A Phase II, Single-Center, Open-Label Study Of Oral Panobinostat In Combination With Lenalidomide and Weekly Dexamethasone In Patients With Multiple Myeloma

Treatment options for patients with multiple myeloma (MM) refractory (ref) to lenalidomide (len) and bortezomib are urgently needed.  A promising strategy is the use of epigenetic agents such as the deacetylase inhibitor (DACi) panobinostat (pan) to modulate genes that affect drug resistance.  Pre-clinical studies with pan demonstrated synergy against MM cells when combined with dexamethasone (dex) and len, supporting this concept (Ocio EM et al. Haematologica 2010).

The safety and preliminary efficacy of this triplet regimen was assessed in a phase 1b study of relapsed (rel) or rel/ref MM patients (Mateos et al, ASCO 2010). The maximum tolerated doses (MTD) in that study are the doses selected for this phase 2 study. However we investigated a modified schedule (table 1) of this triplet regimen. Here, pan is given thrice weekly only every other week (instead of weekly) and dex is given weekly (instead of three 4 day pulses).

To investigate the hypothesis that peripheral blood plasma levels of cytokines/chemokines known to be elevated in MM patients may identify biomarkers of response to this regimen, we examined IL-6, IL-10, IL-17A, Monocyte Chemoattractant Protein (MCP)-1 and Macrophage Derived Chemokine (MDC) levels at baseline and following 4 cycles of treatment.

Inclusion criteria were patients with rel or rel/ref MM, measurable disease, adequate performance status, organ function, and hematologic parameters. Patients previously treated with a DACI or currently receiving medications with a risk of prolonging the QTc interval were excluded.

The primary objective was to evaluate the best overall response rate.   Secondary objectives were to evaluate safety, response duration, and overall and progression-free survival.  Each drug was administered at the doses and schedule shown in Table 1.

Overall, 5 len-refractory patients with disease progression at screening have been enrolled. Patients had a median of 2 lines of prior therapy (range 1–7). High-risk molecular findings were present in 3 patients, including 2 patients with gain of 1q21 by FISH and 1 with del p53.

Very good partial response (VGPR) was achieved in 1/5, partial response (PR) in 1/5, minimal response (MR) in 1/5, and stable disease (SD) in 2/5. Two of these high-risk patients are still on study, and the patient with del p53 had PD at 4 months. Responses are durable, with 3 patients (including both patients with ≥PR) remaining on study for more than 4 months, with a median follow up of 4 months. Two patients progressed within 4 months.

Grade 3 and 4 toxicities (regardless of drug attribution) were primarily hematologic, with neutropenia, thrombocytopenia, and anemia noted in 3, 3, and 1 patient(s) respectively. There were 2 serious adverse events (SAEs) – a grade 3 pulmonary embolism and febrile neutropenia (FN) due to N. meningitidisbacteremia. The non-hematologic toxicities were all grade 1 and 2, consisting of fatigue in 5 patients and diarrhea in 2. Dose modifications were required in 2 patients for len and 2 patients for pan, 1 for FN and the other for asymptomatic T wave inversions.

Cytokine profiling revealed that MDC was reduced by 48%, 7% and 72% respectively in all 3 patients having a durable response (>4 months) following therapy.  Of note, Thymus Activation-Regulated Chemokine (TARC) was identified as a biomarker of treatment response to pan in lymphoma patients (Harrison et al. Leuk Lymphoma 2013).  Both MDC and TARC bind to the chemokine receptor CCR4 and are located on chromosome 16q13. MDC promotes angiogenesis and alters T cell distribution in the bone marrow. These findings suggest a link between DACi and CCR4 receptor ligand MDC levels. Thus, MDC may be a biomarker of sustained response to pan in MM and warrants further investigation.

In rel/ref MM patients, pan in combination with len and dex demonstrates durable responses, even in len-refractory patients with high-risk molecular findings, indicating the essential role of pan in attaining a response. These results suggest that pan modulates expression of genes to restore sensitivity to len, and that MDC may be a biomarker of this activity. This completely oral regimen is well tolerated, with primarily expected hematologic toxicities. Updated results will be presented at the annual meeting.

Jagannath:Celgene: Honoraria; Millenium: Honoraria. Chari:Onyx: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees.