Contributions
Abstract: PB1973
Type: Publication Only
Background
While the role of allo-HCT in MM remains controversial several studies have shown encouraging PFS and OS with this treatment even in patients with high-risk myeloma (HRM). HRM manifests with early relapses and refractoriness. Median OS is 2.5 years despite aggressive therapy with novel agents. Post auto-HCT maintenance with lenalidomide is considered standard of care, but post allo-HCT maintenance presents unique challenges and has not been well studied. Ixazomib (Ixa) is a new oral proteasome inhibitor with activity in bortezomib resistant patients, and is a promising agent in the maintenance setting.
Aims
Here we present preliminary results for this trial. The primary objective is safety defined as day 100 transplant related mortality (TRM), and safety of Ixa maintenance (incidence of grade III-IV GvHD and Ixa related toxicity). Other objectives include determination of efficacy (ORR, PFS, MRD for CR), the ability to start Ixa, and quality of life.
Methods
The protocol was approved by a local institutional review board and ethics committee. The study was conducted in accordance with the Declaration of Helsinki. All subjects provided written informed consent prior to treatment. Eligibility criteria include: age <65; relapsed MM previously treated with auto-HCT, bortezomib and an immunomodulatory agent; one of the following high-risk criteria: deletion (del)17p, t(4;14), t(14;16), t(14;20), amp1q gain or del1p, del13q by conventional karyotyping, hypodiploidy, high-risk GEP, B2M > 5.5mg, plasmablastic morphology (>2%), or relapsed plasma cell leukemia; 8/8 HLA matched unrelated (MUD) or sibling donor. The BEAM conditioning regimen includes: BCNU 300 mg/m2 on day -6; cytarabine 400 mg/m2 daily day -5 to day -2; etoposide 200 mg/m2 daily day -5 to day -2; melphalan 140 mg/m2 on day -1. Oral Ixa 4mg on days 1 and 14 of a 28-day cycle. Ixa may start between day 100 and 180 post HCT, and continue for up to 24 cycles.
Results
Six subjects were enrolled, 3 at OHSU and 3 at Duke, from Sept 2015 to Dec 2016. Median age of 51 (range 46-57), 2 female, and all of white race. High risk factors: del17p, del17p + t(14;16), del17p + amp1q + del1p, del13q + amp1q, amp1q, plasmablastic morphology (>2%). At study entry 2 subjects were in VGPR, and 4 in PR. Three subjects received 8/8 HLA matched MUD, and 3 received sibling donor HCT. GvHD prophylaxis with tacrolimus and methotrexate was given in 3 subjects with the addition of methylprednisone in 3 subjects. Two subjects started Ixa (at day 139 and 128) and remained on therapy for 198 and 59 days respectively; both discontinued for disease progression. Three subjects remain on study, and have not started Ixa. At day 100 post HCT, 4 of 6 subjects were evaluable for response. All had a deepening of response; 3 VGPR, 1 CR. One subject died from BEAM-allo related complications; namely acute stage 4 GvHD (skin and gut), and disseminated adenovirus infection (day 62). Grade 3/4 adverse events include: febrile neutropenia(3); colitis(1); epididimytis(1); mucositis(4); pancreatitis(1); pulmonary edema(2); diarrhea(3); infection(4); staph bacteremia(2); E coli bacteremia(1); adenovirus viremia(1); neutropenia(4); thrombocytopenia(4); acute GvHD(1). Ixa related toxicities include grade 3 neutropenia(2), thrombocytopenia(1), pneumonia(1), nausea and vomiting(1).
Conclusion
Although this is very early data, it is the first clinical trial to report the use of BEAM conditioning followed by Ixa maintenance for relapsed HRM. Thus far stopping rules have not been met, with expected toxicities occurring.
Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical
Keyword(s): High risk, Allo BMT, Multiple Myeloma, Maintenance
Abstract: PB1973
Type: Publication Only
Background
While the role of allo-HCT in MM remains controversial several studies have shown encouraging PFS and OS with this treatment even in patients with high-risk myeloma (HRM). HRM manifests with early relapses and refractoriness. Median OS is 2.5 years despite aggressive therapy with novel agents. Post auto-HCT maintenance with lenalidomide is considered standard of care, but post allo-HCT maintenance presents unique challenges and has not been well studied. Ixazomib (Ixa) is a new oral proteasome inhibitor with activity in bortezomib resistant patients, and is a promising agent in the maintenance setting.
Aims
Here we present preliminary results for this trial. The primary objective is safety defined as day 100 transplant related mortality (TRM), and safety of Ixa maintenance (incidence of grade III-IV GvHD and Ixa related toxicity). Other objectives include determination of efficacy (ORR, PFS, MRD for CR), the ability to start Ixa, and quality of life.
Methods
The protocol was approved by a local institutional review board and ethics committee. The study was conducted in accordance with the Declaration of Helsinki. All subjects provided written informed consent prior to treatment. Eligibility criteria include: age <65; relapsed MM previously treated with auto-HCT, bortezomib and an immunomodulatory agent; one of the following high-risk criteria: deletion (del)17p, t(4;14), t(14;16), t(14;20), amp1q gain or del1p, del13q by conventional karyotyping, hypodiploidy, high-risk GEP, B2M > 5.5mg, plasmablastic morphology (>2%), or relapsed plasma cell leukemia; 8/8 HLA matched unrelated (MUD) or sibling donor. The BEAM conditioning regimen includes: BCNU 300 mg/m2 on day -6; cytarabine 400 mg/m2 daily day -5 to day -2; etoposide 200 mg/m2 daily day -5 to day -2; melphalan 140 mg/m2 on day -1. Oral Ixa 4mg on days 1 and 14 of a 28-day cycle. Ixa may start between day 100 and 180 post HCT, and continue for up to 24 cycles.
Results
Six subjects were enrolled, 3 at OHSU and 3 at Duke, from Sept 2015 to Dec 2016. Median age of 51 (range 46-57), 2 female, and all of white race. High risk factors: del17p, del17p + t(14;16), del17p + amp1q + del1p, del13q + amp1q, amp1q, plasmablastic morphology (>2%). At study entry 2 subjects were in VGPR, and 4 in PR. Three subjects received 8/8 HLA matched MUD, and 3 received sibling donor HCT. GvHD prophylaxis with tacrolimus and methotrexate was given in 3 subjects with the addition of methylprednisone in 3 subjects. Two subjects started Ixa (at day 139 and 128) and remained on therapy for 198 and 59 days respectively; both discontinued for disease progression. Three subjects remain on study, and have not started Ixa. At day 100 post HCT, 4 of 6 subjects were evaluable for response. All had a deepening of response; 3 VGPR, 1 CR. One subject died from BEAM-allo related complications; namely acute stage 4 GvHD (skin and gut), and disseminated adenovirus infection (day 62). Grade 3/4 adverse events include: febrile neutropenia(3); colitis(1); epididimytis(1); mucositis(4); pancreatitis(1); pulmonary edema(2); diarrhea(3); infection(4); staph bacteremia(2); E coli bacteremia(1); adenovirus viremia(1); neutropenia(4); thrombocytopenia(4); acute GvHD(1). Ixa related toxicities include grade 3 neutropenia(2), thrombocytopenia(1), pneumonia(1), nausea and vomiting(1).
Conclusion
Although this is very early data, it is the first clinical trial to report the use of BEAM conditioning followed by Ixa maintenance for relapsed HRM. Thus far stopping rules have not been met, with expected toxicities occurring.
Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical
Keyword(s): High risk, Allo BMT, Multiple Myeloma, Maintenance