ACY-1215

Deacetylase Inhibitors as a Novel Modality in the Treatment of Multiple Myeloma

Paul G. Richardson,a Philippe Moreau,b Jacob P Laubach,a Michelle E Maglio,a Sagar Lonial,c Jesus San-Migueld

Abstract

Deacetylase enzymes remove acetyl groups from histone and nonhistone proteins. Dysregulation of deacetylase activity is a hallmark of malignancy, including multiple myeloma (MM). Deacetylase inhibitors (DACi) cause epigenetic modification and inhibition of the aggresome pathway, resulting in death of MM cells. Panobinostat, a pan-DACi, has shown significant clinical benefit and is the first DACi approved for the treatment of MM. It is approved for use in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory MM who have received ≥ 2 prior regimens including bortezomib and an immunomodulatory drug. Ricolinostat and ACY-241, which selectively inhibit HDAC6 and the aggresome pathway, are currently being studied in combination with dexamethasone and bortezomib or an immunomodulatory drug for the treatment of relapsed and refractory MM. In this review, we discuss the data from key clinical trials investigating deacetylase inhibitors as novel treatment options for MM.

Keywords (up to 6): multiple myeloma, histone deacetylase inhibitors, epigenetic modification

1.0 Introduction

Histone deacetylases (HDACs) are a family of enzymes that regulate target protein activity through removal of acetyl groups [1]. Up to 1750 HDAC target proteins have been identified, including both histones and nonhistone proteins [2]. Dysregulated HDAC activity is an epigenetic hallmark of malignancy, including multiple myeloma (MM), resulting in aberrant gene expression and cellular signaling that promotes cell cycle progression, cell growth and survival, and resistance to apoptosis [3-5].
A total of 18 HDACs have been identified and grouped into 4 classes based on their homology to yeast HDACs, subcellular localization, and enzymatic activities [1, 6, 7]. Class I HDACs include HDAC1-HDAC3 and HDAC8, which are localized to the nucleus and primarily act on histone proteins and transcription factors. Class II HDACs include HDAC4-HDAC7, HDAC9, and HDAC10. They are thought to move between the nucleus and cytoplasm where they act primarily on nonhistone proteins. Class III HDACs are sirtuins, which have differences in their catalytic mechanism and sequences compared with other HDACs. HDAC11, which is the only known class IV HDAC, displays features of both class I and II HDACs.
HDACs are commonly overexpressed in MM, and higher levels of class I HDACs, especially HDAC1, are associated with poorer prognosis [8]. Class I HDACs deacetylate histone lysine residues, resulting in a closed chromatin conformation that represses transcription [2, 3]. HDACs also deacetylate nonhistone proteins, such as tumor suppressor p53, HSP90, STAT3, and NF-κB.
HDAC6 plays an essential role in protein degradation via the aggresome pathway [9]. HDAC6 binds to polyubiquitinated misfolded proteins and recruits them for transport to aggresomes, which are transported by microtubules to an autophagosome, where they are degraded via autophagy. This pathway is vital to MM cells that overproduce misfolded proteins and overburden the proteasome degradation pathway.

