ASH Clinical News ACN_5.4s_March_supplement_web - Page 21

among patients who had a VGPR at study entry, 43 percent of ixazomib-treated patients improved to a CR (n=92/213), com- pared with 32 percent in the placebo arm (n=48/152; p=0.004). Ixazomib-treated patients also had a higher rate of conversion from MRD-positive to MRD-negative status, compared with placebo (12% vs. 7%; p value not provided). All-grade treatment-related adverse events (AEs) occurred in 78 percent of ixazomib-treated patients and 58 percent of placebo- treated patients, but “there were very few side effects that were greater than 10 percent more common in the ixazomib arm,” Dr. Dimopoulos said. These included nausea, diarrhea, and arthralgia. There also was no increase in hepatic, cardiac, or renal AEs and no difference in the rates of new primary malignancy (3% for both arms). Serious AEs also appeared to be more frequent in the ixazomib arm (27% vs 20%), and one patient in the ixazo- mib group and none in the placebo group died during follow-up. However, Dr. Dimopoulos pointed out that 86 percent of patients were able to escalate dose of ixazomib and that discon- tinuation related to AEs “was relatively low across both arms,” at 7 percent and 5 percent, respectively. As a limitation of the study, Dr. Dimopoulos noted that over- all survival data (a secondary endpoint of the study) were not mature and follow-up was ongoing. Researchers are continuing to study ixazomib combinations in different MM settings to further improve patient outcomes, he said. Ixazomib Plus Daratumumab In the second study, Shaji Kumar, MD, from the Mayo Clinic in Rochester, Minnesota, presented results from a phase II trial evaluating the feasibility and efficacy of adding the anti-CD38 monoclonal antibody daratumumab to the standard triplet regi- men of ixazomib, lenalidomide, and dexamethasone (IRd). 2 This all-oral, four-drug combination of daratumumab plus IRd was associated with rapid responses that deepened over time, the authors reported, with no discontinuation due to AEs and no adverse effects on the ability to collect stem cells. Eligible patients had newly diagnosed MM, adequate organ function, and an Eastern Cooperative Oncology Group perfor- mance status score ≤2; participants had received up to one cycle of treatment, “allowing some flexibility to enroll patients who needed immediate therapy,” Dr. Kumar said. Treatment was administered in 12 28-day cycles in the fol- lowing regimen: • ixazomib 4 mg on days 1, 8, and 15 of each cycle • dexamethasone 40 mg on days 1, 8, 15, and 22 of each cycle • lenalidomide 25 mg on days 1-21 of each cycle • daratumumab 16 mg/kg weekly for 2 cycles, then every other week for cycles 3-6, and then every 4 weeks Patients who completed induction therapy went on to maintenance therapy with ixazomib and daratumumab for a maximum of three years, or until disease progression or unacceptable toxicity. As of July 20, 2018 (data cutoff), 38 of 40 enrolled patients (median age = 62 years; range = 41-81 years) were eligible for this analysis. During a median follow-up of 10.2 months (range = 5.7-17.5 months), participants received a median of nine treat- ment cycles (range = 4-18 cycles). All 38 patients were alive at last follow-up, but three patients (7.9%) had progressive disease. Another nine patients discontinued study treatment because they became eligible for a hematopoietic cell transplantation following four cycles of induction treatment. Dr. Kumar highlighted that 24 transplant-eligible patients went on to stem cell collection, with no differences in engraft- ment among the nine patients who underwent transplant com- pared with historical observations. “These are small numbers and it is hard to compare, but [the stem cell collection and engraftment] numbers don’t seem very different from what we typically see in patients with myeloma,” he noted. “The majority of patients had a response by the end of cycle two, with about one-third of patients having achieved a VGPR,” Dr. Kumar reported. Response rates increased by cycle four, and the best response across all cycles included: stringent CR (11%), CR (8%), VGPR (50%), PR (29%), and minimal response (3%). “There was a deepening of response with continued therapy among the patients who did not go into stem cell transplant,” he added, with “most patients experiencing a complete disappear- ance of M protein.” Among all 40 treated patients, Dr. Kumar reported that the number of dose modifications “was fairly low,” ranging from 8 percent with ixazomib (mostly related to lab abnormalities) to 32 percent with lenalidomide (mostly related to cytopenias). Among the 38 patients in this analysis, 22 patients (58%) experienced a grade ≥3 AE, most of which were hematologic (53%). The most common, all-grade AEs were neutropenia (71%), fatigue (69%), lymphopenia (50%), and thrombocytopenia (45%). The researchers concluded that the ixazomib and daratu- mumab regimen is an effective induction therapy, but the find- ings of this trial are limited by the single-arm design, the small number of patients, and an incomplete analysis of MRD data. Dr. Kumar noted that follow-up of a second cohort to explore the possibility of discontinuing dexamethasone after the first two cycles is ongoing. ● The authors of the first study report relationships with Takeda, which sponsored the trial. The authors of the second study report relationships with Takeda, Celgene, Janssen, AbbVie, and Alexion Pharmaceuticals. REFERENCES 1. Dimopoulos MA, Gay F, Schjesvold FH, et al. Maintenance therapy with the oral proteasome inhibitor (PI) ixazomib significantly prolongs progression-free survival (PFS) following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (NDMM): phase 3 Tourmaline-MM3 trial. Abstract #301. Presented at the 2018 ASH Annual Meeting, December 2, 2018; San Diego, CA. 2. Kumar SK, Kapoor P, Laplant B, et al. Phase 2 trial of ixazomib, lenalidomide, dexamethasone and daratumumab in patients with newly diagnosed multiple myeloma. Abstract #304. Presented at the 2018 ASH Annual Meeting, December 2, 2018; San Diego, CA. March 2019 19