Faculty Bibliography

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.

Background: Patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed to immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) have limited treatment options and poor outcomes. The BCMA- targeted CAR T cell therapy idecabtagene vicleucel (ide-cel; bb2121) is being developed to address the unmet need in this setting. Initial results from the ongoing phase II KarMMa study (NCT03361748), in which ide-cel is being investigated in patients with RRMM who had >=3 prior regimens (including an IMiD, a PI, and an anti-CD38 mAb) and were refractory to their last regimen per IMWG criteria, have been released. A systematic literature review identified 2 phase II clinical trials investigating the efficacy and safety of specific therapies under US FDA evaluation in this setting, namely selinexor plus dexamethasone (Sd; NCT02336815) and belantamab mafodotin 2.5 mg/kg (BM; NCT03525678).
Aim(s): To compare the efficacy outcomes of ide-cel from the ongoing KarMMa study with 1) Sd from STORM part 2 and 2) BM from DREAMM-2.
Method(s): Unanchored matching-adjusted indirect treatment comparisons were performed based on individual patient-level data from 128 infused patients in KarMMa and study-level data from 1) STORM part 2 and 2) DREAMM-2. Individual patient data were reconstructed based on the published Kaplan-Meier curves for time-to-event outcomes from the external studies. Between-study differences were summarized, and the most relevant differences in patient characteristics were identified from the literature and based on clinical expertise. Propensity score models were used to weight patients in KarMMa to predict outcomes in a population corresponding to each external study. Odds ratios were calculated for overall response rate (ORR) using weighted logistic regression models. Hazard ratios (HRs) were calculated for progression-free survival (PFS) and overall survival (OS) using weighted Cox proportional hazard models. Sensitivity analyses were performed to explore the relative treatment effects with other cohorts from the KarMMa trial, including the enrolled patients (N = 140) and patients receiving the target dose of 450 x 106 CAR+ T cells (N = 54).
Result(s): Ide-cel was associated with a higher ORR compared with both Sd and BM in a population matched to each external 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 also across different doses for both indirect comparisons, although the effective sample size was reduced substantially in some cases. Summary/Conclusion: Results from the matching-adjusted indirect comparison suggest that ide-cel offers improvements in efficacy compared with both Sd and BM, the only therapies for which there are currently phase II data in RRMM patients after anti-CD38 mAb treatment

Background: Patients (pts) who are triple-class-exposed to immunomodulatory drugs, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) have poor clinical outcomes on subsequent lines of treatment and limited treatment options.
Aim(s): To identify published evidence for therapies that have been investigated or currently used in triple-class exposed pts with relapsed and refractory multiple myeloma (RRMM).
Method(s): Searches were performed 6 January 2020 in Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials databases. Eligible studies had to have been completed <=5 years before the search date. Relevant conference proceedings for 2018 and 2019 were also included in the search. Study quality assessment included use of the Downs and Black checklist. Studies that did not explicitly require previous anti- CD38 mAb exposure but reported the proportion of pts who received this drug class were included.
Result(s): There were 24 studies identified; 11 real-world studies and 13 clinical trials. The Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure (MAMMOTH), a retrospective chart review of MM pts from 14 US academic centers, was the largest real-world study (Leukemia. 2019;33:2266-75). All pts (N = 275) were refractory to daratumumab or isatuximab and 249 received subsequent therapy after anti-CD38 therapy. The overall response rate (ORR) to the first regimen after anti-CD38 therapy was 31% overall and was 29% in the combined triple-refractory and quad-refractory subgroup (N = 148). Median progression-free survival (PFS) and overall survival (OS) after subsequent therapy was 3.4 and 9.3 months, respectively, among those who received >=1 subsequent regimen in the overall population. Other real-world studies were limited to abstracts or had a high risk of bias; ORR and median OS rarely exceeded 30% and 10 months, respectively. Three phase II clinical trials evaluated interventions that are approved or under consideration by the US FDA. STORM part 1 and part 2, assessed selinexor plus dexamethasone, a combination granted accelerated approval in the US for a highly refractory post-daratumumab population (RRMM pts with >=4 prior regimens and refractory to >=2 PIs, >=2 immunomodulatory drugs, and an anti-CD38 mAb); STORM part 2, which also included pts triple-class exposed to daratumumab, an immunomodulatory drug, and a PI (N = 122), reported an ORR of 26% and a complete response rate of 2%. The median duration of response was 4.4 months, median PFS was 3.7 months, and median OS was 8.6 months. The other phase II study, DREAMM-2, investigated belantamab mafodotin, an antibody-drug conjugate targeting B-cell maturation antigen (BCMA) in RRMM. This study evaluated 196 pts refractory to immunomodulatory drugs and PIs, and refractory/ intolerant to an anti-CD38 mAb. After a median follow-up of 6.3 months (2.5 mg/kg cohort, n = 97) and 6.9 months (3.4 mg/kg cohort, n = 99), ORR was 31% and 34%, respectively. Median PFS was 2.9 months (2.5 mg/kg) and 4.9 months (3.4 mg/kg). Median OS was not reported. Summary/Conclusion: Results from this systematic literature review (SLR) indicate that only limited efficacy data are available for therapies investigated in RRMM pts who have had prior exposure to an immunomodulatory agent, a PI, and an anti-CD38 mAb. Outcomes are generally poor, supporting an urgent need for better treatment options for triple-class-exposed pts with RRMM. The studies identified in this SLR provide a benchmark against which therapies in development, such as emerging BCMA-directed therapies, can be compared

