Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib

Abstract

• The combination of ixazomib and dexamethasone has clinical activity in patients with relapsed and or refractory multiple myeloma. • Higher dose of ixazomib leads to improved response rates but with higher rates of treatment related adverse events.Proteasome inhibitors have become an integral part of myeloma therapy. Considerable efforts have gone into optimizing this therapeutic approach to obtain maximal proteasome inhibition with least toxicity. Ixazomib is the first oral proteasome inhibitor to enter the clinic and has been studied as a single agent as well as in various combinations. The current trial was designed to examine the efficacy and toxicity of combining 2 different doses of ixazomib (4 mg and 5.5 mg given weekly for 3 of 4 weeks) with 40 mg weekly of dexamethasone, in relapsed myeloma. Seventy patients were enrolled, 35 patients randomly assigned to each ixazomib dose. Overall, 30 (43%; 95% confidence interval, 31-55) of the patients achieved a confirmed partial response or better, with 31% achieving a response with 4 mg and 54% with 5.5 mg of ixazomib. The median event-free survival (EFS) for the entire study population was 8.4 months; 1-year overall survival was 96%. The EFS was 5.7 months for patients with prior bortezomib exposure and 11.0 months for bortezomib-naïve patients. A grade 3 or 4 adverse event considered at least possibly related to treatment was seen in 11 (32%) patients at 4 mg and in 21 (60%) at 5.5 mg. Dose reductions were more frequent with 5.5 mg dose. Overall, the ixazomib with dexamethasone has good efficacy in relapsed myeloma, is well-tolerated and with higher response rate at 5.5 mg, albeit with more toxicity.

How I manage the toxicities of myeloma drugs

“…Cardiac failure is thought to be a class effect of PIs because it has also occasionally been reported with bortezomib 43 and ixazomib. 44 Although true carfilzomib-induced cardiac failure is infrequent and usually reversible upon drug discontinuation, many myeloma patients are elderly individuals and frequently present with cardiovascular comorbidities, 45 potentially increasing their risk for drug-related cardiotoxicity. Additional risk factors are previous exposure to cardiotoxic agents or mediastinal radiotherapy, high-dose corticosteroids, cardiac amyloidosis, and concomitant doxorubicin treatment.…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…158 In both examples, the ability of a specific agent (e.g., oxaliplatin, cyclophosphamide) but not one of its alike (e.g., cisplatin, melphalan) to drive ICD can be explained by the differential activation of ER stress (and hence differential exposure of CALR in the course of RCD). 100,[157][158][159] Well established ICD inducers include commonly employed anticancer chemotherapeutics such as: (1) (6) bortezomib, a proteasomal inhibitor approved for the therapy MM and mantle cell lymphoma (MCL); [171][172][173][174][175][176][177][178][179][180][181] (7) cyclophosphamide, a DNA-alkylating agent approved for use in patients with chronic myeloid leukemia (CML), AML, ALL, chronic lymphocytic leukemia, MM, ovarian carcinoma, breast carcinoma, mycosis fungoides, lymphoma, neuroblastoma, and retinoblastoma; 177,[182][183][184][185][186][187][188][189][190][191] and (8) oxaliplatin, a platinum-derivative licensed for the therapy of advanced colorectal carcinoma in combination with 5-fluorouracil and folinic acid. 156,157,[192][193][194][195][196][197][198] Moreover, there is some evidence that microtubule-targeting agents including taxanes and vinca alkaloids (which are commonly used for the treatment of multiple carcinomas) can stimulate ICD.…”

Ixazomib in the treatment of relapsed multiple myeloma

“…Комбинация иксазомиба с дексаметазоном (Id) была исследована в проспективном исследовании II фазы [20]. Общий вывод данного исследования заключался в том, что доза еженедельно по 4 мг является оптимальной в отношении как эффективности, так и безопасности.…”

“…Монотерапия иксазомибом в исследованиях I-II фазы сопровождалась развитием тромбоцитопении 3-4-й сте-пени приблизительно в половине случаев [17,18,20]. На терапии IRd частота трансфузий тромбоконцентрата, геморрагических событий и прекращения терапии была сходной с таковой в контрольной группе Rd, хотя частота тромбоцитопении 3-4-й степени была выше в группе иксазомиба (19% против 9%) [23].…”