CMR) by FDG-PET imaging after VenKd treatment. While only 4 pts were evaluated concurrently for MRD by NGS and FDG-PET/CT imaging, the assessments were concordant for 3 pts (2 positive, 1 negative). The discordant result (NGS negative, FDG-PET/CT positive lymph node) indicated clearance of disease in the bone marrow while the presence of a potential soft tissue plasmacytoma remaining after treatment with VenKd. Of the 19 pts evaluated by either NGS or FDG-PET/CT, 8 (42%) achieved MRD negativity by NGS in the bone marrow or CMR by FDG-PET/CT after VenKd treatment. The highest rates of MRD negativity were observed in t(11;14) and BCL2^high subgroups (Table).
Conclusion(s): The combination of VenKd demonstrates promising efficacy in pts with R/R MM, including high rates of MRD, particularly in the t(11;14) and BCL2^high subgroups. Overall, MRD assessments by NGS and FDG-PET/CT were highly concordant in this study and may be complementary for assessment of disease clearance in MM. [Formula presented] Disclosures: Costa: Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genentech: Consultancy; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Celgene: Consultancy, Honoraria. Burwick: AbbVie: Research Funding. Jakubowiak: AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Kaufman: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Tecnopharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi/Genyzme: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Cabanillas: AbbVie: Research Funding. Dail: Genentech: Current Employment, Current equity holder in publicly-traded company. Karve: AbbVie: Current Employment, Current equity holder in publicly-traded company. Masud: AbbVie: Current Employment, Other: may hold stock or stock options. Yang: Abbvie: Current Employment, Current equity holder in publicly-traded company. Bueno: AbbVie: Current Employment, Current equity holder in publicly-traded company. Mudd: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company. Davies: Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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BACKGROUND:The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases. METHODS AND FINDINGS/RESULTS:Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies. CONCLUSIONS:In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies.

UNLABELLED:= 42), OR = 0.9 (0.3-2.2). In this largest cohort to date of patients with multiple myeloma and COVID-19, we found the case fatality rate to be 29% among hospitalized patients and that race/ethnicity was the most significant risk factor for adverse outcome. SIGNIFICANCE:.

Introduction: Patients (pts) with relapsed and refractory multiple myeloma who are triple-class exposed to IMiDs, proteasome inhibitors, and anti-CD38 monoclonal antibodies (mAbs) have limited treatment (Tx) options. The BCMA-targeted CAR T cell therapy, ide-cel, is being developed to address the unmet need in this setting. An SLR identifed 2 phase 2 clinical trials investigating the efficacy and safety of specific therapies under US FDA evaluation in this setting, namely Sd (NCT02336815) and BM 2.5 mg/kg (NCT03525678). Here we compare the efficacy outcomes of ide-cel from the KarMMa study with Sd from STORM part 2 and BM from DREAMM-2.
Method(s): Unanchored matching-adjusted indirect Tx comparisons (MAICs) were performed based on individual pt-level data from 128 infused pts in KarMMa, and study-level data from STORM part 2 and DREAMM-2. Individual pt data were reconstructed based on the published Kaplan-Meier curves for time-to-event outcomes from the studies. Between-study diferences were summarized, and the most relevant differences in pt characteristics were identifed based on clinical expertise. Propensity score models were used to weight pts in KarMMa to predict outcomes in a population corresponding to each study. ORs were calculated for ORR using weighted logistic regression models. HRs were calculated for PFS and OS using weighted Cox proportional hazard models. Sensitivity analyses were performed to explore the relative Tx efects with other cohorts from the KarMMa trial, including the enrolled pts (N=140) and pts receiving the target dose of 450x10⁶ CAR+ T cells (N=54).
Result(s): Ide-cel was associated with a higher ORR vs both Sd and BM in a population matched to each trial (Table). Similarly, ide-cel extended PFS and OS vs both Sd and BM. Results were generally consistent in the sensitivity analyses using the KarMMa enrolled population and across different doses for both indirect MAICs, although the efective sample size was reduced in some cases.
Conclusion(s): Tese data suggest that ide-cel ofers improvements in ef-cacy vs both Sd and BM, the only therapies for which there are currently phase 2 data in pts with RRMM afer anti-CD38 mAb Tx

