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C. Pawlyn et al.
very selected older patients or in those with renal failure. In the Myeloma XI trial the induction therapy for TE and TNE patients was the same triplet combination. This provided the opportunity to compare outcomes for those patients undergoing transplantation with patients of the same age who did not undergo transplantation but who had received the same induction therapy. We performed this analysis from the end of induction (± intensification if given) and only included patients who would have been eligible to continue in the study to avoid survivor and immortal time biases. This comparison showed a marked improvement in PFS and OS associated with ASCT. It is important to note that this comparison between ASCT and no ASCT was not randomized and therefore remains inherently subject to bias. Patients in the TE pathway of the trial were selected on the basis of clinician’s judgement and patient’s preference. We found that the older patients included in the TE pathway had a lower performance sta- tus than younger patients, whereas performance status usually increases with age. This suggests active selection of only the fittest older patients for entry into the TE path- way and consideration of ASCT. Consistent with this, in the age-matched population the performance status and ISS stage were higher in both the TE-noASCT and TNE groups than in the TE-ASCT patients. Unfortunately, data to calculate the International Myeloma Working Group frailty score,26 the Revised Myeloma Comorbidity Index27 or the Hematopoietic Cell Transplant Comorbidity Index28 were not collected within the study. We applied the UK- MRP, an outcome score previously validated only in the TNE population, across the groups and found more patients in the TNE and TE-noASCT groups to have high- er-risk MRP than in the TE-ASCT group. Additionally, the TE-ASCT group had achieved deeper responses at the end of induction. This may have affected their outcomes irre- spective of transplantation. To address this, a matched analysis using IPTW was performed with factors including those associated with frailty and response to induction that were different between the age-matched groups. This analysis confirmed the markedly improved PFS and OS for the ASCT-TE group, suggesting that this finding was not confounded by fitness or prior response. It should be noted that propensity scores only balance measured covariates as confounders, and balance in measured covariates does not necessarily indicate balance in unmea- sured confounders. If unmeasured covariates are con- founders, they can bias treatment effect estimates. These
results should therefore be interpreted with caution. Previous studies in younger, fitter patients under the age of 65 have demonstrated the efficacy of transplantation in the era of modern therapy including studies combining proteasome inhibitors and immunomodulatory agents for all patients as induction therapy. Such approaches may now be considered better than the largely immunomodu- latory agent-based induction delivered in Myeloma XI. In the IFM/DFCI 2009 study patients received bortezomib, lenalidomide and dexamethasone (VRD) induction before randomization between ASCT and consolidation in the form of additional cycles of VRD, with ASCT deferred to first relapse.29 The trial demonstrated an association between improved PFS and early ASCT while follow-up for OS is ongoing. The EMN02 trial conducted a similar comparison but in the context of induction with cyclophosphamide, bortezomib and dexamethasone and compared the use of bortezomib, melphalan and pred-
nisone (VMP) consolidation to ASCT,6 also demonstrating a PFS advantage for first-line ASCT. Our data support the findings of these studies and extend them to older patients who were excluded from these trials. Sub-analysis of IFM/DFCI 2009 suggests that there is no benefit of trans- plantation in patients achieving very deep minimal resid- ual disease-negative responses prior to ASCT. This is of great interest as it could lead to a response-adapted approach to ASCT. Minimal residual disease data were collected for a subset of the patients within the Myeloma XI trial, but there were too few patients in the age- matched population to perform this analysis. Within the last 18 months two large phase III studies showed that the addition of daratumamb to standard induction regimens (lenalidomide-dexamethasone and VMP) dramatically improved the PFS and OS of older patients.30-32 TNE patients were randomized into these studies, although the reason for transplant ineligibility (age, co-morbidities) was not stated. Randomized clinical trials are therefore still warranted for older patients who are fit for transplant comparing an antibody-containing regimen ± transplanta- tion.
In summary, these findings support the use of ASCT for selected, fit older myeloma patients up to the age of 75. With effective clinician selection, older patients undergo- ing ASCT can experience long PFS and OS, comparable to those of younger patients, and without any significant increase in morbidity or mortality.
Disclosures
CP has provided consultancy services for and received travel support from Amgen and Takeda Oncology; honoraria and travel support from Janssen; and consultancy fees, honoraria, and travel support from Celgene Corporation. DAC has received research funding from Celgene Corporation, Amgen, and Merck Sharp and Dohme. TM has received research funding from Celgene Corporation, Amgen, and Merck Sharp and Dohme. JRJ has received honoraria and research funding from Celgene Corporation. MWJ has acted as a consultant for and received honoraria, travel support, and research funding from Janssen; has acted as a consultant for and received honoraria and travel sup- port from Takeda and Amgen; has acted as a consultant for and received honoraria and research funding from Celgene Corporation; and has acted as a consultant for and received hon- oraria from Novartis. GC has provided consultancy and speakers bureau services for and received honoraria and research funding from Takeda, Celgene Corporation, Janssen and Amgen; has acted as a consultant for and received honoraria from Glycomimetics and Bristo-Myers Squibb; and has provided con- sultancy and speakers bureau services for and received honoraria from Sanofi. KDB has received honoraria from Celgene, Janssen, and Amgen; acted in a consulting or advisory role for Celgene, Janssen, Takeda, and Novartis; and received travel support from Celgene, Janssen, and Takeda. MTD has equity ownership and membership on the board of directors or advisory committees of Abingdon Health. MFK has acted as a consultant for and received travel support from Bristol-Myers Squibb and Takeda; has acted as a consultant for Chugai; has acted as a consultant for and received honoraria from Janssen and Amgen; and has acted as a consultant for and received honoraria and research funding from Celgene Corporation. RGO has received honoraria and travel support from Takeda; has provided consultancy services for and received travel support from Janssen; and has acted as a consult- ant for and received honoraria and research funding from Celgene Corporation. WG has provided consultancy services for and
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haematologica | 2022; 107(1)