Is Tandem ASCT Needed in MM Patients with High Risk Cytogenetics in the Era of Maintenance Therapy? Results from the Canadian Myeloma Research Group (CMRG) Database
Authors: Duggan Peter , Reece Donna E. , Song Kevin , Jimenez-Zepeda Victor , McCurdy Arleigh , Louzada Martha L , Mian Hira S , Sebag Michael , White Darrell J , Stakiw Julie , Leblanc Richard , Masih-Khan Esther , Atenafu Eshetu G , Kotb Rami , Aslam Muhammad , Reiman Anthony , Gul Engin , Venner Christopher P. 
Published: November 2020

Background: Recent studies evaluating tandem autologous transplantation for multiple myeloma (MM) show conflicting results in terms of efficacy. However subgroup analysis suggests that those with high-risk disease may benefit the most from tandem transplant. We used the CMRG database to compare single versus tandem ASCT for patients with MM with high-risk cytogenetics.
Methods: The primary objective was to compare PFS in MM patients with high-risk cytogenetics (p53 deletion, t(4;14), t(14;16)) identified from the CMRG database undergoing front-line single or tandem ASCT from 01/2010 to 06/2019. Secondary objectives compared OS, ORR, and outcomes based on whether post-transplant maintenance was given. OS and PFS rates were calculated from the date of first ASCT using the Kaplan-Meier method. ORR was assessed by Chi-square using best response post ASCT.
Results: There were 302 single and 125 tandem transplants, followed by maintenance therapy in 190 (63%) and 96 (77%) respectively. Translocation (4;14) was seen in 209 (49%), t(14:16) in 61 (15.6%) and delP53 in 222 (52%) with more than one abnormality in 65 patients. The most common induction regimen consisted of cyclophosphamide, bortezomib, and steroids, (83%) followed by bortezomib and dexamethasone (8%) and dexamethasone alone (4.7%). Forty-seven patients (11%) required reinduction prior to first ASCT with regimens including RVD (49%), Rd (23%) and others (D/DT/VD-PACE, CyBor-D, KRD, VD, IxaRD, 28%). Maintenance was prescribed to 286 patients with regimens including lenalidomide ± dexamethasone (65%), lenalidomide + proteasome inhibitor ± dexamethasone (22%), proteasome inhibitor ± dexamethasone (11%) and others (2%). Patient characteristics are summarised in table 1.
The overall response rate was 93.9% (94.5% for single ASCT and 92% for tandem ASCT). The PFS at 3 years was 41.1% (single) and 45.7% (tandem) with median PFS 26 vs 35 months respectively (p=0.0621). Three year OS was 71.5% (single) and 83.8% (tandem), median OS 83 vs 89 months (p=0.0060).
Both PFS and OS were improved with the use of maintenance therapy, regardless of single vs tandem transplant. PFS at 3 years was 52.1% for those receiving maintenance therapy compared to 21.7% for no maintenance (median 42 vs 16 months, p&lt;0.0001). Overall survival was 79.5% with maintenance vs 63.6% without (median 92 vs 60 months, p&lt;0.0001). Figures 1 shows PFS and OS for single or tandem transplant, with or without maintenance therapy. There was no difference in PFS or OS after a single or tandem transplant when maintenance was given. PFS for single or tandem ASCT with maintenance at 3 years was 53.7% and 46.3% respectively (p=0.527). Three year OS rates were 76.7% and 85.6% (p=0.0962). However, PFS was better with tandem compared to single ASCT when no maintenance was given. PFS at 3 years for single transplant with no maintenance was 19.0% (median 13 months) vs 48.9% (median 23.7 months) for tandem without maintenance (p=0.0084), while OS were not statistically different (62.4% vs 74.7%, median 60 months vs not reached, p=0.5271).
Conclusions: Tandem ASCT does improve outcomes for MM with high-risk cytogenetics. However, the main benefit was seen in patients who did not receive maintenance therapy. Our data demonstrate the potent anti-myeloma effect of post-ASCT maintenance and raise the question of the optimal role of tandem ASCT in the modern treatment era.

Disclosures
Duggan: Novartis: Honoraria; Amgen: Consultancy; Celgene: Consultancy; Astra Zeneca: Consultancy; Jannsen: Consultancy. Reece:Janssen, Bristol-Myers Squibb, Amgen, Takeda: Consultancy, Honoraria; Janssen, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Otsuka: Research Funding. Song:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene,Takeda: Consultancy, Honoraria; Otsuka: Honoraria. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. McCurdy:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Honoraria; GSK: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Louzada:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Mian:Takeda: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. White:Takeda: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria. Stakiw:Lundbeck: Honoraria; Celgene: Honoraria; BMS: Honoraria; Roche: Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Novartis: Honoraria. Leblanc:Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Kotb:Takeda: Honoraria; Sanofi: Research Funding; Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Karyopharm: Current equity holder in publicly-traded company; Merck: Honoraria, Research Funding. Venner:Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria; Celgene, Amgen: Research Funding.