Increased Rates of MRD Conversion from Positive (+ve) to Negative (-ve) Following ASCT Compared to Chemotherapy Consolidation in Newly Diagnosed Multiple Myeloma Is Prognostic for Improved Progression Free Survival: Dynamic MRD Assessment in the UK-MRA Cardamon Trial

Introduction:

Achievement and maintenance of maximal depth of response to first line therapy is a prerequisite for prolonged progression free survival (PFS) in multiple myeloma (MM) and initial treatment protocols are designed to enhance probability of obtaining a serological complete response (CR) and minimal residual disease (MRD) negativity in the bone marrow (BM). Response adapted treatment can deliver better outcomes than a one-size fits all approach^1,2 if serological and BM markers are used to guide treatment selection. Deepening of response following high dose melphalan ASCT (HDM-ASCT) and immunomodulator-based maintenance treatment is well described³, similar response to transplant-sparing chemotherapy consolidation or HDM-ASCT and prolonged proteasome inhibitor (PI)-based maintenance is understudied. The primary endpoint of CARDAMON has been previously reported⁴, this in depth analysis of MRD conversion pre and post ASCT further describes the benefit of ASCT in improving depth of response compared to chemotherapy alone.

Methods:

Initial treatment comprised 4 x 28-day cycles of KCd (Carfilzomib 20/56mg days 1,2,8,9,15,16,Cyclophosphamide 500mg D1,8,15 and Dexamethasone 40mg D1,2,8,9,15,16) followed by peripheral blood stem cell harvest and consolidation with either HDM-ASCT or 4 further cycles of KCd. Following consolidation all patients received K maintenance for up to 18 x 28-day cycles. Data on serological response and rates of MRD negativity by FLOW cytometry (10-5) assessed at 3 time points: post induction and harvest (induction), post consolidation (HDM-ASCT or KCd) and post maintenance are presented alongside survival data.

Results:

A total of 281 patients were registered for the study and 230 patients completed induction, 218 of which were subsequently randomised (109 HDM-ASCT, 109 KCd). Median follow up was 4.8 years (IQR 4.1-5.8). Post-induction, 64 patients were MRD -ve and 153 MRD +ve (MRD status unknown in 13 patients). Patients achieving CR and MRD -ve at any of the 3 timepoints showed no benefit from ASCT over KCd in PFS (HR (ASCT vs KCd) 0.90, 95% CI 0.50-1.62, p=0.7) or OS (HR 2.56, 95% CI 0.70-9.43, p=0.2).

Patients who were MRD +ve post induction were more likely to convert to MRD-ve with HDM-ASCT (25/64, 39.1%) than with KCd (10/61, 16.4%) consolidation (p=0.005). This effect continued during maintenance treatment such that 26/58 (44.8%) who were MRD +ve post induction became MRD -ve if they had received HDM-ASCT consolidation compared to 14/63 (22.2%) who received KCd (p=0.01). There was no significant difference between randomised consolidation treatment (HDM-ASCT or KCd) in maintaining MRD negativity if it was achieved at the earliest timepoint post-induction and sustained until the end of consolidation (HDM-ASCT 23/26, 88.5% vs KCd 20/25, 80.0%, p=0.4) or until the end of maintenance (HDM-ASCT 22/25, 88.0% vs KCd 17/21, 81.0% p=0.5).

Furthermore, patients with sustained +ve MRD have a significantly worse PFS than those with repeated -ve MRD (Hazard Ratio 1.77, 95% CI 1.12-2.79, p=0.01) or those who convert from MRD +ve to -ve between the end of induction and the end of consolidation (HR 2.71, 95% CI 1.57-4.69, p<0.001). Though not significant, patients who converted from MRD +ve to -ve tended to have better outcomes than those with sustained negativity (HR 0.65, 95% CI 0.35-1.22, p=0.2) suggesting that the superior effect of ASCT continues during K maintenance and a potential synergistic effect of transplantation with PI maintenance. More patients converted from MRD +ve to MRD -ve during maintenance following ASCT (11/39 28.2%) than KCd (8/50 16%) although this difference was not significant (p=0.16).

Discussion:

This post hoc analysis of the CARDAMON study shows that early assessment of MRD status following induction and response driven choice of consolidation may improve outcome in first line treatment of MM and allow those with an early MRD -ve response to avoid the toxicity of HDM-ASCT. Similarly continued use of transplantation approach may be justified in those who are MRD +ve following induction. These results utilising a PI-based induction and post-ASCT treatment remain to be confirmed with quadruplet induction and IMiD-based maintenance.

References:

1. Costa L, et al J Clin Oncol. 2022 1;40(25):2901-2912
2. Royle K-L et al BMJ Open 2022 17;12(11)
3. Jackson G et al Lancet Oncol. 2019;20(1):57-73
4. Yong K et al Lancet Hematol. 2023;10(2):E93-106