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Randomised phase II study to optimise melphalan, prednisolone, and bortezomib in untreated multiple myeloma (JCOG1105).

ABSTRACT: We conducted a randomised phase II study to determine the optimal dose and schedule of melphalan, prednisone, and bortezomib (MPB) (jRCTs031180097). Transplant-ineligible untreated multiple myeloma patients were randomised to Arm A (twice weekly bortezomib in one six-week cycle followed by eight five-week cycles of four times once weekly bortezomib with melphalan and prednisolone on days 1-4) or Arm B (nine four-week cycles of three times once weekly bortezomib with melphalan and prednisolone on days 1-4). The primary end-point was complete response (CR) rate. Of 91 patients randomised to two arms, 88 were eligible. The median cumulative bortezomib doses were 45·8 and 35·1 mg/m² , CR rate was 18·6% [95% confidence interval (CI) 8·4-33·4] and 6·7% (95% CI 1·4-18·3), and the median progression-free survival (PFS) was 2·5 and 1·4 years in Arms A and B [hazard ratio (HR) 1·93 (95% CI 1·09-3·42)], respectively. Frequent grade ?3 haematologic toxicities in Arms A and B were neutropenia (64·4% vs. 28·3%) and thrombocytopenia (35·6% vs. 10·9%). Grade 2/3 peripheral neuropathy was observed in 24·4/2·2% in Arm A and 8·7/0% in Arm B. In conclusion, Arm A was the more promising regimen, suggesting that the twice weekly schedule of bortezomib in the first cycle and higher cumulative dose of both bortezomib and melphalan influences the efficacy of modified MPB.

SUBMITTER: Maruyama D

PROVIDER: S-EPMC7891591 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Randomised phase II study to optimise melphalan, prednisolone, and bortezomib in untreated multiple myeloma (JCOG1105).

Maruyama Dai D Iida Shinsuke S Ogawa Gakuto G Fukuhara Noriko N Seo Sachiko S Miyazaki Kana K Yoshimitsu Makoto M Kuroda Junya J Tsukamoto Norifumi N Tsujimura Hideki H Hangaishi Akira A Yamauchi Takahiro T Utsumi Takahiko T Mizuno Ishikazu I Takamatsu Yasushi Y Nagata Yasuyuki Y Minauchi Koichiro K Ohtsuka Eiichi E Hanamura Ichiro I Yoshida Shinichiro S Yamasaki Satoshi S Suehiro Youko Y Kamiyama Yutaro Y Tsukasaki Kunihiro K Nagai Hirokazu H

British journal of haematology 20200624 3

We conducted a randomised phase II study to determine the optimal dose and schedule of melphalan, prednisone, and bortezomib (MPB) (jRCTs031180097). Transplant-ineligible untreated multiple myeloma patients were randomised to Arm A (twice weekly bortezomib in one six-week cycle followed by eight five-week cycles of four times once weekly bortezomib with melphalan and prednisolone on days 1-4) or Arm B (nine four-week cycles of three times once weekly bortezomib with melphalan and prednisolone on ...[more]