2.0 Mechanism of Action of Deacetylase Inhibitors (DACi’s)

Natural and synthetic DACi’s exist. Some nonselectively inhibit a broad range of DACs (pan-DACi’s), while others selectively target the clinically relevant DACs 1, 2, 3, and/or 6. Pan-DACi that have been studied in MM include panobinostat, vorinostat, and romidepsin; among these, panobinostat is the most potent and is the only one to have shown clinical benefit in MM [10-13]. Due to their lack of specificity, however, pan- DACi may lead to toxicities that limit time on treatment, particularly when used in combination with other agents with overlapping toxicities. HDAC6 inhibitors are also of interest in MM due to their inhibition of the aggresome pathway [14]. HDAC6 inhibitors being studied in MM include ricolinostat and ACY-241. Potency profiles of the DACi’s being studied in MM are shown in Table 1.
DACi’s bind to the catalytic domains of HDACs, downregulating their activity, which in turn inhibits myeloma cell survival and proliferation [16]. Class I DACi’s acetylate histone lysine residues, opening chromatin for protein synthesis and gene expression. Agents that inhibit HDAC6 increase acetylation of tubulin and disrupt transportation of aggresomes, which leads to accumulation of protein aggregates and cell death [17].
Proteasome inhibition with bortezomib or carfilzomib can be used to effectively treat MM; however, MM cells can overcome proteasome inhibition by using the alternative aggresome pathway. Blockade of both the proteasome and aggresome pathways via combination therapy with proteasome inhibitors and DACi’s has synergistic antitumor activity in MM [17]. Triple therapy with DACi, dexamethasone, and a proteasome inhibitor or immunomodulatory drug (IMiD) also results in synergistic deregulation of genes compared with each of the agents used as monotherapy [18].

3.0 Pharmacokinetics/Pharmacodynamics of Panobinostat and Ricolinostat

3.1 Panobinostat

Following administration of a single 20-mg dose of oral panobinostat, the drug is rapidly absorbed, with a time to maximum absorption of 2 hours [19]. The median maximum concentration was 21.2 ng/mL, and the median area under the curve was 96 ng∙h/mL. Panobinostat has a terminal elimination half-life of ≈ 30 hours. The liver and kidney contributed similarly to the elimination of panobinostat, with mean percentages of unchanged panobinostat recovered in urine and feces of only ≈ 2% and 3%, respectively. Both cytochrome P450 and noncytochrome P450 enzymes may play a significant role in panobinostat metabolism, with minor contributions from CYP2D6 and CYP2C19. Panobinostat is extensively metabolized via reduction, hydrolysis, oxidation, and glucuronidation processes into at least 77 metabolites. Coadministration of bortezomib (1.3 mg/m2) and panobinostat (20 mg) did not significantly affect the mean exposure of either agent, while coadministration of dexamethasone (20 mg) reduced panobinostat exposure by ≈ 20% [20].

3.2 Ricolinostat

Ricolinostat is rapidly absorbed and has a half-life of ≈ 3 hours [21]. Exposure of ricolinostat increased dose dependently from 40-160 mg and then plateaued at doses ≥ 160 mg. Coadministration of ricolinostat (40-240 mg once daily [QD] or 160 mg twice daily [BID]) with bortezomib (1.3 mg/m2) or lenalidomide (25 mg) did not significantly affect the pharmacokinetics of the individual agents [22-24]. In combination with bortezomib, ricolinostat’s exposure increased with doses up to 240 mg QD [22]. When pomalidomide (4 mg) and ricolinostat (160 mg QD or BID) were coadministered, Cmax of ricolinostat was reached ≈ 1 hour after the first daily dose and then decreased to background levels within 6 hours [25]. Pharmacodynamic analyses have demonstrated that following ricolinostat administration, the mean fold increase in acetylated tubulin is greater than for acetylated histone, indicating selective HDAC6 inhibition [21, 23, 25, 26].

