Siegel, David S.

8503 Background: Outcomes are poor in triple-class exposed RRMM patients (pts) who progress on immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and CD38 antibodies (mAbs). Ide-cel, a BCMA targeted CAR T cell therapy, showed promising tolerability and efficacy in RRMM pts in the phase I CRB-401 study ( NEJM2019;380:1726). We present primary efficacy and safety data from the pivotal phase II KarMMa trial of ide-cel in RRMM (NCT03361748). Methods: Enrolled pts had ≥3 prior regimens (including IMiD, PI, and CD38 mAb) and were refractory to their last regimen per IMWG criteria. After lymphodepletion (cyclophosphamide 300 mg/m2+ fludarabine 30 mg/m2 x 3), pts received 150─450 × 106 CAR+ T cells (target dose range). Endpoints included overall response rate (ORR; primary), complete response (CR) rate, duration of response (DoR), and PFS. Results: Of 140 pts enrolled, 128 received ide-cel. Median age was 61 y; median no. of prior regimens was 6; 84% were triple- and 26% were penta-refractory. Most pts (88%) had bridging therapy. At data cutoff (16 Oct 2019), median follow up was 11.3 mo. ORR was 73% and median PFS was 8.6 mo; both increased with higher dose (Table). All subgroups had an ORR ≥50%, including older and high-risk pts. Most common any-grade (Gr) toxicities were cytopenias (97%) and cytokine release syndrome (CRS; 84%). CRS was mainly Gr 1/2; 5 pts (5%) had Gr 3, 1 had Gr 4, and 1 had Gr 5 (at 300 × 106). Neurotoxicity developed in 23 pts (18%); 4 (3%) Gr 3 and 0 Gr ≥4. Median peak CAR+ T cell expansion occurred at 11 d. Expansion was higher in responders and parameters (AUC0−28d, Cmax) increased with higher dose, with exposure overlap across doses. Persistence was durable, with CAR+ T cells detected in 29/49 (59%) and 4/11 pts (36%) at 6 and 12 mo. Conclusions: Ide-cel demonstrated deep, durable responses in heavily pretreated RRMM pts. Efficacy and safety reflected prior reports and support a favorable ide-cel clinical benefit-risk profile across the target dose range. Clinical trial information: NCT03361748 . [Table: see text]

Abstract In an effort to identify novel genetic abnormalities in multiple myeloma (MM) we analyzed an initial set, as part of the Multiple Myeloma Research Consortium (MMRC) Genomics Initiative, of 94 MM patient samples on high-resolution array-based comparative genomic hybridization (aCGH) and gene expression profiling (GEP) technologies. The MMRC Genomics Initiative is a three-year research program spanning a full-spectrum of genomic technologies with the goal of analyzing 250 MM patient samples by 2009. Raw data from the Initiative are released in near real time through the MMRC Multiple Myeloma Genomics Portal. This initial aCGH dataset from the Agilent 244K platform represents the highest resolution gene copy number analysis with corresponding GEP released to date in MM. It has confirmed the cytogenetic definitions of MM with the data set being split between patients with hyperdiploid and non-hyperdiploid MM. Furthermore, the 244K platform has helped to refine minimal regions of change present on 1p, 1q, 6q, 8p, 13q, 14q, and 16q. A comprehensive screen of the dataset for genes residing in regions of homozygous deletion identified 105 genes. The most commonly affected gene was CDKN2C(p18) (8.3%) while 12 other regions were recurrently targeted. Several of these regions were recently implicated in the pathogenesis of MM but the large majority represents novel observations. The aCGH and GEP data were integrated using two different programs developed by the core institutions (The Broad Institute of Harvard & MIT and Translational Genomics Research Institute). First, Genomic Identification of Significant Targets in Cancer (GISTIC), which identifies highly significant regions of change and a limited set of candidate genes within these regions, was used to identify 285 genes associated with DNA content alterations. Second, Breakpoint Expression Correlation (BEC), which identifies dysregulated genes on either side of a copy number alteration, was used to identify 194 genes with expression changes associated with a breakpoint. This latter gene list includes all known IgH translocation target genes identified to date in myeloma. Overlapping the gene lists generated by GISTIC, BEC, and the homozygous deletion screen identified a number of genes previously implicated in MM such as CDKN2C(p18), CYLD, BIRC2/BIRC3, and two novel genes, FAM46C and RNF6. Ongoing data integration with RNAi and high content sequencing projects of the current Initiative holds great promise in furthering our understanding of MM. The MMRC Genomics Initiative and resulting efforts from the myeloma research community will increase our understanding of MM at the molecular level, help to identify new targets, and ultimately lead to the development of better, more effective therapies for myeloma.

