Abstract

Conventional immunoglobulin (Ig) markers have been used to define multiple myeloma (MM) responses, but assessment of marrow for minimal residual disease (MRD) may provide better information on disease status/prognosis (Paiva B, et al. Blood 2008; 112: 4017). We therefore initiated a national multi-center ASCT trial with the goal of producing a high rate of MRD-negativity by using bortezomib (btz)-based induction, enhancing the conditioning regimen and utilizing post-ASCT maintenance.

This phase 2 open label-trial was conducted in 10 Canadian centers. After btz-based induction (usually CyBorD) in the absence of disease progression, patients (pts) received BuMel conditioning (IV busulfan 3.2 mg/kg days -5 to -3 or days -6 to -4 + melphalan 140 mg/m2 day -2 or day -3), followed by ASCT on day 0. On day 100 post-ASCT, lenalidomide (len) 10 mg/day was commenced, escalated to 15 mg/day after 3 cycles if appropriate, and continued until disease progression.

Bone marrow aspirate (BMA) samples were shipped centrally for MRD analysis by 15-color multiparameter flow cytometry (MFC) before any therapy, prior to ASCT, on day 100 post-ASCT, every 3 mos for the 1st year and every 6 mos thereafter until progression.

Between 03/2013 - 07/2014, 99 newly diagnosed MM pts provided untreated BMA samples for MRD analysis. To date, 42 of a planned target of 78 pts have completed induction therapy have undergone ASCT and 39 are evaluable so far. 25 of the 99 (25%) who provided initial marrow samples did not meet criteria for enrollment: 3 (3%) had poor BMA samples; 3 (3%) did not have confirmed MM; 6 (6%) did not proceed with ASCT (1 due to progression); 1 (1%) had received dexamethasone prior to MRD analysis; 1 (1%) died during induction and 11 (11%) withdrew consent/opted for standard conditioning.

Median age of the 39 evaluable pts is 53 (39-67); 64% are male. Median serum β2-microglobulin level is 3.64 mg/L (1.7-20) and albumin 37 g/L (2.8-48.1); 17 pts have ISS stage I; 9 have stage II; 9 have stage III MM and 4 have missing data. Ig subtype includes IgGκ in 16 (40%), IgGλ in 4 (10%), IgAκ in 5 (13%), IgAλ in 8 (21%), IgMλ in 1 (3%), κ in 1 (3%); non-secretory in 2 (5%) and no data in 2 pts (5%).

Post-ASCT, only 4 SAEs have occurred: atrial fibrillation (2), acute kidney injury (1) and sepsis (1). There have been no ASCT-related deaths, and no pt has progressed at a median follow-up of 7.8 mos (range: 4.8-10.1).

The best Ig response post-induction in the 31 pts with available restaging data is CR in 5 (16%), VGPR in 9 (29%), PR in 13 (42%), and SD in 1 (3%). 27 pts have reached day 100 post-ASCT and 8 pts have been formally evaluated. In these 8, the Ig response is CR in 2 (25%), VGPR in 5 (63%) and PR in 1 (12%). Table 1 summarizes MRD results to date.

Table 1.

Comparison of conventional Ig response rates and achievement of MRD negativity

# Conventional Ig Responses [# MRD negative]
Time point of assessment #
Evaluable 
Total # MRD negative CR VGPR PR MR 
After btz-based induction 31 5 [3] 9 [1] 13 [2] 
Day 100 post-ASCT 2 [2] 5[0] 1[0] 
During len maintenance 5 [1] 
# Conventional Ig Responses [# MRD negative]
Time point of assessment #
Evaluable 
Total # MRD negative CR VGPR PR MR 
After btz-based induction 31 5 [3] 9 [1] 13 [2] 
Day 100 post-ASCT 2 [2] 5[0] 1[0] 
During len maintenance 5 [1] 

Conclusions: 1) MFC performed on pre-therapy marrow samples to allow subsequent evaluation for MRD was successful in 97% of pts using a central lab; 2) IV BuMel was well-tolerated with few SAEs and no ASCT-related deaths; 3) MRD and conventional Ig responses may not correlate well; 4) Further F/U is required to determine the dynamics of MRD achievement and long term outcomes with this approach.

Disclosures

Reece:Novartis: Honoraria, Research Funding; BMS: Research Funding; Merck: Research Funding; Millennium: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Amgen: Honoraria. Off Label Use: Lenalidomide maintenance after ASCT. Venner:Celgene: Honoraria, Research Funding; Janssen: Honoraria. White:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Sebag:Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Song:Celgene: Honoraria; Otsuka: Honoraria; janssen: Honoraria. Tay:Celgene: Honoraria; Janssen: Honoraria. Kukreti:Celgene: Honoraria. Trudel:Glaxo Smith Kline: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria; Oncoethix: Research Funding. Tiedemann:Celgene: Honoraria; Janssen: Honoraria. Chen:Millennium: Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.

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