Introduction: The oral proteasome inhibitor ixazomib is approved for the treatment of RRMM pts who have received >=1 prior therapy. We report on a pooled analysis of IRd therapy from the INSIGHT MM study and the Czech Registry of Monoclonal Gammopathies (RMG), to evaluate the efectiveness of IRd in RRMM in routine clinical practice.
Method(s): INSIGHT MM is a large, prospective, observational study which has enrolled over 4,200 adult MM pts. The RMG comprises clinical data for >6,000 MM pts enrolled at 19 Czech and 4 Slovak centers. Individual pt level data on demographics, disease characteristics, treatment history, efectiveness, and safety from both registries were integrated and analyzed.
Result(s): At data cutof, 217 pts (83 INSIGHT; 134 RMG) from 11 countries were included. At diagnosis, 32% of pts had ISS Stage III disease, 78% had bone lesions, 46% had anemia, and 12% had elevated creatinine. At study start, median age was 67 years (12% >75 years); 58%/14% of pts had ECOG PS 1/2. Prior therapies included: bortezomib (90%), stem cell transplant (60%), thalidomide (47%), lenalidomide (26%), carflzomib (8%), daratumumab (6%), and pomalidomide (2%). Median time from diagnosis to start of IRd therapy was 42.1 mos. The most common reasons for starting IRd were relapse/progression (87%) and insufcient response (10%). Median duration of follow-up was 12.6 mos. At data cutof, 54% pts had discontinued IRd; median DOT was 11.9 (95% CI: 9.4-15.2) mos; at 12 mos, 49% (41.3-56.2) of pts were still on treatment (KM estimates). Best response to therapy was available for 152 pts. ORR was 74%, with 36% >=VGPR. Median time to first response was 1.2 mos (RMG); median time to best response was 3.7 mos (INSIGHT). Median PFS (mPFS) was 21.6 (95% CI: 13.6-26.7) mos. PFS rate at 12 mos was 62%, and 86 (40%) pts had progressed at data cutof. Median time to next therapy (TTNT) was 31.5 (95% CI: 24.5-35.9) mos, with a 12-month rate of 74%. At data cutof, 53 (24%) pts had died. Median OS was 36.7 (95% CI: 24.4-NR) mos, with 79% of pts alive at 12 mos (Figure). Ixazomib and lenalidomide dose reductions were required in 16% and 36% of pts, including 10% and 21% who required dose reductions due to AEs.
Conclusion(s): The efectiveness of IRd in routine clinical practice (ORR 74%, mPFS 21.6 mos) seen here is comparable to the efficacy reported in TOURMALINE MM1 (ORR 78%, mPFS 20.6 mos). IRd is well tolerated with no new safety signals, and low rates of dose reductions due to AEs

Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs (IMiDs) are at high venous thrombosis (VTE) risk, but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n=1936) and Myeloma XI (n=4358), phase III randomized controlled trials for NDMM, treating transplant-eligible and ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, compared to CTD (cyclophosphamide, thalidomide and dexamethasone), transplant-eligible patients randomized to CVAD induction (cyclophosphamide, vincristine, doxorubicin and dexamethasone) had higher VTE risk (22.5%(n=121/538) vs 16.1%(n=89/554), aHR:1.46,95%CI:1.11-1.93). For transplant-ineligible patients, compared to MP (melphalan and prednisolone), patients randomized to CTDa (attenuated CTD) induction had higher VTE risk (16.0%(n=68/425) vs 4.1%(n=17/419), aHR:4.25,95%CI:2.50-7.20). In Myeloma XI, there was no difference in VTE or arterial thrombosis risk between transplant-eligible pathways, CRD (cyclophosphamide, lenalidomide and dexamethasone) and CTD (VTE:12.2%(n=124/1014) vs 13.2%(n=133/1008), aHR:0.92,95%CI:0.72-1.18; arterial events:1.2%(n=12/1014) vs 1.5%(n=15/1008), aHR:0.80,95%CI:0.37-1.70). For transplant-ineligible patients, there was no difference in VTEs between CRDa (attenuated CRD) and CTDa (10.4%(n=95/916) vs 10.7%(n=97/910), aHR:0.97, 95%CI:0.73-1.29). However, arterial risk was higher with CRDa than CTDa (3.1%(n=28/916) vs 1.6%(n=15/910), aHR:1.91,95%CI:1.02-3.57). Thrombotic events occurred almost entirely within 6m of treatment initiation. Thrombosis was not associated with inferior progression-free or overall survival (OS), apart from inferior OS for patients with arterial events (aHR:1.53, 95%CI:1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated IMWG thrombosis prevention recommendations and compared to Myeloma IX, more patients were on thromboprophylaxis (80.5% vs 22.3%) with lower VTE rates for identical regimens (CTD:13.2% vs 16.1%, CTDa:10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting new approaches are needed.

