Vishwamitra, Deeksha

Background:Patients (pts) with multiple myeloma (MM) often receive immunomodulatory drugs (IMiDs; eg, lenalidomide), proteasome inhibitors (eg, bortezomib), and anti-CD38 monoclonal antibodies (mAbs) as part of their initial treatment. However, most pts relapse following initial treatment, with increasing attrition rates observed at each subsequent line of therapy (LOT), creating an unmet need for treatment options for pts with relapsed/refractory MM (RRMM) who have prior exposure to these agents. Current regimens for pts who have prior exposure to lenalidomide and anti-CD38 mAbs include elotuzumab, pomalidomide, and dexamethasone (EPd; approved in Europe and the US) and pomalidomide, bortezomib, and dexamethasone (PVd; approved in Europe and Australia), but disease control, as well as depth and durability of response, could be improved. Talquetamab (tal) and teclistamab (tec), targeting CD3 and either G protein-coupled receptor family C group 5 member D (GPRC5D, tal) or B-cell maturation antigen (tec), are the first T-cell redirecting bispecific antibodies (BsAbs) approved as monotherapies in Europe and the US for the treatment of pts with triple-class exposed (TCE) RRMM. Use of these novel immunotherapies in earlier LOTs, either with a dual-antigen targeting approach or by enhancing the activity of the BsAb with an IMiD (pomalidomide), may provide deeper, more durable responses and improve pt quality of life. Preliminary data using these combination treatments have shown promising results: in the phase 1b MonumenTAL-2 study (NCT05050097), tal+pomalidomide (tal-P) demonstrated overall response rates (ORRs) of >84% in pts with RRMM with ≥2 prior LOTs and in the phase 1b/2 RedirecTT-1 study (NCT04586426), tal+tec (tal-tec) showed ORRs of >77% in pts with TCE RRMM. MonumenTAL-6 (NCT06208150) is a randomized, open-label, multicenter, phase 3 study comparing the efficacy of tal-P vs investigator's choice of EPd or PVd and tal-tec vs investigator's choice of EPd or PVd in pts with RRMM with 1-4 prior LOTs, including lenalidomide and an anti-CD38 mAb. Study Design and Methods: Eligibility includes pts aged ≥18 years with documented MM per International Myeloma Working Group (IMWG) criteria, with measurable disease at screening, an Eastern Cooperative Oncology Group performance status of 0-2, who have received 1-4 prior LOTs (including lenalidomide and an anti-CD38 mAb in any prior LOT), and have progressive disease on or after their last therapy. Pts with prior exposure to pomalidomide, tec, or GPRC5D-directed therapies are excluded. Approximately 795 pts are randomized 1:1:1 to receive tal-P, tal-tec, or investigator's choice of EPd or PVd. Tal is administered subcutaneously at 0.8 mg/kg every other week (Q2W), and tec is administered subcutaneously at 3.0 mg/kg every 4 weeks (Q4W) following step-up doses of each. Pts are permitted to switch from Q2W to Q4W tal dosing following a confirmed very good partial response or better (≥VGPR) at cycle 5. Pomalidomide, EPd, and PVd are administered per approved dosing schedules. Randomization is stratified by number of prior LOTs (1 vs ≥2), International Staging System stage at screening (I vs II/III), and investigator's choice of treatment (EPd vs PVd). Pts receive study treatment until disease progression, start of subsequent anti-MM treatment, death, intolerable toxicity, withdrawal of consent, or end of study, whichever occurs first. A finite dosing approach is employed for tal and tec. The primary endpoint is progression-free survival (PFS). Secondary endpoints include ORR assessed per IMWG 2016 criteria, ≥VGPR rate, complete response (CR) or better rate, rate of minimal residual disease-negative CR, overall survival, PFS on next LOT, time-to-next treatment, and pt-reported outcomes. This study is actively recruiting, with more than 160 locations in 26 countries. Results will provide insights into the efficacy of the combination of BsAbs in therapeutic strategies that exploit their different mechanisms of action to overcome treatment resistance and improve outcomes of pts with TCE RRMM in earlier LOTs.

