Bortezomib-Based Induction, Augmented Conditioning with Busulfan and Melphalan + ASCT and Lenalidomide Maintenance for Newly Diagnosed Multiple Myeloma: Long-Term Results of the National Canadian Mcrn-001 Study

Autor: Martha L Louzada, Suzanne Trudel, Rodger E. Tiedemann, Vishal Kukreti, Julie Stakiw, Anca Prica, Darrell White, Kevin W. Song, Michael Sebag, Christine Chen, Donna E. Reece, Harminder Paul, Giovanni Piza Rodriguez, Terrance Comeau, Christopher P. Venner, Mariela Pantoja, Jean Roy, Arleigh McCurdy
Rok vydání: 2019
Předmět:
Zdroj: Blood. 134:4570-4570
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2019-129357
Popis: Although melphalan 200 mg/m2 (Mel 200) followed by ASCT has been a standard approach for eligible multiple myeloma (MM) patients (pts) for over 25 years, efforts to improve transplant results continue, particularly in high-risk (HR) pts. One approach has been to augment the high-dose (HD) regimen by adding agents to Mel or performing "tandem" ASCT using Mel each time. The first MCRN Canadian national trial (MCRN-001) was designed to optimize the results of ASCT by using bortezomib (BTZ)-based induction, augmented HD chemotherapy with busulfan + melphalan (BuMel) before ASCT, and lenalidomide (Len) maintenance post-ASCT. We now report longer-term outcomes from this study, including results in HR pts and the incidence of secondary primary malignancies (SPMs). METHODS: Following BTZ-based induction (typically weekly CyBorD), stem cells were harvested and pts received BuMel (busulfan 3.2 m/kg IV days -5 to -3 or days -6 to -4 and Mel 140 mg/m2 days -2 or -3), followed by ASCT on day 0. On day 100, Len maintenance was commenced at a dose of 10 mg/d, escalated if appropriate to 15 mg/d and continued until progression. IMWG criteria were used for clinical response and progression. Bone marrow 8-color multiparameter flow cytometry (10 -4 sensitivity) was measured at diagnosis, before ASCT, on day +100, every 3 months the first year and every 6 months until progression; serum heavy light chain (HLC) (Hevylite®) assay and serum M spike by mass spectrometry (spec) were also evaluated at the same time points. RESULTS: 78 newly diagnosed MM pts were entered between 03/2013-05/2016. Median age was 57 yrs (range 34-69); HR FISH cytogenetics were identified in 15 (19%) and included t(4;14) in 9 [3 also had t(14;16) and 1 also had del 17p]. Four others had t(14;16), including 1 with concomitant del 17p, while 2 additional pts had del 17p. Median follow-up (F/U) is 55.7 mos (range 6-68). There were no early ASCT deaths. Best response in all pts was CR in 44 (56%), VGPR in 31 (40%), for a ≥VGPR rate of 96%, and PR in 3 (4%). For HR pts, best response was ≥VGPR in 93% (CR in 47%). MRD negativity rates increased from 28% after induction to 39% at day +100; 6- and 12-mo MRD negativity rates were 44% and 41%, respectively. A normal HLC ratio was achieved in 58% after induction and 65% at day +100. Among evaluable pts who were MRD negative, 77% after induction and 83% at day +100 also had a normal HLC ratio, while 50 % and 55% who were MRD positive had a normal HLC ratio. Mass spec data will be presented separately. As of 05/31/2019, 24 pts have progressed and 12 have died, 8 from MM. Median PFS and OS for all pts have not yet been reached, but the estimated 5-year PFS is 60% (95% CI 47.5-70.8%) and OS 82% (95% CI 69.7-89.3%). For HR pts, the 5-year PFS is 28% (95% CI 7.2-54.3%) compared with 67% (95% CI 53.9-96.2%) for standard-risk (SR) pts (p=0.0169). 5-year OS was 61.3% (95% CI 30.2-81.9%) versus 86% (95% CI 72.2-93.2%) in HR and SR pts, respectively (p=0.0170). SPMs were diagnosed in a total of 16 (21%) individuals (5 HR), including 1 pt with 2 SPMs (colon and basal cell), at a median of 29 mos (7-55) post-ASCT; 3 were diagnosed after discontinuation of Len. There were 6 skin cancers (melanoma in 1; non-melanoma in 5) -all successfully treated; 4 heme malignancies (2 AML, 1 NHL and 1 Hodgkin's) with 1 death due to AML; and 7 adenocarcinomas (1 in situ endocervical and 6 invasive) with 3 causing death. Therefore, there were 4 deaths (5.1%) in total from SPM. SUMMARY AND CONCLUSIONS: 1) BTZ-based induction and BuMel + ASCT followed by Len maintenance produced an overall ≥VGPR rate of 96% and excellent 5-year PFS, particularly in SR pts; 2) despite a high initial VGPR rate of 93%, a shorter PFS and OS were noted in HR pts; 3) the PFS in HR pts in the current study appears somewhat shorter than that observed in the MD Anderson phase 3 study comparing BuMel versus Mel 200 (Qazilbash, ASH 2017); this observation might be due to the use of different criteria for HR FISH, variable induction and maintenance regimens and a different dose/schedule of Bu and Mel in addition to a shorter median F/U time in the phase 3 trial; 4) nevertheless, HR pts in the current trial still experienced a median PFS of 48.5 mos; 5) with a median F/U of almost 5 years, invasive SPMs were diagnosed in 10 pts; although most were successfully treated, the findings illustrate the need for long-term monitoring of MM pts, particularly in the setting of HD therapy with dual alkylating agents and the longer survival times now observed after ASCT. Figure Disclosures Reece: Otsuka: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Venner:Janssen: Honoraria; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; J&J: Research Funding. Stakiw:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Sanofi: Honoraria; Amgen: Honoraria, Speakers Bureau; Roche: Research Funding; BMS: Honoraria; Janssen: Honoraria, Research Funding, Speakers Bureau; Lundbeck: Honoraria. Sebag:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Comeau:Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy. Song:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Roy:Celgene: Consultancy, Honoraria, Research Funding; Sanofi Canada: Research Funding; ExCellThera: Patents & Royalties: Royalties from sales of UM171, Research Funding; Amgen Canada: Honoraria; Janssen Canada: Honoraria. Louzada:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bayer: Honoraria. McCurdy:Celgene: Honoraria; Janssen: Honoraria. Kukreti:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Trudel:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria; Astellas: Research Funding; Genentech: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria. Prica:Celgene: Honoraria; Janssen: Honoraria. Tiedemann:Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Chen:Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. OffLabel Disclosure: The combination of busulfan IV and melphalan conditioning for ASCT in myeloma is off-label.
Databáze: OpenAIRE
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