8013 Background: The proteasome inhibitor (PI) ixazomib (Ixz) is the first orally administered PI approved for treating multiple myeloma (MM). It has shown clinical activity as a single agent and when used in other combinations. In this phase 1/2 trial, we evaluated Ixz as a replacement therapy for bortezomib or carfilzomib for MM patients who were refractory to a bortezomib- or carfilzomib-containing combination regimen. Methods: This was a phase 1/2, intra-patient, multicenter, open-label trial evaluating the replacement of ixazomib for bortezomib or carfilzomib for MM patients who were refractory in combination with the other agents that the patients had received and failed. Patients received Ixz on days 1, 8 and 15 on a 28-day schedule and the other drugs were administered using the same doses and schedules as they were receiving during their prior regimen. If the Ixz maximum tolerated dose (MTD) for a particular combination regimen was previously determined, then patients were enrolled directly into Phase 2 (PhII). If not, MTD was determined during the Phase 1 (PhI) portion of the trial. Results: To date, a total of 40 patients have been enrolled; 37 patients (21 were enrolled in PhI and 16 in PhII) had completed at least one cycle of this treatment. Patients received a median of 5 prior treatments (range, 1-22). The median follow-up time for all patients was 1.6 months (range, 0.1-10.7 months), whereas that of PhII was 2.2 months (range, 0.2-10.7 months). There was no clinical benefit (CBR; 0%) nor any overall response rate (ORR; 0%) for patients receiving Ixz 3 mg (PhI). Nine patients (43%) showed stable disease (SD) while 12 (57%) exhibited disease progression (PD). In PhII (4mg Ixz) portion of the trial, ORR and CBR were both 18.7% with 16 (43.2%) patients showing SD, and 18 (48.6%) patients displaying PD. Common ≥ Gr3 adverse events were anemia (11%), thrombocytopenia (5.4%), hyponatremia (5.4%), dehydration (5.4%) and neutropenia (2.7%). Conclusions: Replacement of bortezomib or carfilzomib with Ixz infrequently leads to responses among RRMM patient who have progressed while on proteasome inhibitor -containing combination regimens. Clinical trial information: NCT02206425.

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SummaryImmunomodulatory drugs including thalidomide, lenalidomide (LEN) and pomalidomide (POM), are effective for treating multiple myeloma (MM). POM has shown enhanced efficacy with dexamethasone (DEX). Pegylated liposomal doxorubicin (PLD) with bortezomib is US Food and Drug Administration-approved for treating MM. PLD with LEN or thalidomide has shown efficacy for MM patients. LEN with DEX, PLD and bortezomib achieves high response rates. We evaluated the combination of POM with DEX 40 mg and PLD 5 mg/m 2 with the latter two drugs administered on days 1, 4, 8 and 11 on a 28-day cycle for the treatment of relapsed/refractory MM patients. During Phase 1, the maximum tolerated dose of POM was 4 mg, and was used in Phase 2, which also required patients to be refractory to LEN. However, neutropenia ≥ grade 3 was observed in 10/17 (59%) patients, and the dose was lowered to 3 mg. Median PFS was 5Á4 months (range, 0Á3-29Á0 + months). Overall response rates for patients in Phase 2 were 39% and 31% among subjects receiving POM at 3 mg and 4 mg, respectively, and clinical benefit rates were 51% and 44%, respectively. POM, PLD and DEX is a treatment option for relapsed/refractory MM patients including those who are refractory to LEN.

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