Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma

Abstract

Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50–77]) and a median of four prior regimens (range: 2–14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1–74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.

Involvement of Alarmins in the Pathogenesis and Progression of Multiple Myeloma

“…Unfortunately, a considerable portion of patients with MM still relapse and, therefore, require new therapies, moreover, reducing the duration of response to each therapeutic regimen over time. In particular, relapsed and refractory MM (RRMM) can make use of new molecules capable of inhibiting histone deacetylase (HDACis), including panobinostat, which influences transcriptional activation and other nuclear events by increasing histone acetylation [145].…”

“…Panobinostat combined with bortezomib and dexamethasone blocks the chaperone function of HSP90, resulting in slowdown in MM cell proliferation [145][146][147]. Notably, molecules that inhibit HDACis block angiogenesis and osteoclastogenesis, reducing the secretion of VEGF and hypoxia-inducible factor-1 (HIF1)-α as well as inducing the degradation of all three VEGF receptors [145][146][147][148]. S100A9 also plays a role in the bone marrow microenvironment to induce angiogenesis and promote the progression of MM.…”

How to Treat High-Risk Myeloma at Diagnosis and Relapse

“…These include bendamustine in combination with bortezomib, carfilzomib, or lenalidomide as well as the histone deacetylase inhibitor panobinostat in combination with dexamethasone and bortezomib, carfilzomib, lenalidomide, or lenalidomide and bortezomib. [125][126][127][128][129][130][131][132] Newer, recently approved agents also play an important role in addressing high-risk disease. The STORM trial evaluated the combination of selinexor, an oral inhibitor of XPO1 (i.e., exportin 1), and dexamethasone in disease refractory to an immunomodulatory drug, proteasome inhibitor, and daratumumab.…”

MYC inhibitors in multiple myeloma

“…In addition to the suppression of the IRF4-MYC axis, sensitive cells showed suppression of the TF ATF4, reduced global protein synthesis and alterations in the ER stress pathway [75] . In fact, panobinostat, a broad-spectrum histone deacetylase (HDAC) inhibitor, functions with almost the same mechanism of action, downregulating the mRNA of heme oxygenase-1, as well as IRF4 and MYC, causing the arrest of primary CD138 + patient cells and inducing their apoptosis [76] . Indeed, panobinostat is one of the few epigenetic drugs approved by the FDA for the treatment of MM [113] .…”