Outcomes of multiple myeloma (MM) patients with del 17p as a sole high risk cytogenetic abnormality who underwent either single or tandem upfront autologous stem cell transplant approaches in EBMT centres between 2016 and 2022

Abstract Introduction Approximately 10% of patients with newly diagnosed multiple myeloma (MM) have the FISH cytogenetic abnormality, Del 17p, of whom one fifth also have t(4;14) or t(14;16), these additional translocations being associated with worse survival outcomes in this setting. While upfront autologous stem cell transplantation (ASCT) remains the standard of care in all transplant-eligible patients, there is no consensus on the role of tandem ASCT in patients with high-risk disease. We therefore compared outcomes in MM patients with Del 17p as the sole reported high risk cytogenetic abnormality (Del 17p only) who had either single or tandem transplants in EBMT-registered centres between 2016 and 2022 inclusive. Methods Adult MM patients with Del 17p only who had a first MM ASCT during this time and were alive and relapse free six months after the transplant were selected from the EBMT registry. We performed multivariable analysis for OS and PFS in this cohort, thereby providing covariate-adjusted survival estimates of the Upfront/Tandem transplant effect. Results A total of 1,668 MM patients with Del 17p only underwent ASCT between 2016 and 2022 inclusive. Data was available on 1,347 patients who reached the six-month landmark of whom 766 (56.9%) had a single and 581 (43.1%) a tandem transplant. The median age at ASCT was slightly younger in the tandem cohort (Tandem vs Single, Median (IQR) 60.3 (55.1-65.3) years vs 61.7 (56.3-67.3) years, p<0.001). Other baseline variables (Sex, MM type, International Staging System (ISS) stage) were similar. The interval from diagnosis to transplant was shorter in the tandem group (6.2 (5.1-8.2) mths vs 6.9 (5.4-9) mths, p=0.004) and fewer had achieved a Complete Response (77 (13.6%) vs 139 (18.5%), p=0.033). Karnofsky scores (>80 vs <=80, p= 0.92) were comparable as was the proportion who received full dose Melphalan 200mg/m2 for the first transplant (450 (77.5%) vs 576 (75.6%), p=0.56). The proportion of tandem vs single transplants in this high-risk cohort gradually increased from 2017 to 2021 (2017: 27.4% vs 72.6%, 2018: 41.2% vs 58.8%, 2019: 46% vs 54%, 2020: 52.1% vs 47.9%, 2022: 52% vs 48%). Multivariable analysis was performed for the following variables: transplant type, patient age at first ASCT (decades), MM type, ISS stage, disease status at ASCT-1, Conditioning (Mel200 vs Mel140 vs Mel Other vs Other conditioning) and Karnofsky score (<=80, >80). The median follow-up from the 6-month landmark was 1.8 years (95% CI 1.69-1.92). Tandem ASCT was associated with superior PFS (HR 0.81 (0.67-0.97), p=0.024) and OS (HR 0.75 (0.58-0.98), p=0.037) whereas ISS (International Staging System) stage III was associated with inferior PFS (HR 1.33 (1.06-1.69), p=0.015) and OS (HR 1.44 (1.04-2.00), p=0.027). IgA isotype (HR 1.34 (1.07-1.68), p=0.011) and disease status at ASCT-1 <=PR (HR 1.68 (1.28-2.20), p<0.001) were also associated with inferior PFS. The PFS rates in the single and tandem ASCT groups were 72% (69-76%) and 81% (77-85%) at one year and 42% (37-46%) and 47% (40-54%) at three years (p=0.039) Patients after a single transplant had an average PFS of 23.7 months over the next three years whereas patients after a tandem ASCT had an average PFS of 26.1 months, the difference being 2.4 months (p=0.004). The OS rates in the single and tandem ASCT groups were 91% (89-93%) and 93% (90-96%) at one year and 69% (65-73%) and 72% (65-78%) at three years (p=0.048). Patients after a single transplant had an average OS of 30.5 months over the next three years whereas patients after a tandem ASCT had an average OS of 31.8 months, the difference being 1.3 months (p=0.035). Conclusions Among patients with multiple myeloma with Del 17p as the sole reported high risk cytogenetic abnormality undergoing ASCT, tandem transplants were associated with modest improvements in progression-free and overall survival compared to single transplants. However, outcomes remained inferior to those seen in broader clinical trial populations - an OS rate of 81% at four years was reported in the transplant arm of the IFM-2009 trial (RVd+ASCT) - underscoring the high-risk nature of this isolated del(17p) subgroup. While tandem ASCT appears beneficial, the clinical advantage is limited and should be weighed against the increased treatment burden and resource use.