Introduction Lenalidomide maintenance after autologous stem cell transplant (ASCT) is standard of care for myeloma (MM) patients, based on trials in which lenalidomide was planned to continue until disease progression. As outcomes for myeloma patients continue to improve, understanding whether time limited maintenance is as effective as treatment to progression is a critical question. Optimal duration may differ in subgroups of patients e.g. those with standard vs high-risk genetics or those who have achieved minimal residual disease negativity (MRD-ve). Data from the UK NCRI Myeloma XI trial were analysed to explore these questions.
Methods Myeloma XI is a phase III randomised controlled trial which recruited newly diagnosed patients with pathways for both transplant eligible (TE) and ineligible patients. In the TE pathway there was a maintenance randomisation at 3 months after ASCT with patients allocated to either lenalidomide maintenance (10mg D1-21/28, planned to continue until disease progression) or observation.
Progression-free survival (PFS) data were analysed landmarked from multiple time points (2, 3, 4, and 5 years) after the time of maintenance randomisation, including all patients who had not had an event or were censored prior to that time point. Data were analysed for all patients, within genetic risk sub-groups and by MRD status. MRD was assessed at the time of maintenance randomisation using flow cytometry with a median sensitivity of 0.004%. Molecular high-risk (HiR) was defined as the presence of del(17p), gain(1q), t(4,14), t(14;16) or t(14;20). The percentage of patients experiencing key side effects over time was also explored including all patients taking lenalidomide in each 6-month time interval.
Results In the TE pathway 1248 patients entered the maintenance randomisation and were allocated to observation (n=518) or lenalidomide (n=730). Median follow up was 44.7 months (IQR 32.4-62.7). As previously reported, lenalidomide maintenance was associated with a significant PFS benefit, median PFS from randomisation was 64 months for those receiving lenalidomide vs 32 months for those observed (HR 0.52, [95%CI 0.45, 0.61], p<0.001). This was consistent for both SR (HR 0.40, [95%CI 0.28, 0.58], p<0.0001) and HiR (HR 0.50, [95%CI 0.35, 0.70], p<0.0001) patients and for those MRD-ve (HR 0.72, [95%CI 0.55, 0.95], p=0.022) and MRD+ve (HR 0.37, [95%CI 0.27, 0.50], p<0.0001) at the start of maintenance therapy.
The magnitude of the PFS benefit was consistent when landmarked from 2y after randomisation (HR 0.51 [95%CI 0.40, 0.66], p<0.001), 3y (HR 0.47, [95%CI 0.33, 0.67], p<0.0001) and 4y (HR 0.56 [95%CI 0.33, 0.95], p=0.031), but the benefit appeared to diminish at subsequent time points.
There was more evidence for the benefit of longer duration of lenalidomide maintenance in patients MRD+ve at the start of maintenance therapy than those MRD-ve. In MRD +ve patients landmarked from 2y the HR was 0.34 [95%CI 0.19, 0.59], p<0.0001, 3y HR 0.26 [95%CI 0.11, 0.58], p=0.001 and 4y HR 0.14 [95%CI 0.04, 0.48], p=0.002. In MRD -ve patients landmarked from 2y the HR was 0.63 [95%CI 0.43, 0.94], p=0.025 but from 3y was no longer statistically significant (3y HR 0.65 [95%CI 0.36, 1.15], 4y HR 0.68 [95%CI 0.27, 1.69]). In patients with both standard and high-risk disease there was evidence of ongoing benefit of lenalidomide maintenance beyond 2-3 years.
Patients continuing lenalidomide maintenance long term did not experience worsening bone marrow suppression. In the first 6 months neutropenia was seen in 57% of patients, grade 1 (G1) 21%, G2 19%, G3 15% and G4 2.5%. This gradually reduced the longer patients were on maintenance therapy, e.g. during months 54-60 neutropenia was seen in only 40% of patients G1 20%, G2 17%, G3 3%, G4 0%.
Discussion In this analysis there is clear evidence that continuing lenalidomide maintenance beyond 3 years is associated with improved PFS, supporting recent findings from the DETERMINATION and STAMINA studies. There does, however, appear to be a time after ASCT at which continuing maintenance may no longer have ongoing benefit over observation. The current analysis suggests that between 4 and 5 years the impact diminished in all patients, earlier in the subgroup of patients MRD-ve after ASCT. Ongoing long term follow up of this and other studies is needed to define the optimal time point at which a randomised trial of stopping or continuing maintenance should be implemented.
Pawlyn:Janssen: Consultancy, Honoraria, Other: Travel support; Celgene/BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy. Menzies:Takeda: Research Funding; Celgene/BMS: Research Funding; Amgen: Research Funding. Davies:Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Henderson:Celgene/BMS: Research Funding; Amgen: Research Funding; Takeda: Honoraria. Cook:Sanofi: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Jenner:Takeda: Consultancy; GSK: Consultancy; Pfizer: Consultancy; Janssen: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria. Jones:Janssen: Honoraria. Kaiser:GSK: Consultancy; Karyopharm: Consultancy; Takeda: Honoraria; Seattle Genetics: Consultancy; Pfizer: Consultancy; Janssen: Honoraria, Research Funding; BMS/Celgene: Honoraria, Research Funding; AbbVie: Consultancy. Drayson:Abingdon Health: Current equity holder in private company. Owen:Astra-Zeneca: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cairns:Takeda: Research Funding; Amgen: Research Funding; Celgene/BMS: Honoraria. Jackson:BMS: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; J and |J: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Oncopeptides: Consultancy.
Asterisk with author names denotes non-ASH members.
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