PMID: 32583431

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Project description:Substantial efficacy has been demonstrated with bortezomib-melphalan-prednisone in phase III studies in transplant-ineligible myeloma patients using various twice-weekly and once-weekly bortezomib dosing schedules. In VISTA, the regimen comprised four 6-week twice-weekly cycles, plus five 6-week once-weekly cycles. In the GIMEMA MM-03-05 study, the bortezomib-melphalan-prednisone regimen was either per VISTA ('GIMEMA twice-weekly'), or comprised nine 5-week once-weekly cycles ('GIMEMA once-weekly'). In the GEM2005MAS65 study, the regimen comprised one 6-week twice-weekly cycle, plus five 5-week once-weekly cycles. We evaluated the cumulative bortezomib dose administered during bortezomib-melphalan-prednisone, as well as efficacy and tolerability, using patient-level study data. Over all bortezomib-melphalan-prednisone cycles (nine in VISTA/GIMEMA; six in GEM2005MAS65), the median cumulative bortezomib dose administered was 38.5, 42.1, 40.3, and 32.9 mg/m(2) in VISTA, GIMEMA twice-weekly, GIMEMA once-weekly, and GEM2005MAS65, respectively, and the respective proportions of planned bortezomib dose actually delivered were 57.0%, 62.3%, 86.1%, and 90.4%. Response rates following bortezomib-melphalan-prednisone were 74-87% and appeared generally similar between studies. Three-year survival rates were 67.9-75.7% across studies. Grade 3/4 peripheral neuropathy rates were 13% in VISTA and 14% in GIMEMA twice-weekly, but were lower at 2% in GIMEMA once-weekly and 7% in GEM2005MAS65. Discontinuations and bortezomib dose reductions due to peripheral neuropathy were reduced in GIMEMA once-weekly versus VISTA and GIMEMA twice-weekly. Exclusive or predominant use of once-weekly bortezomib dosing in GIMEMA once-weekly and GEM2005MAS65 resulted in high efficacy, comparable with that demonstrated in VISTA, and similar cumulative bortezomib dose with reduced toxicity. Trials are registered with ClinicalTrials.gov: VISTA (Identifier:00111319), GIMEMA MM-03-05 (Identifier:01063179), and GEM2005MAS65 (Identifier:00443235).

Project description:BackgroundRetrospective studies suggest that conditioning therapy with busulfan plus melphalan could result in longer progression-free survival compared with melphalan alone in patients with multiple myeloma undergoing autologous haemopoietic cell transplantation (auto-HCT). We aimed to test this hypothesis in a randomised trial.MethodsThe primary objective of the study was to compare progression-free survival with conditioning of busulfan plus melphalan with melphalan alone in patients with multiple myeloma. Patients with newly diagnosed multiple myeloma who were eligible for cell transplantation, aged 70 years or younger, with at least stable disease, were randomly assigned (1:1) to treatment. Patients received either busulfan plus melphalan, with a test dose of busulfan 32 mg/m2 followed by pharmacokinetically adjusted doses on days -7, -6, -5, and -4 to achieve a target daily area under the curve (AUC) of 5000 mmol-minute and melphalan 70 mg/m2 per day on days -2 and -1 (total melphalan dose 140 mg/m2), or a melphalan dose of 200 mg/m2 on day -2. Randomisation was performed via a Clinical Trial Conduct Website at the University of Texas MD Anderson Cancer Center. The accrual is complete and final results are presented here. The study is registered with ClinicalTrials.gov, number NCT01413178.FindingsBetween Oct 12, 2011, and March 22, 2017, 205 patients were assessed for eligibility and randomly assigned to treatment. The primary analysis of progression-free survival was measured in 202 patients who received treatment: 104 patients in the busulfan plus melphalan group and 98 patients in the melphalan alone group. 90 days after auto-HCT, 102 (98%) of 104 patients given busulfan plus melphalan and 95 (97%) of 98 patients given melphalan alone achieved partial response or better. The median follow-up in the busulfan plus melphalan group was 22·6 months (IQR 15·2-47·1) and 20·2 months (IQR 8·8-46·6) in the melphalan alone group. Median progression-free survival was 64·7 months (32·9-64·7) with busulfan plus melphalan versus 43·5 months (19·9-not estimated) with melphalan alone (hazard ratio 0·53 [95% CI 0·30-0·91]; p=0·022). There were no treatment-related deaths by day 100 in either group. Grade 2-3 mucositis was observed in 77 (74%) of 104 patients in the busulfan plus melphalan group versus 14 (14%) of 98 patients in the melphalan alone group.InterpretationThese findings, if confirmed in other ongoing studies, suggest that busulfan plus melphalan could replace melphalan alone as the conditioning regimen for auto-HCT in patients with newly diagnosed myeloma.FundingThis study was funded in part by the National Institutes of Health (NIH) through MD Anderson's Cancer Center Support Grant (CA016672).