Abstract Background: Venous thrombotic events (VTE) are a common complication of therapy with the lenalidomide plus dexamethasone regimen. The incidence of VTE with RD is approximately 20%, and can be lowered with the use of effective thromboprophylaxis, avoidance of erythropoietin, and the use of lower doses of dexamethasone. The goal of this study was to determine the impact of VTE on overall survival of patients with newly diagnosed myeloma by studying events occurring in ECOG E4A03 phase III trial of lenalidomide plus high (standard) dose dex (RD) versus lenalidomide plus low dose dex (Rd) in newly diagnosed myeloma (MM). Methods: Pts with untreated, symptomatic MM were eligible. Pts in the RD arm (Arm A) received lenalidomide 25 mg/day PO days 1–21 every 28 days plus dex 40 mg days 1–4, 9–12, and 17–20 PO every 28 days; pts in the Rd arm (Arm B) received lenalidomide at the same dose plus dex 40 mg days 1, 8, 15, and 22 PO every 28 days. The trial initially did not mandate routine thromboprophylaxis, but recommended that such treatment be considered. After the first 264 patients were enrolled the trial was amended to require mandatory thromboprophylaxis of aspirin for all patients, with a recommendation to use stronger thromboprophylaxis with either warfarin (target INR 2–3) or low molecular weight heparin among patients in the RD arm. Results: 445 pts (median age, 65 yrs) were accrued; 223 randomized to RD, 222 to Rd. Median follow-up time is 30 months. Overall VTE including deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 18.5% of patients; 25.6% in Arm A and 11.4% in Arm B. Rates for the first 4 cycles of treatment were 20.2% in Arm A and 8.2% in Arm B, P<0.01. Rates did not change substantially before and after the prophylaxis amendment. A partial response (PR) or higher was seen in 82.1% of pts who experienced VTE compared with 74.6% of pts who did not experience VTE, P=0.19. Overall VGPR rates also were not inferior. Pts who had VTE, however, had significantly higher other grade 3–5 toxicities such as hyperglycemia (14.6% vs 7.5%, P=0.051), cardiac ischemia (4.9% vs 0.8%, P=0.002), non-neuropathic weakness (13.4% vs 6.4%, P=0.039), infection/pneumonia (17.1% vs 11.1%, P=0.138) and fatigue (18.3% vs 10.5%, P=0.060). In a Cox PH model, VTE status as a time-varying covariate was marginally significant: HR 1.54 95%CI (0.96–2.47), P=0.074, suggesting patients that develop VTE have a higher hazard of death. Conclusions: The occurrence of VTE may adversely affect the survival of patients with newly diagnosed myeloma receiving Rev-Dex. VTE was associated with a higher frequency of other serious adverse events. Prevention of VTE events is a priority. Besides lowering the dose of dexamethasone, studies investigating optimum thromboprophylaxis are needed.

