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Letters to the Editor
Planned withdrawal of dexamethasone after poma- lidomide low-dose dexamethasone induction for lenalidomide-refractory multiple myeloma (ALLG MM14)
Immune dysfunction, a key feature of myeloma (MM), plays an important role in promoting tumor growth and therapy resistance1 with multiple mechanisms of immune evasion described. Pomalidomide (POM) is an immunomodulatory (IMiD) compound2 that mediates direct anti-proliferative effects on tumor cells, as well as immune-modulatory effects on T cells, natural killer (NK) cells and monocytes.3 POM plus low-dose dexam- ethasone (LoDEX) is a standard treatment option for patients with relapsed/refractory MM (RRMM), howev- er, dexamethasone can antagonize the immunostimula- tory capacity of ImiD.3,4 Consequently, the immunostim- ulatory effects of IMiD may be better exploited in the longer term without concomitant DEX, particularly be relevant in the minimal disease burden setting (i.e., maintenance) when some inherent immune recovery has occurred. To our knowledge, our study is the first to evaluate this in a prospective, randomized manner, demonstrating (i) regulatory T- cell (Treg) depletion fol- lowing POM-LoDEX induction was partially abrogated following withdrawal of dexamethasone in mainte- nance, and (ii) enrichment of heterogenous neutrophil populations and an increase in activated NK cells with commensurate decrease in inhibited NK cells following POM-LoDEX induction.
ALLG MM14 was a prospective, randomized, multi- center, open-label parallel-group phase II trial comparing POM maintenance to POM-LoDEX maintenance follow- ing induction with POM-LoDEX. Eligible patients with RRMM, who had failed at least two prior therapies (including a history of lenalidomide failure [Table 1]) were enrolled. The study was conducted according to the Alfred Hospital Institutional Ethics Review Board, in accordance with the Declaration of Helsinki (ACTRN12615000447550).
Patients received four cycles of induction (1 cycle: 28 days): POM (4 mg orally days 1-21) plus LoDEX (40 mg orally days 1, 8, 15, and 22). Patients who achieved sta- ble disease (SD) or better (“responders”) were then ran-
domized (1:1) to continue on one of two arms of main- tenance: POM or POM-LoDEX. Accrual continued until 80 patients were randomized. Correlative peripheral blood (PB) samples for immune studies were collected at baseline (pre-induction) and maintenance (C1D1, C3D1, C6D1 and C10D1).
The primary objective was to determine whether co- administration of DEX with POM in maintenance signif- icantly impacted NK-cell numbers, by comparing the change in PB NK-cell quantification from baseline to maintenance (C6D1) time points utilizing mass cytome- try (CyTOF) (powered to detect an increase of 30% in NK-cell numbers in POM compared to POM-LoDEX). (ALLG MM14 was not powered to detect differences in secondary exploratory/clinical endpoints so conclusions on the clinical impact of one strategy over the other can- not be drawn). Exploratory CyTOF studies analyzed sequential PB samples to define differences in immune cell profiles in: (i) (all patients) responders versus non- responders; and (ii) (randomized patients) POM versus POM-LoDEX maintenance. Secondary clinical objectives were to compare (following randomization to POM or POM-LoDEX maintenance): (i) survival (progression-free survival/ overall survival [PFS/OS]), (ii) safety/toxicity and (iii) response/survival following initiation of post- progression therapy.
For CyTOF analysis cells were stained with sub-set defining antibodies (myeloid, B, T and NK cells) (Online Supplementary Table S1). Supervised analysis was per- formed to determine differences in canonical immune cell populations (NK cells and Treg), reported as a proportion of population (%).5,6 CD3-CD19-CD56+ NK cells were prede- fined from patient datasets. Boolean gating was then per- formed using seven NK-cell activation/inhibitory markers (CD158a/CD158b/CD159a/CD314/CD335/CD336/CD 337). Boolean populations that comprised ≥3% of the total NK-cell population (median) were then compared. A Mann-Whitney test was used to determine statistical significance for each of the defined populations between clinical groups. Analyses of the primary NK endpoints was confined to patients who had assessments at both baseline and maintenance C6D1. Treg (CD3+CD4+CD127loCD25hiCD45RO+) were defined by manual gating and assessed in all patient samples at all time points: a one-way ANOVA with a Kruskal Wallis
Table 1. Characteristics of 154 enrolled patients. Characteristic
Male sex, n (%)
Age in years, median (range)
ISS Stage
Not Known
Stage 1 Stage 2 Stage 3
Prior lines of therapy, median (range) Lenalidomide failure*
Bortezomib refractory
Prior autologous stem cell transplant Prior allograft
Prior anti-CD38 therapy
Time in years from diagnosis to study enrollment, median (range)
All Patients n=154
79 (51.3%) 67.4 (36.0-88.6)
66 (42.9%) 35 (22.7%) 36 (23.4%) 17 (11.0%)
4.5 (2-14) 154 (100%) 128 (83.1%) 96 (62.3%) 1 (0.7%)
0 (0.0%) 5.5 (1.2-17.8)
POM n=40
20 (50.0%) 68.4 (50.3-85.4)
17 (42.5%) 9 (22.5%) 9 (22.5%) 5 (12.5%)
5 (3-9) 40 (100%) 29 (72.5%) 24 (60.0%) 0 (0.0%) 0 (0.0%)
5.9 (2.4-12.8)
POM-LoDEX n=38
17 (44.7%) 66.2 (36.0-81.1)
16 (42.1%) 9 (23.7%) 10 (26.3%) 3 (7.9%)
5 (3-14) 38 (100%) 33 (86.8%) 31 (81.6%) 1 (2.6%) 0 (0.0%)
6.4 (1.9-17.8)
*Lenalidomide (LEN) failure defined as failing to respond: (1) disease progression during treatment or within 60 days of completing a LEN containing regimen or (2) fail- ure to achieve at least a minimal response (MR) (after 2 cycles). POM: pomalidomide; LoDEX: low-dose dexamethasone. ISS: international staging system.
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