PURPOSE/OBJECTIVE:Copy number changes and translocations have been studied extensively in many datasets with long term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets. METHODS:we performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the Total Therapy Trials (TT). RESULTS:As expected, the most commonly mutated genes were NRAS, KRAS, and BRAF making up 44% of patients. Double-Hit, BRAF and DIS3 mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF mutated patients showed co-occurring alterations in KRAS, NRAS or activating BRAF mutations suggesting they play a role in the oncogenesis of multiple myeloma (MM) by facilitating MAPK activation and may lead to chemo resistance. CONCLUSION/CONCLUSIONS:Overall, these data highlight the importance of mutational screening to better understand newly diagnosed MM (NDMM) and may lead to patient specific mutation-driven treatment approaches.

Preclinical data suggests that bortezomib can inhibit genotoxic stress response pathways and thereby restore sensitivity to DNAdamaging chemotherapeutic agents. This was the rationale for this study combining bortezomib with two chemotherapy agents. The trial recruited patients from 2006 to 2013 but has never been analysed or reported and provides insights into the role of standard chemotherapy agents in relapsed myeloma, for which there is little published evidence. VIM was a single centre phase 1/2 study of bortezomib, idarubicin and melphalan in relapsed or refractory myeloma. Phase 1 was a 3+3 design with escalating doses of idarubicin and melphalan in combination with 1.3 mg/m2 bortezomib administered on D1,4,8,11 on a 4 weeks cycle. Phase 2 was dose expansion at the maximum tolerated dose (MTD) in a further 20 patients to explore efficacy. Treatment was for 3 cycles. Following VIM, patients were allowed to directly proceed to other treatments including autologous transplant (ASCT). The primary objective was safety and tolerability. Secondary endpoints were response, Progression Free and Overall Survival (PFS, OS). Key inclusion criteria were relapsed or refractory myeloma following >=1 previous therapies, platelet count >=70 x109/L, white cell count >=3.0 x109/L and creatinine clearance of >=40 mls/min. Dose limiting toxicity was defined as any grade 4 non-haematological toxicity, any grade 3 nonhaematological toxicity not resolving to grade 2 within 2 weeks of end of cycle and any grade 4 haematological toxicity except neutropenia not resolving to grade 3 within 2 weeks of end of cycle. The study recruited 3, 3, 7 patients on dose levels 1, 2 and 3 respectively during the dose escalation phase. The MTD dose was defined as level 2 which was: Idarubicin 5 mg/m2 PO D4, 5; melphalan 15 mg/m2 IV D4; bortezomib 1.3 mg/m2 D1, 4, 8, 11 on a 4 weeks cycle. An additional 20 patients were recruited to the dose expansion phase. Median patient age was 62. Median prior lines of therapy was 4 (range 2-8). Adverse Events at the MTD level are listed in table 1. The main toxicity was haematological, with 74% of patients having grade >=3 neutropenia, 78% grade >=3 thrombocytopenia. 26% of patients experienced grade >=3 infective complications. There were 3 deaths on treatment; all had progressive or refractory disease at time of death, two with concurrent respiratory infection but neither were neutropenic or directly treatment related. In the intention to treat (ITT) cohort, the overall response rate (ORR) was 79%, with 46% achieving >=very good partial response (VGPR) of which 14% were near complete response (nCR, defined as no paraprotein by serum protein electrophoresis and <5% plasma cells on trephine but without immunofixation to confirm CR). In the MTD cohort the ORR was 85%, with 50% >=VGPR and 20% nCR. PFS reflects the heterogeneity of treatment after VIM, including ASCT. Median OS was 19.0 months in the ITT cohort and 26.1 months in the MTD cohort. Treatment options at relapse have multiplied since this trial was designed. However, VIM is a generic, relatively inexpensive, steroid free regimen with defined toxities and significant efficacy. The main side effects, as expected, were haematological. Responses were higher than expected for median 5th line therapy suggesting possible synergy in this combination and reminding us that standard chemotherapies can have a role in relapsed myeloma if other options are unavailable and blood counts are reasonable

Disease factors such as tumor burden and molecular risk affect myeloma patient outcomes as well as patient factors that impact the capacity to deliver treatment. How the relative importance of these factors changes with patient age has not previously been investigated comprehensively. We analyzed data from 3894 patients of all ages uniformly treated in a large clinical trial of myeloma patients, Myeloma XI. Even with novel therapeutic approaches progression-free survival (PFS) and overall survival (OS) are affected by age with a stepwise reduction in PFS and OS with each decade increase. Renal function deteriorated with increasing age whilst the frequency of t(4;14) and del(17p) decreased and gain(1q) increased. The relative contribution of performance status, international staging score and molecular risk to progression-free and overall survival varied by age group. Molecular events have a larger effect on outcome in younger patients with their relative contribution diminishing in the elderly. Performance status is important for patient outcome at all ages suggesting that physical frailty may be a more important predictor of outcome than age itself. Significant differences in the factors driving patient outcomes at different ages are important to consider as we design disease segmentation strategies to deliver personalized treatment approaches.