Abstract Background: Outcome of patients with Multiple Myeloma (MM) is influenced by a variety of baseline prognostic factors, most importantly presence of chromosomal abnormalities. Nevertheless, these biologically determined risk-factors do not account for a significant subset of patients whose outcome varies greatly from what one expects based on the underlying prognostic characteristics. We have previously demonstrated that outcome in myeloma is dictated not only by baseline risk-factors but also response to therapy (R2, risk and response dependent outcome). We studied response duration following initial therapy as a prognostic factor for long-term overall survival in myeloma in three ECOG clinical trials that enrolled patients with newly diagnosed myeloma. Methods: Data from three studies with long-term, mature follow up were analyzed: E9486, E5A93, and E1A00. The regimens used in these studies included Thalidomide/Dex, Dex, VBMCP, VBMCP + alpha-IFN, and VBMCP + Cyclophosphamide. Among progressed/relapsed patients, the association between time to progression and overall survival since relapse was explored using Cox proportional hazards model, in which time to progression was analyzed as a continuous variable. In addition, the association between response duration and overall survival since relapse was explored similarly among relapsed responders. Treatment effect and calendar time of diagnosis have been adjusted in the model. Also, to determine the best cut off point associated with the best differentiation of patients with short OS after relapse, an outcome-oriented method using log likelihood value was applied. Results: Among the 1136 patients enrolled in the three studies, 625 patients who have documented disease relapse have been included in the current study. Of these, 471 patients had responded to the treatment before relapse. Only 33 patients are alive as of Dec., 2007. For all 625 patients, the time to progression (continuous variable) was significantly associated with overall survival from the time of relapse/progression (P<0.0001), with hazard ratio of 0.77 (95%CI: 0.72~0.81) at time to progression increasing by 1 year (i.e., the later the progression/relapse, the lower the risk). The best cutoff point of the time to progression is 3 yrs (the 75th percentile). The hazard ratio of patients progressing within 3 yrs since randomization vs. after 3 yrs is 2.4 (95% CI: 1.9 ~ 2.9) and P-value<0.0001. The median OS from relapse was 0.96 years for the former vs. 2.43 years in the latter group (Figure). Among the 471 relapsed responders, the response duration (continuous variable) was also significantly associated with overall survival since relapse (P<0.0001), with hazard ratio of 0.76 (95%CI: 0.70~0.81) at response duration increasing by 1 year (i.e., the longer the response duration, the lower the risk). The effects seen with each regimen are detailed in the table. The best cutoff point of the response duration is 2 yrs (median). The hazard ratio of patients with response duration less than or equal to 2 yrs vs. more than 2 yrs is 2.1 (95% CI: 1.7 ~ 2.6) and P-value<0.0001. Conclusions: Among patients treated with alkylator based therapy, the duration of response from the initial therapy is an important predictor of the subsequent outcome among patients with myeloma. Given the heterogeneity of the disease and imprecise predictive ability of the known baseline prognostic factors, the duration of response to initial therapy should be taken into account, to deliver risk and response-adapted therapy. The prognostic value of this feature across different clinical trials, points towards the role of underlying disease biology, both disease aggressiveness and ability to rapidly develop resistance to therapies as two important determinants of outcome. Table 1: Hazard ratio of overall survival since relapse for patients progressed within 3 yrs since randomization vs. after 3 yrs in each treatment arm Treatment arm Treatment arm HR (95% CI) P-value TTP<=3yrs vs. >3 yrs Thal/Dex N/A N/A Dex 0.4 (0.05, 3.9) 0.46 VBMCP(E5A93+ E9486) 1.9 (1.4, 2.7) 0.0001 VBMCP+alpha2IFN (E5A93+ E9486) 3.0 (2.2, 4.1) <0.0001 VBMCP+CYCLOPHOSPHAMIDE 2.3 (1.5, 3.6) 0.0001 Response duration <=2 yrs vs. >2 yrs Thal/Dex 0.2 (0.003, 18.5) 0.51 Dex 0.15 (0.02, 0.98) 0.048 VBMCP(E5A93+ E9486) 1.7 (1.2, 2.3) 0.0009 VBMCP+alpha2IFN (E5A93+ E9486) 3.0(2.1, 4.3) <0.0001 VBMCP+CYCLOPHOSPHAMIDE 2.1 (1.4, 3.3) 0.006 Figure 1: Overall survival since relapse between patients progressed within 3 yrs since randomization vs. after 3 yrs. Figure 1:. Overall survival since relapse between patients progressed within 3 yrs since randomization vs. after 3 yrs.

Abstract The Multiple Myeloma Research Consortium (MMRC) Genomics Initiative is a three-year program to analyze tumor tissue from hundreds of multiple myeloma (MM) patients via gene expression profiling (GEP), comparative genomic hybridization (aCGH), and exon re-sequencing. In addition, RNAi knockdown of selected genes in MM tumor cell lines is being evaluated to identify potential new targets. All genomic data generated is scheduled for placement in an open-access Multiple Myeloma Genomics Portal pre-publication and in near real-time (www.broad.mit.edu/mmgp). Additionally, samples are also destined for drug validation and correlative science on clinical protocols as this study moves forward. This comprehensive project is spearheaded by the MMRC and conducted via collaboration with the Eli and Edythe L. Broad Institute of MIT and Harvard, the Translational Genomics Research Institute (TGen), Mayo Clinic Arizona, and The Dana-Farber Cancer Center. The study is supported by the collection from member institutions of the MMRC of bone marrow aspirates and matched peripheral blood samples from over 1000 patients. Specific genomic technologies that are currently being employed across this sample set include GEP using Affymetrix Human Genome U133A 2.0 Plus Arrays, and, in parallel, efforts to identify regions of genomic gain and loss are using Agilent Human Genome CGH arrays. In contrast to other large-scale genomic projects based on exon-sequencing of targeted gene sets, this project will be the first to perform genome-scale single molecule sequencing (SMS) of DNA from patient specimens. Results will be targeted against candidate classes of genes (e.g. kinases, phosphatases, known oncogenes and tumor suppressors), and genes from GEP or within candidate regions of copy gain or loss identified by the aCGH experiments. Mutations will be further validated in an independent set of patient specimens. Finally we will attempt to identify points of vulnerability of MM through systematic loss-of-function screens in myeloma cell lines using high-throughput RNA interference (using both shRNA and siRNA platforms). Importantly, data generated from this genomics initiative will ultimately be made public pre-publication through the established MMRC Multiple Myeloma Genomics Portal. Data from all aspects of this project (sample collection and analyte isolation, GEP, aCGH, SMS, RNAi and bioinformatics) will be described in this presentation. The power of this study is the comprehensive collection of gene expression, CGH, and genome sequencing on a single reference set of clinically annotated samples. The addition of RNAi screens makes this a very important and unique data resource, which we hope will help expedite the discovery of novel targeted agents for MM scientific community.

