A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma

Abstract

Phase 3 studies combining histone deacetylase inhibitors with bortezomib were hampered by gastrointestinal (GI) intolerance, which was not observed when combined with immunomodulatory drugs. This study is a single-center phase 2 study of panobinostat with lenalidomide and dexamethasone (FRD). Twenty-seven relapsed multiple myeloma patients were enrolled. Twenty-two patients (81%) were lenalidomide refractory and 9 (33%), 14 (52%), and 7 (26%) were refractory to pomalidomide, bortezomib, and carfilzomib, respectively. High-risk molecular findings were present in 17 (63%) patients. Responses included 2 complete responses (CRs), 4 very good partial responses (VGPRs), 5 partial responses (PRs), and 9 minimal responses (MRs) for an overall response rate of 41%, clinical benefit rate of 74%, and a disease control rate of 96%. The median progression-free survival (PFS) was 7.1 months. In the 22 lenalidomide-refractory patients, there were 1 CR, 4 VGPRs, 3 PRs, and 7 MRs, with a median PFS of 6.5 months. Median overall survival was not reached. Grade 3/4 toxicities were primarily hematologic. Gene expression profiling of enrollment tumor samples revealed a set of 1989 genes associated with short (<90 days) PFS to therapy. MAGEA1 RNA and protein expression were correlated with short PFS, and laboratory studies demonstrated a role for MAGE-A in resistance to panobinostat-induced cell death. FRD demonstrates durable responses, even in high-risk, lenalidomide-refractory patients, indicating the essential role of panobinostat in attaining responses. MAGEA1 expression may represent a functional biomarker for resistance to panobinostat. In contrast to PANORAMA 1, there were no significant GI toxicities and primarily expected hematologic toxicities. This trial was registered at www.clinicaltrials.gov as #NCT00742027.

Graphical abstract

Figure 1.

Progression-free survival for all patients. Kaplan-Meier PFS curve for all patients treated with FRD.

Figure 2.

Progression-free survival for lenalidomide-refractory patients. Kaplan-Meier PFS curve for lenalidomide-refractory patients treated with FRD (n = 22).

Figure 3.

Overall survival. Kaplan-Meier overall survival curve for all patients treated with FRD (n = 27).

Figure 4.

Correlation of MAGE-A1 expression with PFS in patients treated with FRD and knockdown of MAGE-A in HMCLs. MAGE-A1 expression is correlated with resistance to FRD chemotherapy. (A) Analysis of gene expression profiling data by RNASeq from CD138⁺ myeloma cells obtained at screening based on PFS < 90 days (short PFS) vs PFS > 90 days (long PFS) enriched a set of 1898 differentially expressed genes (down- or upregulated relative to comparator). MAGEA1 was the most highly upregulated gene associated with short PFS (blue circle). (B) Quantitative analysis of MAGEA1 transcript abundance in short vs long PFS subjects demonstrated significantly higher expression associated with short PFS (P < .005). (C) Western blot for MAGE-A1 protein in lysates from screening specimens. OD, relative optical density = OD (MAGE-A1)/OD β-actin load control. (D) Quantitative analysis of MAGE-A1 relative OD in short vs long PFS subjects demonstrated significantly higher protein expression associated with short PFS (P < .05). (E-H) MM.1r (E,G) or H929 (F,H) HMCL were treated with MAGE-A shRNA lenti or controls for 24 hours (MM.1r) or 48 hours (H929) and then incubated with increasing concentrations of panobinostat (E-F) or lenalidomide (G-H). Cell viability was assessed 24 hours later by Cell TiterGlo assay (ProMega). Knockdown of MAGE-A was correlated with a significant increase in sensitivity to panobinostat-induced cell death. MM.1r (E), 50% inhibitory concentration (IC₅₀) of shMA group = 3.8 nM vs IC₅₀ of shNT group 5.6 nM, P < .005. H929 (F), IC₅₀ (shMA) = 7.4 nM vs IC₅₀ (shNT) = 9.2 nM, P < .01. Error bars indicate standard error of the mean; data pooled from 3 experiments. Con, control; mRNA, messenger RNA.