Upfront Autologous Stem Cell Transplantation (ASCT) Vs Carfilzomib-Cyclophosphamide-Dexamethasone (KCd) Consolidation in Transplant-Eligible, Newly Diagnosed (NDTE) Multiple Myeloma (MM): Results of the Cardamon Study According to Cytogenetic Risk
Authors: Yong Kwee , Wilson William , Camilleri Marquita , Ramasamy Karthik , Streetly Matthew , Sive Jonathan , Bygrave Ceri A , Chapman Michael , de Tute Ruth M. , Chavda Selina J , Phillips Elizabeth H , Cuadrado Maria del Mar , Pang Gavin , Jenner Richard , Dadaga Tushhar , Kamora Sumaiya , Cavenagh James , Clifton-Hadley Laura , Owen Roger G , Popat Rakesh 
Published: November 2021

Abstract
Background: Upfront ASCT for NDTE MM continues to be challenged as standard of care due to high MRD neg rates following novel induction and consolidation (cons) strategies. The Cardamon study reported that KCd consolidation did not meet the statistical boundary for non-inferiority to ASCT following KCd induction, however the margin was small, with no benefit for MRD negative pts. For this analysis we focussed on the outcomes according to cytogenetic risk.
Methods: NDTE pts received 4 x KCd induction (K 20/56 mg/m 2 biweekly, C 500 mg D 1,8,15, d 40 mg weekly) before 1:1 randomisation to ASCT or 4 x KCd cons. All received 18 months K maintenance (56mg/m 2 D1,8,15). High risk (HR) was defined as any one of the HR cytogenetic abnormalities (CA) del(17p) (≥50%), t(4;14), t(14;16), t(14;20), ultraHR (uHR) as ≥2 of the HR CA, 1p- or 1q+, and standard risk (SR) as neither HR nor uHR. CA were identified by FISH on CD138 enriched cells. Subgroup analyses evaluated the impact of each single CA, including t(11;14). Flow cytometric MRD (10 -5) was assessed post induction, pre-maintenance and after 6 months maintenance, on ITT basis. The primary objective of this analysis was outcomes according to cytogenetic risk, including the impact of treatment arm.
Results: Of 281 pts registered, 259 were included with complete FISH data, 52 (20%) had HR CA, and 41 (16%) were uHR. Post induction, ≥VGPR rate was 60% in HR pts, 56% in uHR pts, and 59% in SR pts. MRD neg rates were 23%, 27% and 23% and increased to 53%, 56% and 45% with ASCT and 27%, 27% and 32% with Cons, for HR, uHR and SR respectively.
With a median follow-up of 2.8 years, the observed 2-year PFS from randomisation for ASCT was 76.6% vs 68.8% for cons (HR: 0.77 (70% CI 0.61, 0.97), p=0.2); calculated difference in 2-year PFS rate (cons vs ASCT) was -6.2% (70% CI -10.7%, -0.1%, not non-inferior).
HR and uHR pts had inferior outcomes to SR overall, with 2-year PFS rates of 49%, 50% and 76% respectively (HR vs SR: HR=2.58, p&lt;0.001, uHR vs SR: HR=3.04, p&lt;0.001). This was true regardless of randomisation, with 2-year PFS rates from randomisation of 61%, 63% and 80% with ASCT (HR vs SR: HR=3.27, p=0.002, uHR vs SR: HR=4.24, p&lt;0.001) compared to 44%, 41% and 75% with cons (HR vs SR: HR=3.22, p&lt;0.001, uHR vs SR: HR=4.11, p&lt;0.001). Early relapse (within 18 months of registration) rate in HR and uHR was 38% and 32% vs 15% in SR (p=0.001, p=0.02 respectively). There was no evidence of a statistically significant PFS benefit for ASCT over cons in the HR, uHR or SR subgroups with HRs of 0.77 (p=0.5), 0.81 (p=0.5) and 0.81 (p=0.6) respectively.
Analysis by single CA was limited by the small pt numbers in each group, however pts with t(4;14) had worse PFS (HR: 2.62, p&lt;0.01) than those without t(4;14), similarly with del(17p) (≥50%) (HR: 3.57, p&lt;0.01) and 1p- (HR: 2.76, p&lt;0.01).
While numbers are small and the interaction does not meet significance (p=0.16), pts with t(11;14) tended to demonstrate a benefit for ASCT over cons (2-year PFS 89% vs 67%).
Conclusions: HR or uHR pts receiving KCd induction, followed by ASCT or KCd cons, had a significantly shorter PFS compared to SR pts. Consolidation with KCd did not meet the boundary for non-inferiority to ASCT, though the margin is small and none of the HR, uHR and SR cytogenetic risk groups had a statistically significant PFS benefit with ASCT.

Disclosures
Yong: GSK: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Research Funding; BMS: Research Funding; Amgen: Honoraria; Sanofi: Honoraria, Research Funding; Autolus: Research Funding. Ramasamy: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer oncology: 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, Other: Travel, Conference registration, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Adaptive biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Streetly: BMS-Celgene: Consultancy; Sanofi: Consultancy; EUSA Pharma: Consultancy. Clifton-Hadley: Bristol-Myers Squibb Pharmaceuticals Ltd..: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Amgen: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Celgene: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Merck Sharp and Dohme: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Janssen-Cilag: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Pfizer: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Millennium pharmaceutics inc.: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.. Popat: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen and BMS: Other: travel expenses.