Pomalidomide in combination with dexamethasone results in synergistic anti‐tumour responses in pre‐clinical models of lenalidomide‐resistant multiple myeloma

Abstract

Pomalidomide is an IMiD(®) immunomodulatory agent, which has shown clinically significant benefits in relapsed and/or refractory multiple myeloma (rrMM) patients when combined with dexamethasone, regardless of refractory status to lenalidomide or bortezomib. (Schey et al, ; San Miguel et al, 2013; Richardson et al, 2014; Scott, ) In this work, we present preclinical data showing that the combination of pomalidomide with dexamethasone (PomDex) demonstrates potent anti-proliferative and pro-apoptotic activity in both lenalidomide-sensitive and lenalidomide-resistant MM cell lines. PomDex also synergistically inhibited tumour growth compared with single-agent treatment in xenografts of lenalidomide-resistant H929 R10-1 cells. Typical hallmarks of IMiD compound activity, including IKZF3 (Aiolos) degradation, and the downregulation of interferon regulatory factor (IRF) 4 and MYC, seen in lenalidomide-sensitive H929 MM cell lines, were also observed in PomDex-treated lenalidomide-resistant H929 MM cells. Remarkably, this resulted in strong, synergistic effects on the induction of apoptosis in both lenalidomide-sensitive and resistant MM cells. Furthermore, gene expression profiling revealed a unique differential gene expression pattern in PomDex-treated samples, highlighted by the modulation of pro-apoptotic pathways in lenalidomide-resistant cells. These results provide key insights into molecular mechanisms of PomDex in the lenalidomide-resistant setting.

Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma

“…12 However, despite similarities in the chemical structure, pomalidomide has a distinct immunomodulatory and antimyeloma activity and has demonstrated clinical and preclinical efficacy in lenalidomide-resistant MM. [13][14][15] Despite the theoretical antagonism between IMiD and proteasome inhibitor mechanisms of action, clinical data support the observation of a synergistic effect with this combination of agents.…”

Pomalidomide in Combination with Low-Dose Dexamethasone as the Treatment of "Double Refractory"

“…Важными особенностями собственно помали-домида считаются сочетание структурных черт талидомида и леналидомида, наибольшая анти-TNF-активность в своем классе, сохранение цитоста-тической активности в условиях резистентности к леналидомиду, подтвержденной в исследованиях на биологических моделях опухолей [19].…”

“…В результате происходит арест клеточного цикла в фазе G0/G1, подавление активности ядерного фактора транскрипции (NF-κB), снижение экспрессии антиапоптотических белков cIAP2 (клеточный инги-битор белка апоптоза 2) и FLIP (FLICE-ингибирующий белок), что приводит к активации каспазы-8 и запуску программы клеточной гибели [19,20].…”

Safety and efficacy of pomalidomide, dexamethasone and pegylated liposomal doxorubicin for patients with relapsed or refractory multiple myeloma

“…Patients treated with the low‐dose DEX and POM showed a higher ORR (31%) than those treated with the high‐dose DEX (ORR = 10%) (San Miguel et al , ). Additional preclinical work has demonstrated the synergistic activity of the combination of DEX and POM and showed that this combination displays synergistic anti‐tumour responses consisting of anti‐proliferative and pro apoptotic responses (Rychak et al , ). Furthermore, in LEN resistant human MM models, gene expression profiling displayed unique changes in pro‐apoptotic and immunomodulatory pathways, indicating a specific potential molecular mechanism for this phenomenon (Rychak et al , ).…”