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

Abstract

Key Points• FRD is a well-tolerated oral triplet regimen with durable responses in myeloma.• Correlative analysis identified MAGEA1 as a functional biomarker of resistance.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.

Weekly carfilzomib, lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A phase 1b study

“…For example, Berenson and colleagues evaluated accelerated elotuzumab infusion in 70 patients with NDMM or RRMM, and reported two deaths (due to ischemic colitis and chronic obstructive lung disease) that occurred in patients who received only one cycle of treatment . Seven deaths were reported among 46 patients enrolled into a phase 1b study of panobinostat, lenalidomide, and dexamethasone . In a phase one study of pomalidomide, bortezomib, and dexamethasone in lenalidomide‐refractory and proteasome inhibitor‐exposed relapsed or relapsed and refractory MM patients (n = 34), one patient died in cycle three due to cardiac arrest …”

MAGE-A inhibit apoptosis and promote proliferation in multiple myeloma through regulation of BIM and p21Cip1

“…In this setting, upregulation of BAX and decreased proliferation was only observed in p53 wt HMCL, indicating that MAGE regulates at least one other p53-independent pathway. MAGE expression has been associated with poor clinical outcome in MM, and correlated with resistance to chemotherapy in clinical trials and laboratory models, including resistance to panobinostat in MM patients [10][11][12][13]. These results support the hypothesis that MAGE-A are oncogenic targets that inhibit apoptosis and promote proliferation in myeloma cells.…”

Efficacy of Panobinostat for the Treatment of Multiple Myeloma

“…Carfilzomib-panobinostat regimen necessitated less-frequent dose reductions due to toxicity, compared to established bortezomib-panobinostat-dexamethasone regimen. Combination of lenalidomide with panobinostat was also well tolerated with less commonly severe thrombocytopenia, fatigue, and diarrhea, compared to bortezomib, panobinostat, and dexamethasone standard regimen [79]. Regarding patients that received more complex combinations like VRD-panobinostat regimen [84,85], they developed less frequently severe gastrointestinal toxic effects, at a cost of more often severe hematologic adverse events, particularly thrombocytopenia.…”

“…Combination of lenalidomide and panobinostat was evaluated in a phase 2 clinical trial [79]. 27 heavily pretreated patients with a median of 3 prior lines of treatment received this combination.…”