4.0 Clinical Development of DACi’s

4.1 Vorinostat + Bortezomib

The first completed phase 3 clinical trial of an HDACi in patients with MM was a randomized, double-blind, placebo-controlled trial led by Dimopoulos and colleagues that compared vorinostat plus bortezomib (n = 317) vs bortezomib plus placebo (n = 320) in patients with relapsed or refractory MM [13]. Vorinostat 400 mg was administered orally on days 1-14, and bortezomib 1.3 mg/m2 was administered intravenously on days 1, 4, 8, and 11 of each 21-day cycle. The overall response rate (ORR) and median progression-free survival (PFS) were significantly higher in the vorinostat arm (ORR: 56.2% in the vorinostat arm vs 40.6% in the placebo arm; P < .0001; median PFS was 7.63 months in the vorinostat arm vs 6.83 months in the placebo arm; P = .0100). However, the 0.8-month PFS benefit was not considered clinically meaningful, and this small improvement in PFS suggests that the responses in the vorinostat arm were not durable. Additionally, more patients in the vorinostat arm than the placebo arm had grade 3/4 adverse events (AEs), including thrombocytopenia, fatigue, nausea, vomiting, diarrhea, and upper respiratory tract infections. Different treatment schedules, a different route of bortezomib administration, or the addition of dexamethasone may improve tolerability and/or efficacy of the combination. 4.2 Panobinostat + Bortezomib + Dexamethasone PANORAMA 1 was a multicenter, randomized, double-blind phase 3 clinical trial conducted by San-Miguel and colleagues that compared panobinostat plus bortezomib and dexamethasone (n = 387) vs bortezomib plus dexamethasone and placebo (n = 381) in patients with relapsed or relapsed and refractory MM [12]. Panobinostat was administered orally at a dose of 20 mg on days 1, 3, 5, 8, 10, and 12; bortezomib 1.3mg/m2 was administered intravenously on days 1, 4, 8, and 11; and dexamethasone 20 mg was administered orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. Patients in both treatment arms had a median age of 63 years (range, 56-69 years for the panobinostat arm and 56-68 years for the placebo arm) and had received a median of 1 previous line of treatment (range, 1-3 for both arms). Patients refractory to bortezomib were excluded. Panobinostat significantly improved PFS by nearly 4 months; median PFS was 12.0 months in the panobinostat arm vs 8.1 months in the placebo arm (P < .0001). This benefit was maintained regardless of age, clinical staging by the International Staging System, number of previous lines of therapy, or prior treatment with bortezomib or IMiDs. The ORR was not significantly increased in the panobinostat arm vs the placebo arm (60.7% vs 54.6%; P = .09), but the rate of deep responses (complete response [CR] plus near CR) was significantly increased in the panobinostat arm (28% vs 16%; P = .0006). Final overall survival (OS) was 40.3 months in the panobinostat arm and 35.8 months in the placebo arm, but this difference was not statistically significant (HR, 0.94; 95% CI, 0.78-1.14) [27]. Common grade 3/4 laboratory abnormalities and AEs included thrombocytopenia (67% in the panobinostat arm vs 31% in the placebo arm), lymphopenia (53% vs 40%), diarrhea (26% vs 8%), asthenia or fatigue (24% vs 12%), and peripheral neuropathy (17% vs 15%). AEs led to a higher rate of discontinuations in the panobinostat arm (25%) vs the placebo arm (13%). Results from subgroup analyses showed that the benefit from panobinostat plus bortezomib and dexamethasone was greatest in patients who had received ≥ 2 prior regimens including bortezomib and IMiDs [28]. Median PFS for this subgroup (n = 147) was 12.5 months in the panobinostat arm and 4.7 months in the placebo arm (HR, 0.47; 95% CI, 0.31-0.72). Similar to the overall study population, final median OS was not significantly different between the 2 treatment arms (25.5 months in the panobinostat arm and 19.5 months in the placebo arm; HR, 1.01; 95% CI, 0.68-1.50) [27]. In general, the safety profile of panobinostat in this subgroup was consistent with that in the overall study population [28]. Based on these results demonstrating that panobinostat in combination with bortezomib and dexamethasone provides a significant clinical benefit, regulatory agencies in the United States, Europe, the United Kingdom, and Japan have approved the use of panobinostat in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory MM who have received ≥ 2 prior regimens including bortezomib and an IMiD. Efforts are ongoing to improve the safety profile of this regimen, including by reducing and better managing AEs associated with this regimen. Consistent with medical practice at the time the PANORAMA 1 study was initiated, bortezomib was administered intravenously twice per week. Clinical practice has since shifted toward subcutaneous administration once per week, based on results from recent studies that demonstrated that subcutaneous administration as well as once-weekly dosing of bortezomib can improve tolerability [29, 30]. Thus, the tolerability of panobinostat-bortezomib-dexamethasone may be improved with once-weekly subcutaneous administration of bortezomib. Results from the single-arm, phase 2 PANORAMA 2 study demonstrate that panobinostat is also capable of recapturing responses in patients with bortezomib-refractory MM [31]. The study enrolled 55 patients with MM who had received ≥ 2 prior lines of therapy, including an IMiD, and who were refractory to bortezomib-based therapy. Treatment with panobinostat plus bortezomib and dexamethasone resulted in an ORR of 34.5% and a clinical benefit rate of 52.7%. The median PFS and OS were 5.4 months and 17.5 months, respectively [32]. 4.3 Ricolinostat + Bortezomib and Dexamethasone In an ongoing phase 1b clinical trial (ACY-100), Vogl and colleagues are investigating escalating doses of ricolinostat in combination with bortezomib and dexamethasone [22]. Ricolinostat is being administered at doses ranging from 40-160 mg QD or 160 mg BID on days 1-5 and 8-12; bortezomib 1.0-1.3 mg/m2 is being administered intravenously or subcutaneously on days 1, 4, 8, and 11; and dexamethasone 20 mg is being administered on the same day of and the day after bortezomib administration during a 21-day cycle in patients with relapsed or relapsed and refractory MM. A total of 57 patients who had a median age of 65 years (range, 46-83 years) and had received a median of 4 prior regimens (range, 2-13) were enrolled. Common grade 3/4 treatment-emergent AEs included thrombocytopenia (34%), anemia (20%), fatigue (7%), hypokalemia (7%), hyperglycemia (7%), diarrhea (5%), increased alanine aminotransferase (5%), and hyponatremia (5%). Treatment-emergent AEs and serious AEs were more common among patients treated with BID dosing. Median duration of therapy was 5 months for the combined 160-mg and 240-mg QD dosing groups (n = 19) and 4 months for the combined 160-mg BID dosing groups (n = 24). In total, 52 patients were evaluable for response. The ORR was 29%, and the clinical benefit rate (CBR) was 42%. ORRs for the QD and BID dosing groups were 29% and 33%, respectively, and CBRs were 43% and 56%, respectively. Among bortezomib-refractory patients, the ORR was 13% and the CBR was 31%. Based on these results, the recommended phase 2 dose (RP2D) is ricolinostat 160 mg QD in combination with bortezomib and dexamethasone. 5.0 Novel DACi Combinations 5.1 Panobinostat + Carfilzomib Three ongoing, early-phase clinical trials are investigating different doses and schedules of panobinostat in combination with carfilzomib or carfilzomib plus dexamethasone for relapsed and refractory MM. The first of the ongoing studies is being conducted by Berdeja and colleagues and is a phase 1/2 clinical trial; it is investigating panobinostat 20 mg or 30 mg administered on days 1, 3, 5, 15, 17, and 19 plus carfilzomib 20 mg/m2 given on days 1 and 2 of cycle 1 and carfilzomib 27-56 mg/m2 for subsequent doses given on days 1, 2, 8, 9, 15, and 16 of 28-day cycles in patients with relapsed or relapsed and refractory MM [33]. Dose level 4 (panobinostat 30 mg plus carfilzomib 20-45 mg/m2) and dose level 6 (panobinostat 20 mg plus carfilzomib 20-56 mg/m2) were expanded. A total of 80 patients who had a median age of 65 years (range, 41-91 years) and had received a median of 4.5 prior therapies (range, 1-9) were enrolled. Median time on treatment was 6 months (range, 1-45). Each expansion dose level had 32 evaluable patients. Median follow-up time was 24.3 months for dose level 4 and 9.5 months for dose level 6. The ORR for dose level 4 was 72%, including 6% stringent CR, 34% very good partial response (VGPR), and 31% partial response (PR). The ORR for dose level 6 was 84%, including 3% CR, 34% VGPR, and 47% PR. Median time to best response was 7 weeks (range, 3-64 weeks) for dose level 4 and 8 weeks (range, 3-39 weeks) for dose level 6. Median PFS was 8.4 months (95% CI, 4.9-19.6 months) for dose level 4 and 8.6 months (95% CI, 6.1-13.6 months) for dose level 6. Median OS was 28.2 months (95% CI, 13.7 months to not reached) for dose level 4 and not reached for dose level 6. Grade 3/4 AEs of interest for dose levels 4 and 6, respectively, included thrombocytopenia (41% vs 42%), diarrhea (6% vs 9%), nausea (6% vs 6%), fatigue (15% vs 12%), vomiting (6% vs 3%), and dyspnea (3% vs 9%); no patients experienced grade 3/4 peripheral neuropathy. Grade 3/4 cardiac toxicities included congestive heart failure (3% vs 3%) and supraventricular tachycardia (3% vs 3%); 1 patient in the dose level 4 group with a history of cardiac issues died due to congestive heart failure possibly related to treatment. Both expansion dose levels demonstrated efficacy and were well tolerated. Between the 2 expansion dose levels, an increase in carfilzomib dose from 45 mg/m2 to 56 mg/m2 did not increase cardiopulmonary toxicity, whereas a decrease in panobinostat dose from 30 mg to 20 mg appeared to reduce low-grade GI toxicity, supporting further clinical development of dose level 6. Shah and colleagues are conducting the second clinical trial, a phase 1/1b study investigating panobinostat 15-30 mg on days 1, 3, 5, 8, 10, and 12 of a 28-day cycle plus carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 on days 8, 9, 15, and 16 of cycle 1; and 27-45 mg/m2 in cycles 2 and beyond) and dexamethasone (4 mg on days 1, 2, 8, 9, 15, and 16) in patients with relapsed and/or refractory MM [34]. Enrollment for phase 1 of the study included 21 patients who had a median age of 61 years (range, 42-73 years) and had received a median of 5 prior lines of therapy (range, 2-15). There was 1 dose-limiting toxicity (DLT; grade 4 thrombocytopenia with epistaxis) observed with panobinostat 20 mg plus carfilzomib 20-6 mg/m2. Common grade 3/4 AEs included thrombocytopenia (52%), anemia (43%), neutropenia (29%), fatigue (19%), lung infection/pneumonia (19%), elevated creatinine (14%), diarrhea (10%), and nausea (5%). The ORR was 29%, including 10% VGPR and 19% PR; the CBR was 38%. Enrollment into the expansion phase is planned at a maximum recommended dose of panobinostat 20 mg plus carfilzomib 20-5 mg/m2. The third study, a phase 1 clinical trial conducted by Kaufman and colleagues, is investigating panobinostat 15-20 mg on days 1, 3, 5, 8, 10, 12, 15, 17, and 19 in combination with carfilzomib 20-45 mg/m2 on days 1, 2, 8, 9, 15, and 16 and dexamethasone 4 mg on the same days as carfilzomib during the first cycle and optional for subsequent cycles in patients with relapsed and refractory MM [35]. In total, 26 patients who have a median age of 65 years (range, 49-75 years) and had received a median of 3 prior lines of therapies (range, 1-7) were enrolled. The maximum tolerated dose was determined to be panobinostat 20 mg plus carfilzomib 20-6 mg/m2. Common grade 3/4 AEs included anemia (38%), thrombocytopenia (38%), neutropenia (19%), fatigue (12%), and decreased appetite, diarrhea, elevated creatinine, hyperglycemia, hypertension, and hyponatremia (8% each). The ORR was 46%, including 4% CR, 19% VGPR, and 23% PR. Among patients with bortezomib-refractory disease, the ORR was 44%. All responses occurred within the first 2 months of treatment. Median duration of response was 7.5 months, and 2 patients maintained response for 18 months. At a median follow-up of 8.7 months, median PFS was 11.4 months (95% CI, 6.8-16 months). 