Project description:BackgroundThe introduction of immunomodulatory agents, proteasome inhibitors, and autologous haematopoietic stem-cell transplantation has improved outcomes for patients with multiple myeloma, but patients with high-risk multiple myeloma have a poor long-term prognosis. We aimed to address optimal treatment for these patients.MethodsSWOG-1211 is a randomised phase 2 trial comparing eight cycles of lenalidomide (25 mg orally on days 1-14 every 21 days), bortezomib (1·3 mg/m2 subcutaneously on days 1, 4, 8, and 11 every 21 days), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days; RVd) induction followed by dose-attenuated RVd maintenance (bortezomib 1 mg/m2 subcutaneously on days 1, 8, and 15; lenalidomide 15 mg orally on days 1-21; dexamethasone 12 mg orally on days 1, 18, and 15 every 28 days) until disease progression with or without elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1-2, on days 1 and 11 for cycles 3-8, and on days 1 and 15 during maintenance). Patients were randomly assigned (1:1) to either RVd or RVd-elotuzumab. High-risk multiple myeloma was defined by one of the following: gene expression profiling high risk (GEPhi), t(14;16), t(14;20), del(17p) or amp1q21, primary plasma cell leukaemia and elevated serum lactate dehydrogenase (two times the upper limit of normal or more). The primary endpoint was progression-free survival, and all analyses were done on intention-to-treat basis among eligible patients who were evaluable for response. This study is registered with ClinicalTrials.gov, NCT01668719.Findings100 (RVd n=52, RVd-elotuzumab n=48) patients were enrolled between Oct 27, 2013, and May 15, 2016, across 26 cooperative group institutions in the USA. Median age was 64 years (IQR 57-70, range 36-85). 74 (75%) of 99 had International Staging System stage II or stage III disease, 47 (47%) of 99 had amp1q21, 37 (37%) of 100 had del17p, 11 (11%) of 100 had t(14;16), eight (9%) of 90 were GEPhi, seven (7%) of 100 had primary plasma cell leukaemia, five (5%) of 100 had t(14;20), four (4%) of 100 had elevated serum lactate dehydrogenase, and 17 (17%) had two or more features. With a median follow-up of 53 months (IQR 46-59), no difference in median progression-free survival was observed (RVd 33·64 months [95% CI 19·55-not reached], RVd-elotuzumab 31·47 months [18·56-53·98]; hazard ratio 0·968 [80% CI 0·697-1·344]; one-sided p=0·45]. 37 (71%) of 52 patients in the RVd group and 37 (77%) of 48 in the RVd-elotuzumab group had grade 3 or worse adverse events. No significant differences in the safety profile were observed, although some notable results included grade 3-5 infections (four [8%] of 52 in the RVd group, eight [17%] of 48 in the RVd-elotuzumab group), sensory neuropathy (four [8%] of 52 in the RVd group, six [13%] of 48 in the RVd-elotuzumab group), and motor neuropathy (one [2%] of 52 in the RVd group, four [8%] of 48 in the RVd-elotuzumab group). There were no treatment-related deaths in the RVd group and one death in the RVd-elotuzumab group for which study treatment was listed as possibly contributing by the investigator.InterpretationIn the first randomised study of high-risk multiple myeloma reported to date, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. However, progression-free survival in both study groups exceeded the original statistical assumptions and supports the role for continuous proteasome inhibitors and immunomodulatory drug combination maintenance therapy for this patient population.FundingNational Institutes of Health, National Cancer Institute, Bristol Myers Squibb, Celgene, Leukemia and Lymphoma Society.

Dataset Information

Randomised phase II study to optimise melphalan, prednisolone, and bortezomib in untreated multiple myeloma (JCOG1105).

Publications

Randomised phase II study to optimise melphalan, prednisolone, and bortezomib in untreated multiple myeloma (JCOG1105).

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