e19505 Background: CFZ combined with dexamethasone is approved to treat pts with RRMM, with CFZ given once-weekly at 70 mg/m2 (Kd70 QW) or twice-weekly at 56 mg/m2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW. We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION-1 trials. Methods: Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION-1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION-1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW. Results: Among BTZ non-refractory pts with 2–3 lines of prior therapy, median progression-free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well-tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69). Conclusions: This post hoc analysis suggests that once-weekly Kd70 has a comparable benefit-risk profile to twice-weekly Kd56. Clinical trial information: NCT02412878, NCT01677858, NCT01568866.

e19517 Background: Investigators cite complicated test (T) schedules as barriers to the conduct of clinical trials, especially T that do not contribute to outcome or pt safety. In MM protocols, some T are prone to being done inaccurately (e.g. UPEP, 24 hour urine collections), or are not useful (e.g. uric acid, AST/ALT) in determination of response (R) or safety. These T lead to increased cost, protocol violations, and do not enhance outcome. Methods: We analyzed data submitted for pts on E4A03 to examine frequency of missing data for R T: serum and urine (U) PEP, immunofixation (IFE) bone surveys (BS), and safety labs for C1-4. Results: Table outlines % pts with completed T. Most had T for serum M protein, as well as heme T but serum and U PEP, and IFE dropped off by C4. Other T e.g. uric acid were completed in 77%. Only 79% of pts had a BS repeated at C4. Incorrect or missing U data led to categorization of 16/445 (3.6%) pts as ineligible and was most frequent reason for ineligibility (69%). Missing U data led to 13/26 pts not evaluable. Analysis of SAE during the C1-4 revealed no SAE for hyperuricemia and < 5 SAE for AST/ALT. Only 5% of pts had lab-based SAE filed in 4 C. Conclusions: Required U T and BS to assess R in E4A03 were missing or completed inadequately and caused pts to be ineligible and or not evaluable. Such T need to be eliminated or replaced. Strategies to monitor data submission in real time may reduce subject loss due to T error. The requirement for routine T should be reassessed to create simpler trial design. Clinical trial information: NCT00098475. [Table: see text]

8035 Background: Patients (pts) with relapsed and refractory multiple myeloma (RR MM) who are refractory or intolerant to both bortezomib (BTZ) and immunomodulators (IMiDs; thalidomide [Thal] or lenalidomide [Len]) (ie, “double-refractory/intolerant”), have few therapeutic options and a poor prognosis. Carfilzomib (CFZ), a next generation proteasome inhibitor (PI), has shown durable single-agent activity in clinical studies including 003-A1, an open-label, single-arm phase 2b trial in RR MM. The present analysis describes clinical activity in pts from 003-A1 with double-refractory/intolerant disease and in other groups of clinical interest including pts with disease refractory to all 5 approved classes of anti-MM tx (alkylators, anthracyclines, corticosteroids, IMiDs, and PIs) in clinical use (“refractory to all approved tx”). Methods: Pts from 003-A1 with double-refractory/intolerant disease were analyzed, as were pts with disease refractory to all approved tx. CFZ was given on days 1, 2, 8, 9, 15, 16 of 28-day cycles (C), (20 mg/m2 in C1; 27 mg/m2 in C2–12). Primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR), overall survival, and safety. Results: The study ORR was 22.9% with median DOR of 7.8 mo (N=266). 228 pts (86%) with double-refractory/intolerant disease had ORRs of 20.6% and a median DOR of 7.4 mo. Conclusions: Single-agent CFZ demonstrated clinically meaningful, durable responses in pts with double-refractory/intolerant MM or disease refractory to all 5 approved classes of tx. The ORRs across groups of clinical interest were generally consistent with results for the entire study population. These results are notable for a next-generation PI and demonstrate the activity of single-agent CFZ in pts with advanced stage MM. [Table: see text]