5.2 Vorinostat + Lenalidomide + Dexamethasone DACi’s have also been studied in combination with IMiDs. Among these, a phase 1 clinical trial led by Siegel and colleagues investigated vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory MM [36]. A total of 31 patients were enrolled into 5 dosing cohorts and received vorinostat 300 or 400 mg on days 1-7 and 15-21, lenalidomide 10-25 mg on days 1-21, and dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. The median patient age was 63 years (range, 52-79), and patients had received a median of 4 prior regimens (range, 1-10). The maximum tolerated dose was not reached, thus the RP2D was the maximum planned dose of vorinostat 400 mg, lenalidomide 25 mg, and dexamethasone 40 mg. Across all patients, the ORR was 47%, including 3% CR, 3% near CR, 13% VGPR, and 27% PR. The ORR was 43% for the 14 patients in the dose escalation cohorts and 50% for the 16 patients enrolled at the maximum planned dose. ORRs were lower among patients relapsed and refractory to prior lenalidomide (10%, n = 10) or proteasome inhibitors (15%, n = 13). The median duration of response was 134 days (range, 106-302 days) in patients in the dose-escalation cohorts and 139 days (range, 97-547 days) in patients who received the maximum planned dose. Common AEs included anemia (58%), diarrhea (55%), fatigue (55%), and cough (45%), which were generally manageable with dose reduction and supportive care. 5.3 Panobinostat + Lenalidomide + Dexamethasone Chari and colleagues are conducting an ongoing phase 2 clinical trial investigating panobinostat 20 mg on days 1, 3, 5, 15, 17, and 19 in combination with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, and 15 of a 28-day cycle in patients with relapsed or relapsed and refractory MM [37]. In total, 27 patients who had a median age of 64 years (range, 51-75 years) and had received a median of 3 prior regimens (range, 1-10) were enrolled. The ORR was 40.7%, including 7.4% CR, 14.8% VGPR, and 18.5% PR. Protein expression levels of cereblon, Ikaros, and Aiolos were similar between responders and nonresponders, suggesting that panobinostat, rather than lenalidomide, may significantly contribute to depth of response. Median PFS was 7.1 months. Among the 22 patients who were refractory to prior lenalidomide treatment, the ORR was 36.4% and median PFS was 6.5 months. Grade 3/4 toxicities were primarily hematologic, including neutropenia (59%), thrombocytopenia (31%), and anemia (5%), and were generally manageable. No dose changes were required due to gastrointestinal toxicities, and only 1 patient discontinued therapy due to toxicity (asymptomatic QTc prolongation). 5.4 Ricolinostat + Lenalidomide + Dexamethasone Ricolinostat is also being studied in combination with lenalidomide and dexamethasone in an ongoing phase 1b clinical trial (ACE-MM-101) led by Yee and colleagues. Lenalidomide 15-25 mg was administered on days 1-21 and dexamethasone 40 mg was administered on days 1, 8, 15, and 22 of a 28-day cycle in patients with relapsed or relapsed and refractory MM [24]. Ricolinostat was administered using a range of doses and schedules. In total, 38 patients who had a median age of 63 years (range, 46-82 years) and had received a median of 2 prior therapies (range, 1-9) were enrolled. Across the range of doses and treatment schedules, ricolinostat in combination with lenalidomide and dexamethasone was well tolerated. Common grade 3/4 treatment-emergent AEs included neutropenia (34%), fatigue (18%), and diarrhea, anemia, thrombocytopenia, and hypophosphatemia (5% each). No maximum tolerated dose was identified. The RP2D of ricolinostat in combination with lenalidomide 25 mg and dexamethasone was set at 160 mg QD on days 1-21. The ORR was 55%; ORRs among subgroups included, 25% in lenalidomide-refractory patients (n = 12); 55% in bortezomib refractory (n = 11); 40% in lenalidomide and bortezomib refractory (n = 5); and 69% in lenalidomide nonrefractory (n = 26). Responders remained on study for a median of 12 months, with some patients remaining on study for up to 33 months. 