BACKGROUND:Multiple Myeloma (MM) is a hematological malignancy with genomic heterogeneity and poor survival outcome. Apart from the central role of genetic lesions, epigenetic anomalies have been identified as drivers in the development of the disease. METHODS:Alterations in the DNA methylome were mapped in 52 newly diagnosed MM (NDMM) patients of six molecular subgroups and matched with loci-specific chromatin marks to define their impact on gene expression. Differential DNA methylation analysis was performed using DMAP with a ≥10% increase (hypermethylation) or decrease (hypomethylation) in NDMM subgroups, compared to control samples, considered significant for all the subsequent analyses with p<0.05 after adjusting for a false discovery rate. RESULTS:We identified differentially methylated regions (DMRs) within the etiological cytogenetic subgroups of myeloma, compared to control plasma cells. Using gene expression data we identified genes that are dysregulated and correlate with DNA methylation levels, indicating a role for DNA methylation in their transcriptional control. We demonstrated that 70% of DMRs in the MM epigenome were hypomethylated and overlapped with repressive H3K27me3. In contrast, differentially expressed genes containing hypermethylated DMRs within the gene body or hypomethylated DMRs at the promoters overlapped with H3K4me1, H3K4me3, or H3K36me3 marks. Additionally, enrichment of BRD4 or MED1 at the H3K27ac enriched DMRs functioned as super-enhancers (SE), controlling the overexpression of genes or gene-cassettes. CONCLUSIONS:Therefore, this study presents the underlying epigenetic regulatory networks of gene expression dysregulation in NDMM patients and identifies potential targets for future therapies.

IMPORTANCE/OBJECTIVE:New York City is a global epicenter for the SARS-CoV-2 outbreak with a significant number of individuals infected by the virus. Patients with multiple myeloma have a compromised immune system, due to both the disease and anti-myeloma therapies, and may therefore be particularly susceptible to coronavirus disease 2019 (COVID-19); however, there is limited information to guide clinical management. OBJECTIVE:To assess risk factors and outcomes of COVID-19 in patients with multiple myeloma. DESIGN/METHODS:Case-series. SETTING/METHODS:Five large academic centers in New York City. PARTICIPANTS/METHODS:Patients with multiple myeloma and related plasma cell disorders who were diagnosed with COVID-19 between March 10th, 2020 and April 30th, 2020. Exposures: Clinical features and risk factors were analyzed in relation to severity of COVID-19. Main Outcomes and Measures: Descriptive statistics as well as logistic regression were used to estimate disease severity reflected in hospital admissions, intensive care unit (ICU) admission, need for mechanical ventilation, or death. RESULTS:Of 100 multiple myeloma patients (male 58%; median age 68, range 41-91) diagnosed with COVID-19, 74 (74%) were admitted; of these 13 (18%) patients were placed on mechanical ventilation, and 18 patients (24%) expired. None of the studied risk factors were significantly associated (P>0.05) with adverse outcomes (ICU-admission, mechanical ventilation, or death): hypertension (N=56) odds ratio (OR) 2.3 (95% confidence interval [CI] 0.9-5.9); diabetes (N=18) OR 1.1 (95% CI 0.3-3.2); age >65 years (N=63) OR 2.0 (95% CI 0.8-5.3); high dose melphalan with autologous stem cell transplant <12 months (N=7) OR 1.2 (95% CI 0.2-7.4), IgG<650 mg/dL (N=42) OR=1.2 (95% CI 0.4-3.1). In the entire series of 127 patients with plasma cell disorders, hypertension was significantly associated with the combined end-point (OR 3.4, 95% CI 1.5-8.1). CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Although multiple myeloma patients have a compromised immune system due to both the disease and therapy; in this largest disease specific cohort to date of patients with multiple myeloma and COVID-19, compared to the general population, we found risk factors for adverse outcome to be shared and mortality rates to be within the higher range of officially reported mortality rates.