Replacement of ixazomib for relapsed/refractory multiple myeloma patients refractory to a bortezomib or carfilzomib-containing combination therapy.

Berenson, James R.; Cohen, Alexa; Spektor, Tanya M.; Bitran, Jacob D.; Chen, Gigi Qiqi; Moezi, Mehdi M.; Bessudo, Alberto; Ye, Joseph Z.; Hager, Steven; Moss, Robert A.; Cartmell, Alan; Coleman, Teresa; Hrom, John; Eshaghian, Shahrooz; Maluso, Tina; Swift, Regina A.; Lim, Stephen

doi:10.1200/jco.2017.35.15_suppl.8013

“…Less is known about the therapeutic efficacy of ixazomib for patients who are bortezomib resistant; however, preclinical experiments point toward activity of ixazomib on cells from patients resistant to bortezomib, 31 and several studies have shown activity even in bortezomib refractory patients, 14 , 32 although responses may be infrequent. 33 , 34 Response and survival rates in this trial were lower than in a study of bortezomib/pomalidomide/dexamethasone, 35 possibly reflecting the modest response rate for bortezomib-refractory patients. Other possible approaches include optimizing the dose and schedule of the ixazomib, especially for bortezomib-refractory patients.…”

Section: Discussionmentioning

confidence: 67%

Phase I/II trial of the oral regimen ixazomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma

Krishnan

¹

,

Kapoor

²

,

Palmer

³

et al. 2018

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In this phase I/II trial, a triplet regimen of ixazomib (Ixa: 3 or 4 mg), pomalidomide (Pom: 4 mg), and dexamethasone (Dex: 40 mg) was administered to 32 lenalidomide-refractory multiple myeloma (MM) patients; 31 were evaluable for response and toxicity. At dose level 1 (DL1, 3 mg Ixa), 1/3 patients experienced grade 3 fatigue, grade 3 lung infection, grade 4 neutropenia, and grade 4 thrombocytopenia; all were considered dose limiting. Per 3+3 phase I design, an additional 3 patients were enrolled to DL1, with no further dose limiting toxicity (DLT). At dose level 2 (DL2, 4 mg Ixa), 1/3 patients had dose-limiting febrile neutropenia, neutropenia, and thrombocytopenia (grade 4 each). DL2 was expanded to enroll 3 additional patients with no further DLT, establishing the recommended phase II dose (RP2D). In phase II, 19 additional patients were treated at RP2D. With a median follow-up of 11.9 months, 48% achieved ≥partial response (PR), with 5 patients (20%) achieving very good partial response (VGPR) and 76% experiencing ≥stable disease. The most common adverse events (≥grade 2) were anemia, neutropenia, thrombocytopenia, and infections. Peripheral neuropathy was infrequent. In summary, Ixa/Pom/Dex is a well-tolerated and effective oral combination therapy for patients with relapsed/refractory MM.

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“…In an experimental in vivo model, ixazomib showed activity on cells from bortezomib resistant patients 24 . This observation has been corroborated in several clinical trials; however, the variability in response observed across studies, and the small-scale study designs preclude any definite conclusions 25,26 . Responses observed in this study were comparable to bortezomib-bendamustine-dexamethasone which resulted in ORR of 60.8% in RRMM that included patients with prior exposure, but not refractory to bortezomib 11 .…”

Section: Discussionmentioning

confidence: 70%

Phase I/II trial of bendamustine, ixazomib, and dexamethasone in relapsed/refractory multiple myeloma

Dhakal

¹

,

D’Souza

²

,

Hamadani

³

et al. 2019

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In this phase I/II trial, BID, bendamustine (70, 80, or 90 mg/m 2 ), ixazomib (4 mg), and dexamethasone (40 mg), was administered to 28 patients with relapsed and/or refractory multiple myeloma (RRMM) exposed to bortezomib and lenalidomide and refractory to at least one. A 3 + 3 dose escalation based on dose-limiting toxicities (DLTs) was employed in phase I (total 15); 2/6 patients developed DLTs (neutropenia and thrombocytopenia) at dose level 3 establishing the recommended phase II dose as bendamustine 80 mg/m 2 , ixazomib 4 mg, and dexamethasone 40 mg. The median age was 67 years (range, 42–72), and 43% were females. Patients received a median of 4 (range, 4–9) prior lines of therapy, of which ~50% were double refractory. In phase II, total 19 patients were treated. With a median follow-up of 17 months, 11% achieved very good partial response, 50% achieved partial response, and 27% achieved stable disease. Median progression free (PFS) and overall (OS) survival were 5.2 months (95% CI, 1.96–8.3) and 23.2 months (95% CI 16.3–30.07). The most frequent adverse events were anemia, thrombocytopenia, leukopenia, nausea, diarrhea, and infections. Peripheral neuropathy was infrequent. BID is a well-tolerated and effective combination therapy for patients with RRMM.

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“…Less is known about the therapeutic efficacy of ixazomib for patients who are bortezomib resistant; however, preclinical experiments point toward activity of ixazomib on cells from patients resistant to bortezomib, 31 and several studies have shown activity even in bortezomib refractory patients, 14, 32 although responses may be infrequent. 33, 34 Response and survival rates in this trial were lower than in a study of bortezomib/pomalidomide/dexamethasone, 35 possibly reflecting the modest response rate for bortezomib-refractory patients. Other possible approaches include optimizing the dose and schedule of the ixazomib, especially for bortezomib-refractory patients.…”

Section: Discussionmentioning

confidence: 67%

Phase I/II trial of the oral regimen ixazomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma

Krishnan

¹

,

Kapoor

²

,

Palmer

³

et al. 2017

View full text Add to dashboard Cite

In this phase I/II trial, a triplet regimen of ixazomib (Ixa: 3 or 4 mg), pomalidomide (Pom: 4 mg), and dexamethasone (Dex: 40 mg) was administered to 32 lenalidomide-refractory multiple myeloma (MM) patients; 31 were evaluable for response and toxicity. At dose level 1 (DL1, 3 mg Ixa), 1/3 patients experienced grade 3 fatigue, grade 3 lung infection, grade 4 neutropenia, and grade 4 thrombocytopenia; all were considered dose limiting. Per 3+3 phase I design, an additional 3 patients were enrolled to DL1, with no further dose limiting toxicity (DLT). At dose level 2 (DL2, 4 mg Ixa), 1/3 patients had dose-limiting febrile neutropenia, neutropenia, and thrombocytopenia (grade 4 each). DL2 was expanded to enroll 3 additional patients with no further DLT, establishing the recommended phase II dose (RP2D). In phase II, 19 additional patients were treated at RP2D. With a median follow-up of 11.9 months, 48% achieved ≥partial response (PR), with 5 patients (20%) achieving very good partial response (VGPR) and 76% experiencing ≥stable disease. The most common adverse events (≥grade 2) were anemia, neutropenia, thrombocytopenia, and infections. Peripheral neuropathy was infrequent. In summary, Ixa/Pom/Dex is a well-tolerated and effective oral combination therapy for patients with relapsed/refractory MM.

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Replacement of ixazomib for relapsed/refractory multiple myeloma patients refractory to a bortezomib or carfilzomib-containing combination therapy.

Cited by 11 publications

References 0 publications

Phase I/II trial of the oral regimen ixazomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma

Phase I/II trial of the oral regimen ixazomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma

Phase I/II trial of bendamustine, ixazomib, and dexamethasone in relapsed/refractory multiple myeloma

Phase I/II trial of the oral regimen ixazomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma

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