Page 193 - Haematologica - Vol. 105 n. 6 - June 2020

global quality of life (QoL), future perspective and role and emotional functioning, and less fatigue and pain in both arms. The latter being of large effect size. In general, improvement occurred after 6-12 months of maintenance only and was independent of the World Health Organisation performance at baseline. Patients treated with MPR-R reported clinically relevant worsening of diarrhea, and patients treated with MPT-T reported a higher incidence of neuropathy. Patients who remained on lenalidomide maintenance therapy for at least three months reported clinically meaningful improvement in global QoL and role functioning at six months, remaining stable thereafter. There were no clinically meaningful deteriorations, but patients on thalidomide reported clinically relevant worsening in neuropathy. In general, HRQoL improves both during induction and maintenance therapy with immunomodulatory drugs. The side effect profile of treatment did not negatively affect global QoL, but it was, however, clinically relevant for the patients. (Clinicaltrials.gov identifier: NTR1630) .
HRQoL with thalidomide and lenalidomide
Introduction
Multiple myeloma (MM) is a malignancy of the plasma cells in the bone marrow. Patients with MM are at high risk of developing bone destructions and fractures, hyper- calcaemia, renal failure and anemia.1,2 Compared to patients with other hematological malignancies, patients with MM report a higher incidence and severity of symp- toms with a reduced health-related quality of life (HRQoL) as a consequence.3-5 However, there is limited data on the effect of first line treatment on HRQoL in transplant ineligible, newly diagnosed patients with MM (NDMM), especially throughout maintenance treatment.6 In several of these trials, the immunomodulatory drugs (IMiDs) thalidomide and/or lenalidomide were investigat- ed.7-13 HRQoL during treatment with thalidomide and lenalidomide were compared head to head in the FIRST and the ECOG E1A06 trials only.10,14
The FIRST trial compared continuous therapy with lenalidomide and dexamethasone (Rd), with Rd for 18 months, and melphalan-prednisone-thalidomide (MPT) for 18 months.14 Clinically relevant changes were pub- lished only for six HRQoL scales.9 These were preselected as they were perceived to be clinically relevant. Both Rd and MPT resulted in a statistically significant improve- ment in all subscales, except side effects of treatment that worsened over time in both arms. There were no differ- ences between arms in global quality of life (QoL), physi- cal functioning, pain and fatigue; although Rd treated patients reported significantly less side effects of treat- ment and less disease symptoms at three months com- pared to MPT. A post hoc prediction model was developed, suggesting that HRQoL was at least maintained or further improved beyond 18 months. Unfortunately, the effect of Rd continuous versus 18 months only on HRQoL cannot be deduced with certainty from this study, as HRQoL data beyond 18 months was lacking.13
In contrast to the FIRST trial, in the ECOG E1A06 trial, the Functional Assessment of Cancer Therapy- Neurotoxicity Trial Outcome Index (FACT-Ntx TOI) score was used for HRQoL evaluation, instead of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. It was shown that melphalan-pred- nisone-lenalidomide (MPR) followed by lenalidomide maintenance (MPR-R) resulted in a superior HRQoL after 12 months only, compared to MPT followed by thalido- mide maintenance (MPT-T).10 However, the HRQoL effects of lenalidomide and thalidomide maintenance ther- apies were not investigated separately.
The effect of MPR-R on HRQoL might be deduced from the MM-015 trial, comparing MPR-R, MPR and mel- phalan-prednisolone (MP).11,15 After six months of mainte- nance, patients who actually received MPR-R therapy reported a statistically significant improvement in HRQoL in 5 of 6 subscales, versus in 2 of 6 subscales only in MP and MPR treated patients. However, also from this study, HRQoL data beyond six months of maintenance therapy is lacking.6,11
Recently, the data from the MRC IX study showed that maintenance therapy with thalidomide resulted in an inferior global QoL after three months with a persistent trend for detriment at six and 12 months.12 This is impor- tant as, especially after achieving disease control with induction therapy, long-term continuation of mainte- nance therapy may turn the pros of maintenance therapy into cons because of side effects that negatively affect HRQoL. The data on lenalidomide maintenance therapy, however, is limited.10,11,13,16 Data from a prospective obser- vational cohort study showed no negative impact of lenalidomide maintenance therapy following autologous stem cell transplantation.16 To the best of our knowledge, prospective analyses after six months of maintenance therapy in non-transplant eligible patients with NDMM are lacking. Only the post hoc analysis of the FIRST trial is available.13
We here report data on all the collected HRQoL sub- scales from the open-label, randomized HOVON- 87/NMSG18 study, thereby providing HRQoL data, not only during induction, but also during maintenance ther- apy with lenalidomide and thalidomide therapy.17 Although currently both IMiD-based regimens are mainly replaced by Rd continuously, either combined with borte- zomib during induction or not, the impact of long term lenalidomide on HRQoL is of interest. In addition, we discuss methods to account for the impact of differences in discontinuation rate due to toxicity between the two arms on the outcome of HRQoL analysis.
Methods
Study design
Study details have been published previously.17 In brief, symp- tomatic patients with NDMM >65 years of age or transplant ineligible patients ≤65 years were included. Patients were ran- domized between nine 28-day induction cycles of MPT, fol- lowed by thalidomide maintenance (MPT-T) or nine 28-day induction cycles of MPR followed by lenalidomide maintenance
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