Upfront autologous stem cell transplantation (ASCT) versus carfilzomib-cyclophosphamide-dexamethasone (KCd) consolidation with K maintenance in transplant-eligible, newly diagnosed (NDTE) multiple myeloma (MM).

Abstract

8000 Background: Upfront ASCT for NDTE MM remains under evaluation with high MRD rates following novel induction and consolidation (cons) strategies. Current phase 3 trials support ASCT, however these employ lenalidomide maintenance which predominantly benefits standard risk (SR) patients (pts). The CARDAMON trial investigated the role of ASCT using K based induction and maintenance. Methods: NDTE pts received 4 x KCd induction (K 20/56 mg/m2 biweekly, C 500 mg D 1,8,15, d 40mg weekly) before 1:1 randomisation to ASCT or 4 x KCd cons. All received 18 months K maintenance (56mg/m2 D1,8,15). Flow cytometric MRD (10-5) was assessed post induction, pre-maintenance and at 6 months maintenance. Primary endpoints were ≥VGPR post induction and 2-year PFS from randomisation. 210 randomised pts were needed to exclude a 10% non-inferiority margin with 15% 1-sided alpha, 80% power. Results: 281 pts were registered, median age 59y (33–74), 24% high risk [t(4;14), t(14;16), t(14;20) or del(17p)]. Post induction, ≥VGPR rate was 58.5%, ORR was 87% with similar responses for high risk vs SR. 52 pts did not proceed to PBSCH (6 MR, 16 PD, 19 toxicity, 4 deaths: 3 infection, 1 cardiac event, 7 other). 109 were randomised to ASCT, 109 to KCd cons. ≥VGPR rate was 78.5% after cons and 80.0% after ASCT (p = 0.8). Median KCd cons dose was 55.5 mg/m2, 99 (90.8%) pts completed 4 cycles, 104 (95.4%) pts received ASCT. After 2.6 years follow-up, median PFS was not reached for ASCT vs 3.8 years for cons (HR: 0.82 (70% CI 0.65, 1.05, p = 0.4). Observed 2-year PFS for ASCT was 75.5% vs 70.7% for cons; calculated difference in 2-year PFS rate (cons vs ASCT) was -4.5% (70% CI -9.2%, +1.1%, non-inferior). High risk pts had inferior outcomes to SR overall regardless of randomisation (2-year PFS ASCT: 52% vs 82% (HR 4.09); cons 48% vs 77% (HR 2.83)). 2 year PFS did not differ according to randomisation: SR 82% (ASCT) vs 77% (cons) HR: 1.29 (0.71-2.35); high risk: 52% (ASCT) vs 48% (cons) HR: 1.06 (0.50-2.23). MRD negativity post induction was 24.3% and similar by genetic risk. MRD negative rates were higher post ASCT (53.1%) than cons (35.8%) (p = 0.02) independent of genetics: SR 49% (ASCT) vs 36% (cons); high risk: 57% (ASCT) vs 32% (cons). G3+ adverse events to induction were infections (18.7%), hypertension (11.2%), anaemia (10.4%), cardiac disorders (3.6%), vomiting (2.2%), fatigue (2.2%), diarrhoea (1.8%). Conclusions: In NDMM receiving KCd induction and K maintenance, KCd cons was non-inferior to ASCT. High risk pts had inferior outcomes, that were not influenced by ASCT or cons randomisation. Clinical trial information: NCT02315716. [Table: see text]

Autologous Stem Cell Transplantation in Multiple Myeloma: Where Are We and Where Do We Want to Go?

“…In SR patients, 4-year PFS was 82% vs. 67% in KRd-ASCT and KRd12 groups, respectively (HR = 0.43, p = 0.032); in HR patients, it was 62% vs. 45% (HR = 0.61, p = 0.040), and in the DH group, 55% vs. 33% (HR = 0.52, p = 0.063), respectively [ 85 ]. In contrast, similar PFS rates with KCd plus ASCT and KCd induction/consolidation were seen within the high-risk subset of the phase III CARDAMOM trial, and these results may suggest that ASCT exerts lower efficacy in the high-risk patients when triplet combination used as induction therapy does not include a PI and an IMID [ 86 ].…”

Impact of autologous transplantation on survival in patients with newly diagnosed multiple myeloma who have high‐risk cytogenetics: A meta‐analysis of randomized controlled trials

“…The search strategy yielded 3305 citations. We identified 2 additional conference abstracts after hand searching 20,21 . After screening 3307 citations, 42 articles met the inclusion criteria; among these, 6 unique RCTs with 2959 patients were included in our systematic review and meta‐analysis.…”

“…After screening 3307 citations, 42 articles met the inclusion criteria; among these, 6 unique RCTs with 2959 patients were included in our systematic review and meta‐analysis. The 6 RCTs were: Intergroupe Francophone du Myélome (IFM) 2009 (ClinicalTrials.gov identifier NCT01191060), 22,23 EMN02/HO95 (ClinicalTrials.gov identifier NCT01208766), 3,4 RV‐MM‐EMN‐441 (ClinicalTrials.gov identifier NCT01091831), 24 RV‐MM‐PI‐209 (ClinicalTrials.gov identifier NCT00551928), 25 FORTE (ClinicalTrials.gov identifier NCT02203643), 21,26 and CARDAMON (ClinicalTrials.gov identifier NCT02315716) 20 . Figure 1 highlights the PRISMA flowchart for our study.…”

“…Maintenance therapy included lenalidomide in 3 RCTs, carfilzomib in 1 RCT, and patients were randomized to carfilzomib‐lenalidomide versus lenalidomide or lenalidomide versus no maintenance in 2 RCTs. All trials administered maintenance therapy until disease progression or unacceptable toxicity, except IFM 2009 and CARDAMON trials, which administered maintenance for a maximum of 12 months and 18 months, respectively 20,22 …”

“…We identified 2 additional conference abstracts after hand searching. 20,21 After screening 3307 citations, 42 articles met the inclusion criteria; among these, 6 unique RCTs with 2959 patients were included in our systematic review and meta-analysis. The 6 RCTs were: Intergroupe Francophone du Myélome (IFM) 2009 (ClinicalTrials.…”