Background: Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by a complex genomic landscape with molecular and clinical heterogeneity. Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor currently under investigation as a potential targeted therapy for the treatment of relapsed/refractory (RR) MM. Using a next-generation sequencing (NGS)-based approach, the mutational landscape and gene expression profile (GEP) of patients (pts) with RRMM in BELLINI was evaluated for potential impact on observed clinical outcomes in key biomarker subgroups. Methods: BELLINI (NCT02755597) is a randomized, double-blind, multicenter Phase 3 study of bortezomib + dexamethasone (Bd) + either Ven or placebo (Pbo) in pts with RRMM who received 1-3 prior therapies and were sensitive or naïve to proteasome inhibitors. Pts were randomized 2:1 to receive Ven 800 mg/d or Pbo + Bd. 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 (qPCR), cytogenetic abnormalities by interphase fluorescence in situ hybridization (FISH), identification of somatic mutations by whole-exome sequencing (WES), and transcriptomic analysis by RNA sequencing (RNAseq). Correlation between mutational status, BCL2high status (Harrison et al. Blood. 2019:134 suppl:142), cytogenetics, GEP, and survival outcomes were examined by pairwise t-test and by hazard ratio (HR) from Cox proportional hazard model. Results: As of the data cutoff (13 Sep 2019), 291 pts were randomized (194 to Ven and 97 to Pbo); 262 pts (90.0%) were evaluable by FISH, 257 pts (88.3%) by qPCR, 197 pts (67.7%) by WES, and 184 pts (63.2%) by RNAseq. The mutational landscape of evaluable pts was highly heterogeneous (Figure 1A). MAPK pathway mutations were the most prevalent (62/197 pts; 31.5%); however, recurrent mutations in the NF-kB pathway (TRAF3 or CYLD) were also observed (12/197 pts; 6.1%). Within the MAPK pathway, the most frequently mutated genes were KRAS (39/197 pts; 19.8%), NRAS (8/197 pts; 4.1%), BRAF (8/197 pts; 4.1%), and NF1 (12/197 pts; 6.1%). Although a higher rate of pts with a MAPK mutation was observed in the t(11;14) and BCL2high subgroup compared to pts without these biomarkers (39/101 pts [38.6%] vs 23/95 pts [24.2%]; P=.04), improvement in progression-free survival (PFS) with Ven+Bd was observed in pts with (HR=0.08; 95% CI, 0.02-0.31; P<.001) or without (HR, 0.31 [95% CI, 0.16-0.63]; P=.001) a MAPK pathway mutation. High somatic mutation loads are associated with increased genomic instability, resistance to therapy, and decreased overall survival (OS) in MM. High tumor mutation burden (TMB), defined as ≥20 mutations/megabase of sequenced DNA, was observed in 12/197 pts (6.1%). Although there were a limited number of high TMB pts, reduced PFS (HR, 4.55 [95% CI, 2.33-8.88]; P<.001) and OS (HR, 3.89 [95% CI, 1.76-8.56]; P<.001) compared to low TMB pts was observed regardless of treatment arm. WES detected a recurrent BCL2 mutation (Ala43Thr) in 15/197 pts (7.6%). This BCL2 mutation has not previously been identified in MM and did not appear to affect survival outcomes among pts in either arm. Supervised clustering of RNAseq data grouped pts into respective MM GEP (Zhan et al. Blood. 2006;108:2020) at the following frequencies: CD-1 (2.7%), CD-2 (8.2%), HY (40.2%), MF (1.6%), MS (10.9%), LB (5.4%), and PR (31.0%). As shown in Figure 1B, 16/20 pts (80%) allocated to the CD-1/CD-2 cluster had a t(11;14) mutation, but 17/20 pts (85%) and 2/3 pts (67%) in MS and MF GEP groups had t(4;14) or t(14;16) mutations, respectively. The HY GEP group was primarily (56/74 pts; 76%) hyperdiploid by FISH. Though a higher rate of pts with a HY GEP (50/98 pts [51.0%] vs 24/86 pts [27.9%]; P<.001) and a lower rate of PR GEP (11/98 pts [11.2%] vs 46/86 pts [53.5%]; P<.001) were observed in the t(11;14) and BCL2high subgroups compared with non-t(11;14) and BCL2low subgroups, respectively, improvement in PFS with Ven+Bd was independent of GEP classification. Conclusion: Using an integrative approach of genomic and transcriptomic profiling, response to Ven+Bd in key biomarker subgroups was shown to be independent of concurrent mutations in key oncogenic signaling pathways and GEPs known to be prognostic in MM; however, high mutation load appears to be a clinically relevant risk factor that negatively affects survival in MM. Disclosures O'Dwyer: Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Research Funding; Carrick Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy; ONK Therapeutics: Consultancy, Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Spencer:Roche: Honoraria; Sanofi: Consultancy, Honoraria; Pharmamar: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; HaemaLogiX: Consultancy, Honoraria, Research Funding. Kumar:Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genecentrix: Consultancy; Cellectar: Other; MedImmune: Research Funding; Karyopharm: Consultancy; Sanofi: Research Funding; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Carsgen: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding. Popat:AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol Myers Squibb: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria. Moreau:Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Novartis: Honoraria. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Jalaluddin:AbbVie: Current Employment, Other: may hold stock or stock options. Yang:Abbvie: Current Employment, Current equity holder in publicly-traded company. Lu:AbbVie: Current Employment, Current equity holder in publicly-traded company. Zha:Abbvie: Current Employment, Current equity holder in publicly-traded company. Dunbar:Abbvie: Current Employment, Current equity holder in publicly-traded company. Vishwamitra:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Mantis:Abbvie: Current Employment, Current equity holder in publicly-traded company. Melhem-Bertrandt:AbbVie: Current Employment; Astellas: Ended employment in the past 24 months. Ross:AbbVie: Current Employment, Current equity holder in publicly-traded company. Harrison:F. Hoffmann-La Roche: Consultancy, Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Janssen: Honoraria; Haemalogix: Consultancy; BMS: Consultancy, Honoraria.

AbstractVenetoclax (Ven) is a selective small‐molecule inhibitor of BCL‐2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open‐label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21–day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL‐2) and BCL2L1 (BCL‐XL) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow‐up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF‐kB. VenDex demonstrated efficacy and manageable safety in heavily‐pre‐treated patients with t(11;14) R/R MM.