Highlights from Dec. 4, 2018
Daratumumab in combination with lenalidomide and dexamethasone may represent a new standard of care for patients with newly diagnosed multiple myeloma ineligible for transplant
Thierry Facon, MD (Hopital Claude Huriez, Lille, France), presented results from the phase 3 MAIA trial evaluating efficacy of daratumumab in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma. In all, 737 patients (ineligible for high-dose chemotherapy or autologous stem cell transplant due to age [greater than or equal to 65] or comorbidities) were randomized 1:1 to receive 28 day cycles of lenalidomide (25mg QD days 1-21) + dexamethasone (40mg on d1, d8, d15, d22) with or without daratumumab (16mg/kg QW cycles 1/2, Q2W cycles 3-6, Q4W starting cycle seven). At median follow up of 28 months, patients treated with daratumumab (n=364) had a 44 percent reduction in risk of disease progression compared to patients who received lenalidomide/dexamethasone only (HR = 0.56, 95 percent CI: 0.43 – 0.73; p less than 0.0001). Progression-free survival (PFS) benefit was observed across subgroups when treated with daratumumab. The overall response rate (ORR) of patients receiving daratumumab was 93 percent (complete response [CR] = 30, stringent CR [sCR] = 17, very good partial response [VGPR] = 32, PR = 14], significantly increased compared to the lenalidomide/dexamethasone cohort (ORR = 81 percent, CR = 12, sCR = 12, VGPR = 28, PR = 28; p less than 0.0001). 24 percent of patients treated with daratumumab had minimal residual disease (MRD) -negative disease, while only 7 percent of patients receiving lenalidomide/dexamethasone were MRD-negative. MRD-negative status correlated with a PFS benefit in both cohorts. An overall survival (OS) benefit was also observed in patients treated with daratumumab compared to those in the lenalidomide/dexamethasone cohort (events = 17 percent and 21 percent, respectively; HR = 0.78, 95 percent CI = 0.56 – 1.1). No new safety signals were observed compared to previous trials. Together, these data support combination daratumumab + lenalidomide + dexamethasone as a new standard of care for patients with newly diagnosed multiple myeloma.
Ibrutinib + rituximab provides clinical benefit over chemoimmunotherapy in patients with untreated chronic lymphocytic leukemia
Tait Shanafelt, MD (Stanford University, Stanford, Calif., USA), presented data from the phase 3 E1912 clinical trial comparing efficacy of ibrutinib + rituximab versus standard chemoimmunotherapy in newly diagnosed patients with chronic lymphocytic leukemia (CLL). In all, 529 patients (median age = 58) were randomized 2:1 to receive ibrutinib (420mg PO daily) + rituximab (cycle two = 50mg/m2 day 1, 325mg/ m2 day 2; cycle 3-7 = 500mg/ m2 day 1) or fludarabine (cycles 1-6 = 20mg/m2 days 1-3) + cyclophosphamide (cycles 1-6 = 250mg/ m2 days 1-3) + rituximab (cycle one = 50mg/ m2 day 1, 325mg/ m2 day 2; cycle 3-7 = 500mg/ m2 day 1). At median follow up of 33.6 months (0 – 51.1), patients treated with ibrutinib + rituximab had significantly increased PFS compared to the chemoimmunotherapy cohort (HR = 0.35, 95 percent CI: 0.22 – 0.5, p less that 0.00001). PFS benefit of treatment with ibrutinib + rituximab was observed across all subgroups, with the caveat that some groups had a small number of patients. OS benefit was also observed in the intent to treat population treated with ibrutinib + rituximab compared to chemoimmunotherapy (HR = 0.17, 95 percent CI: 0.05 – 0.54, p less than 0.0003). Grade three or higher treatment-related adverse events were significantly less in the ibrutinib/rituximab cohort (58.5 percent) compared to the chemoimmunotherapy cohort (72.1 percent, p = 0.004), most commonly neutropenia in both populations (22.7 percent and 43.7 percent, respectively). Together, these data demonstrate clinical benefit of ibrutinib + rituximab compared to fludarabine + cyclophosphamide + rituximab as first-line therapy in patients with CLL.
Bcl-2 Gly101Val mutation confers venetoclax resistance in patients with chronic lymphocytic leukemia
Piers Blomberry, MBBS (University of Melbourne, Melbourne, Australia), discussed research towards elucidating CLL resistance mechanisms against the Bcl-2 inhibitor venetoclax. Pre-clinical research suggests that specific acquired mutations in murine CLL models can confer resistance to venetoclax. To determine whether similar resistance-driving mutations arise in humans, researchers analyzed tumor samples of 21 patients with relapsed CLL who were treated with venetoclax and progressed. Analyses revealed the presence of a BCL2 Gly101Val mutation in four patients, and structural analyses indicate that Gly101Val is near the venetoclax-binding site within Bcl-2. This mutation was only present in patient samples immediately before disease progression. Further sequencing analyses reveal that Gly101Val is not observed in patient samples of other hematologic malignancies or in patients with venetoclax-naïve CLL. Experiments suggest that both ex vivo Gly101Val human CLL cells and cell lines overexpressing Gly101Val are less susceptible to venetoclax cytotoxicity compared to CLL cells with unmutated genotypes. Venetoclax affinity was found to be 180-fold less in Gly101Val Bcl-2 compared to WT Bcl-2, and that Gly101Val mutation lessens the ability of venetoclax to displace BAX and BAK from Bcl-2. In summary, these analyses suggest that specific acquired mutations can confer venetoclax resistance in CLL, providing foundational information for both treatment decisions as well as future drug development.