Efficacy and Tolerability of Ixazomib, Daratumumab and Low Dose Dexamethasone (IDd) in Unfit and Frail Newly Diagnosed Multiple Myeloma (NDMM) Patients; First Interim Safety Analysis of the Phase II HOVON 143 Study

Abstract

Introduction Data from clinical trials indicate that elderly non-transplant eligible newly diagnosed multiple myeloma (nte-NDMM) patients also benefit from novel therapies. However, overall survival is inferior in unfit and frail compared to fit patients as defined by the International Myeloma Working Group (IMWG) frailty index, caused by a high discontinuation rate due to toxicity. Therefore, there is a need for less toxic treatment for unfit and frail patients. In view of the favorable safety profile of ixazomib and daratumumab, we investigated the efficacy and feasibility of treatment with ixazomib, daratumumab and low dose dexamethasone (IDd) in unfit and frail patients. This trial was registered at www.trialregister.nl as NTR6297. Methods In this prospective multicenter phase II trial treatment consisted of 9 28 day-induction cycles consisting of ixazomib (I) 4 mg (days 1, 8, 15), daratumumab (D) 16 mg/kg (cycle 1-2: days 1, 8, 15, 22; cycle 3-6: days 1, 15; cycle 7-9: day 1) and dexamethasone (in combination with daratumumab (d); cycle 1-2: 20 mg; subsequent cycles 10 mg) followed by maintenance therapy with I (days 1, 8, 15, 29, 36, 43) and D (day 1) of 8-week cycles, until progression for a maximum of 2 years. The primary objective is to determine the overall response rate (ORR) on induction therapy. Aiming for an ORR of at least 65% and considering 50% as a too low ORR, with an optimal Simon 2-Stage design, α = 0.10 and β = 0.20, 60 unfit and 60 frail patients should be included, increased to 66 for both populations to account for ineligibility. A pre-specified safety analysis was planned when for the first 10 unfit and 10 frail patients separately the data of the first 4 cycles of induction therapy are available. Inclusion criteria were NDMM, either being unfit or frail according to the IMWG frailty index. Main exclusion criteria were severe cardiac dysfunction, chronic obstructive pulmonary disease with an FEV1 <50% of expected and a creatinine clearance of <20 ml/minute. We here report the results of the planned safety interim analysis of the first 10/32 included frail patients who completed the first 4 induction cycles. The safety interim analysis of the first 10 unfit patients is planned in September, of which the results will be available at the ASH meeting. In addition, we here report the severe adverse events (SAE) for 58 eligible patients (26 unfit, 32 frail) who were included in the study until July 16, 2018. Results The demographic data of the first 10 frail patients are described in Table 1. Median FU of the first 10 frail patients is 5.2 months (range 0.6-9) and of the 58 included patients 1.6 months (range 0-9). Toxicity is described in Table 2. Hematological toxicity was limited, being mainly thrombocytopenia; 3/10 grade 3, 1/10 grade 4, the latter being disease-related. Non-hematological toxicity was manageable, with only 2 grade 3 gastro-intestinal events and 1 pulmonary embolism. No infusion related reactions and neuropathy were reported. There were minor dose reductions only. The median and inter-quartile range of relative dose intensity (RDI) were 1.0 (0.9, 1.0) for ixazomib, 0.9 (0.9, 1.0) for daratumumab and 1.0 (0.9, 1.0) for dexamethasone. SAEs occurred in 9/26 unfit and 14/32 frail patients, mainly caused by prolongation of hospitalization (82% and 88% respectively). Two patients died during cycle 1, both not related to therapy. One 81-year old patient unexpectedly died at home at day 35 of cycle 1 (delay due to low platelet count) after having recovered from thrombocytopenia and a decreased renal function, grade 3, probably caused by cotrimoxazole and valaciclovir. The second 81-year old patient had a thrombocytopenia of 18x109/l related to MM and died of gastrointestinal bleeding for which he declined therapy at day 15 of cycle 1. In the first included 58 patients a total of 4 patients died (6.9%, 4/32 frail (12.5%) and 0/26 unfit (0%)), of whom 2 not related to therapy (see above) and 2 possibly therapy-related; 1 due to Influenza B and 1 acute pre-renal failure due to vomiting and diarrhea. Preliminary response during the first 4 cycles of therapy is promising is; ORR 70% of which 20% VGPR, 10% MR, 10% SD and 10% not evaluable. Conclusion This planned safety analysis of frail patients in the HOVON 143 showed that Ixazomib-Daratumumab-low dose dexamethasone is feasible with a low rate of therapy-related toxicity and mortality. Preliminary response rates are promising. Disclosures Levin: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Sonneveld:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Daratumumab for the Management of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: Current and Emerging Treatments

“…Maintenance therapy until progression or for maximum of 2 years included daratumumab plus ixazomib. Results of the 65 frail patients enrolled in the study (median age 81 years, range 70–92 years) have been recently presented at the last European Hematology Association (EHA) Congress ( 30 ). Overall response rate, primary endpoint, was 78% with 36% of the patients achieving at least a VGPR.…”

Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma

“…Similarly, single-agent ixazomib maintenance has been utilized following ixazomib-based induction in four phase 1/2 studies 45,[80][81][82][83] ; a pooled analysis of maintenance patients from these studies reported deepening responses in 23% of patients, as well as a median PFS of 21.4 months and a 3-year OS of 82% from the start of maintenance, with limited new-onset AEs 84 . Ixazomib-daratumumabdexamethasone followed by ixazomib maintenance is being evaluated in unfit and frail patients in the phase 2 HOVON-143 study, which has reported promising safety and response data for the induction phase 85 . However, in the randomized phase 2 HOVON-126/NMSG21#13 trial, in which patients received ixazomib-thalidomidedexamethasone induction and were then randomized to ixazomib or placebo maintenance 86 , preliminary data showed no response or PFS benefit with ixazomib maintenance to date, although ixazomib did not result in additional toxicity compared to placebo ( Table 6).…”

Daratumumab in untreated newly diagnosed multiple myeloma

“…Updated efficacy results are awaited. 40 Ongoing trials of daratumumab-based combinations in transplant ineligible NDMM patients are listed in Table 1. 41…”