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
Authors: Reece Donna E , Piza Rodriguez Giovanni , Pantoja Mariela A , White Darrell J , Venner Christopher P , Stakiw Julie , Sebag Michael , Comeau Terrance , Song Kevin , Roy Jean , Louzada Martha L , McCurdy Arleigh , Kukreti Vishal , Trudel Suzanne , Prica Anca , Tiedemann Rodger E , Paul Harminder K , Chen Christine I 
Published: November 2019

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.

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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.