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C. Pawlyn et al.
based on the individual patient’s fitness rather than a strict age cut-off. Standard-of-care conditioning for ASCT con- sists of melphalan given at a dose of 200 mg/m2 although a lower dose of 140 mg/m2 may be delivered in the case of renal impairment and is sometimes considered by clinicians for the treatment of older patients.
The European Bone Marrow Transplant (EBMT) registry has documented an increase in the number of patients aged over 65 undergoing ASCT in recent years. Between 2001- 2005, 2,478 patients aged 65-69 years underwent ASCT, constituting 14.1% of transplanted patients, and the num- ber rose to 3,860 (15.8%) in the years 2006-2010. A similar pattern was seen for those aged 70 or over: 497 (2.8%) in 2001-2005 and 740 (3%) in 2006-2010.7 In this analysis there was no apparent difference in transplant-related mor- tality between those aged 60-64, 65-69 and ≥70 years, with the rates being 1.8%, 2.1% and 2.4%, respectively. This trend is mirrored in data from the USA-based Center for International Blood and Marrow Transplant Research (CIBMTR).8
Two randomized studies of ASCT in older patients were conducted using dose-reduced melphalan (100 mg/m2) tan- dem transplantation following conventional chemotherapy induction regimens. The first study randomized patients aged 50-70 years between melphalan prednisolone (MP) and vincristine, doxorubicin and dexamethasone for two cycles followed by dose-reduced melphalan and ASCT for two cycles (VAD+ASCT100).9 The use of ASCT was asso- ciated with improved event-free survival and OS. The sec- ond study randomized patients between MP, MP plus thalidomide and VAD+ASCT100. This study demonstrated an improvement in OS for VAD+ASCT100 versus MP but the use of MP plus thalidomide was superior to both approaches.10 These data supported the use of ASCT100 in the context of conventional chemotherapy induction in older patients but the combination of both immunomodu- latory agent induction and ASCT was not examined.
Several previous retrospective studies have examined outcomes following ASCT for patients over the age of 65 or 70 following immunomodulatory and/or proteasome inhibitor-based induction. A large retrospective study of patients treated at the Mayo Clinic (USA) compared 207 patients aged 70 and over to 1,765 patients aged less than 70.11 There was no significant difference in PFS, OS or trans- plant-related mortality between the groups. A similar analysis of patients treated in Heidelberg (Germany), found no difference between outcomes for those aged 60-64, 65- 69 or 70-75 years.12 Retrospective data analysis has also been used to compare ASCT and no-ASCT treatment strategies in small cohorts of patients over the age of 65.13,14 These studies support the use of ASCT in patients over the age of 65 thought to be fit, but did not address whether ASCT is preferred over conventional therapy for patients in this older age group. To our knowledge, no randomized comparison of ASCT to no-ASCT has been undertaken in patients over the age of 65 in the current treatment land- scape.
Data from the UK National Cancer Research Institute (NCRI) Myeloma XI trial, a large phase III randomized con- trolled trial with pathways for transplant-eligible (TE) and - ineligible (TNE) patients, was used to explore the efficacy and toxicity of ASCT in older patients including an analysis using an age-matched population.15,16 Patients in the trial were randomized between induction treatment with thalidomide- or lenalidomide-based triplets, with the same
combinations being used in both the TE and TNE path- ways. This gives the opportunity to examine outcomes for TE patients of different ages, but also to compare outcomes for similar patients receiving the same induction therapy with or without ASCT.
Methods
Myeloma XI is a phase III, open-label, parallel-group, multi-arm, adaptive trial and recruited newly diagnosed patients of all ages. Eligible patients were aged ≥18 years. The trial was designed to reflect a population as close to real-world as was considered safe. Exclusion criteria were therefore limited, but included previous treatment for myeloma (excluding local radiotherapy, bisphospho- nates, and corticosteroids), previous or concurrent malignancies (including myelodysplastic syndromes), grade ≥2 peripheral neu- ropathy, acute renal failure (unresponsive to up to 72 h of rehydra- tion, characterized by creatinine >500 μmol/L or urine output <400 mL/day or requiring dialysis), and active or prior hepatitis C virus infection. There were separate pathways for TE and TNE patients.
The trial was performed in accordance with the Declaration of Helsinki 1996, and the study was approved by the national ethics review board (National Research Ethics Service, London, UK), institutional review boards of the participating centers, and the competent regulatory authority (Medicines and Healthcare Products Regulatory Agency, London, UK). All patients provided written informed consent. The trial was registered with the EU Clinical Trials Register (EudraCT number, 2009-010956-93).
The details of the trial therapy and most primary outcomes have been published already.15,16 In brief, patients in both path- ways were randomized between a thalidomide-containing triplet (cyclophosphamide, thalidomide and dexamethasone) or a lenalidomide-containing triplet (cyclophosphamide, lenalidomide and dexamethasone). Induction treatment was given for a mini- mum of four cycles (in the TE pathway) or six cycles (TNE) and to maximum response, and there was an induction intensification question for those with a suboptimal response to initial induction. All TE patients were planned to undergo an ASCT. Patients in both pathways underwent maintenance randomization between lenalidomide (± vorinostat) and observation.
The choice of pathway, TE or TNE, was left to the local inves- tigator based on co-morbidities and the patient’s/clinician’s prefer- ence. There was no age limit for entry into the TE pathway. Induction therapy in the TNE pathway was administered with an attenuation of dexamethasone dosing (Online Supplementary Table S1) but was otherwise similar between pathways.
All participants in the intensive pathway who responded (with at least a minimal response) to induction chemotherapy were planned to go on to receive high-dose melphalan and ASCT. Peripheral blood stem cell harvest was planned to commence after the participant had completed the induction and intensification (if applicable) treatment. Stem cell mobilization and stem cell harvest were performed according to local practice but with advice to aim for the collection of enough stem cells for at least two transplants. High-dose melphalan and ASCT were given according to local practice. Adjustment for renal insufficiency was advised. Participants with serum creatinine <200 mmol/L prior to transplan- tation were to receive the standard dose of 200 mg/m2 melphalan while those with serum creatinine >200 mmol/L were to receive 140 mg/m2. There was no recommendation to reduce the melpha- lan dose based on age in the protocol.
This is a retrospective, exploratory analysis of data from the Myeloma XI trial. For the first set of analyses patients in the TE
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haematologica | 2022; 107(1)