7522 Background: Lenalidomide (len), an analog of thalidomide (thal) is a novel, oral immunomodulatory agent that is effective against multiple myeloma (MM). Two randomized, Phase III trials (MM009 and MM010) have recently demonstrated superior responses and overall survival (OS) for patients (pts) treated with len and dexamethasone (dex) in comparison with dex-placebo. This is a prospective subgroup analysis to assess the impact of prior therapy with thal on the sensitivity of MM to subsequent lenalidomide. Methods: We evaluated 692 pts from both trials (MM009 and MM010). The pts had relapsed/refractory MM, were not refractory to dex and were randomized to receive either len (25 mg daily for 3 weeks (wks) every 4 wks) plus dex (40 mg on days 1–4, 9–12, 17–20 every 4 wks for 4 cycles, then 40 mg on days 1–4 every subsequent cycle) or placebo plus dex. Standard criteria were used to evaluate response and TTP. Results: Pooled data from 692 pts showed superior median TTP (48.1 vs 20.1 wks) and OR (59.2% vs 22.5%) in pts treated with len/dex compared to dex-placebo (p <0.001). Although subgroup analysis of pts with prior thal therapy revealed that pts who received len/dex had significantly improved OR, PR CR and median TTP than pts who received dex-placebo, OR, CR and TTP were highest in len/dex pts not previously treated with thal. Multivariate analysis indicates that after controlling for the treatment factor and baseline disease characteristics, whether or not pt had prior exposure to thal is a marginally significant variable to predict TTP. The risk of deep venous thrombosis and pulmonary embolism in these subgroups will be updated on further analysis. Conclusions: Lenalidomide in combination with dexamethasone is more effective than dexamethasone-placebo regardless of prior thalidomide in relapsed/refractory multiple myeloma. [Table: see text] [Table: see text]

LBA8025 Background: We compared lenalidomide plus high (standard) dose Dex (R+HighD) versus lenalidomide plus low dose Dex (R+LowD) in newly diagnosed MM. Methods: Pts with untreated, symptomatic MM were eligible. Pts in both arms received lenalidomide 25 mg/day PO days 1–21 every 28 days. In addition, pts in the R+HighD arm received Dex 40 mg days 1–4, 9–12, and 17–20 PO every 28 days; pts in the R+LowD arm received Dex 40 mg days 1, 8, 15, and 22 PO every 28 days. The primary null hypothesis was that response rates at 4 months on the 2 arms are equivalent. Planned sample size was 196 eligible pts per arm with one-sided 0.10 Type I and 0.05 Type II error rate. Pre-planned interim analysis is performed by an independent DMC when full information is available on 25%, 50% and 75% of accrual. All analysis were intent to treat. Results: 445 pts (median age, 65 yrs) were accrued; 223 randomized to R+HighD, 222 to R+LowD. Arms were well balanced for age, gender, stage, bone lesions, hemoglobin, beta-2 microglobulin, performance status, bone marrow plasma cells, and M protein levels at baseline. Major grade 3 or higher toxicities included thromboembolism (22.1% with R+HighD vs 6.1% in R+LowD), infection/pneumonia (15.7% vs 7.5%) and hyperglycemia (9.7% vs 6.6%). Grade 3 or higher non-hematologic toxicities occurred in 65.9% (R+HighD) versus 54.9% (R+LowD) respectively; corresponding grade 4 or higher rates were 20.3% vs 13.1% respectively. Overall survival (OS) at first interim analysis was significantly superior with R+LowD, P<0.001; one year survival 96.5% (R+LowD) versus 86% (Rev+HighD). OS differences in favor of R+LowD were seen in pts <65 (P=0.015; one year rate 98% vs 90%) and pts 65 and older (P=0.004; one year rate 95% vs 83%), respectively. DMC recommended release of survival results, and recommended switching all pts to R+LowD. DMC also recommended closure of an expansion phase trial of R+HighD investigating optimal thromboprophylaxis. Conclusions: Lenalidomide plus low-dose dexamethasone is associated with superior OS compared to lenalidomide plus high-dose dexamethasone. This study has major implications for future use of high-dose dexamethasone in the treatment of MM. No significant financial relationships to disclose.