5.5 Ricolinostat + Pomalidomide + Dexamethasone Raje and colleagues are conducting an ongoing phase 1b/2 clinical trial (ACE-MM-102) that is investigating ricolinostat 160 mg QD or BID on days 1-21 in combination with pomalidomide 4 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle in patients with relapsed and refractory MM [25]. In total, 73 patients who had median age of 67 years (range, 47-80 years) and had received a median of 2 prior regimens (range, 2-6) were enrolled. Common grade 3/4 treatment-emergent AEs included neutropenia (27%), anemia (12%), thrombocytopenia (6%), and diarrhea (5%). No DLTs were observed with 160 mg BID. The RP2D was 160 mg QD, based on diarrhea and fatigue leading to dose reductions with BID dosing. At a median follow-up time of 4 months, 55 patients were evaluable for response; the ORR was 42%. The ORR was similar among patients who were refractory to prior lenalidomide and bortezomib (38%) and those with high-risk cytogenetics (del17p and/or t(4;14); 55%). 5.6 ACY-241 + Pomalidomide + Dexamethasone In an ongoing phase 1a/1b clinical trial (ACE-MM-200), Niesvizky and colleagues are investigating a single cycle of ACY-241 monotherapy followed by ACY-241 in combination with pomalidomide and dexamethasone in patients with relapsed or relapsed and refractory MM [38]. Patients received escalating doses of ACY-241 orally on days 1-21 of a 28-day cycle as monotherapy. If no DLT was observed during cycle 1 of monotherapy, patients continued to cycle 2 of combination therapy with pomalidomide 4 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22. At the time of data cutoff, 10 patients who had a median age of 62 years (range, 46-82 years) and had received a median of 2 prior therapies (range, 1-5) had been enrolled. Preliminary results showed that ACY-241 is well tolerated as monotherapy (at doses tested of 180 mg and 360 mg QD) and in combination with pomalidomide and dexamethasone (at an ACY-241 dose of 180 mg QD); no DLTs were observed. When given as monotherapy, there were no treatment-related grade 3 or 4 AEs. In combination with pomalidomide and dexamethasone, the only grade 3 and 4 treatment-emergent AEs were hematologic (thrombocytopenia, 60%; neutropenia, 50%; anemia, 30%; and decreased white blood cell count, 20%). At the time of data cutoff, most patients had only received 1 cycle of combination therapy. There was 1 confirmed and 1 unconfirmed PR. 5.7 Panobinostat + Bortezomib + Lenalidomide + Dexamethasone Panobinostat is also being studied in a 4-drug combination with bortezomib, lenalidomide, and dexamethasone in the relapsed and refractory and newly diagnosed MM settings. In an ongoing phase 1b study led by Laubach and colleagues, patients with relapsed or relapsed and refractory MM received panobinostat 10, 15, or 20 mg on days 1, 3, 5, 8, 10, and 12 of 21-day cycles [39]. Panobinostat was given in combination with lenalidomide 15 mg on days 1-14, subcutaneous bortezomib 1.0 mg/m2 on days 1, 4, 8, and 11 of cycles 1-8 and days 1 and 8 of subsequent cycles, and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 1-8 and days 1 and 8 of subsequent cycles. A total of 16 patients who had a median age of 62 years (range, 50-77 years) and had received a median of 4 prior lines of therapy (range, 2-14) were enrolled. Among the 14 patients evaluable for response, the ORR was 36%, including 7% CR and 29% PR. The maximum tolerated dose was determined to be panobinostat 10 mg, which was well tolerated. Grade 3/4 AEs among the 10-mg group (n = 11) included thrombocytopenia (18%), hypophosphatemia (18%), anemia (8%), leukopenia (9%), dyspnea (9%), febrile neutropenia (9%), hyperglycemia (9%), and lung infection (9%). Shah and colleagues are investigating the panobinostat-bortezomib-lenalidomide-dexamethasone combination in patients with newly diagnosed MM in a phase 1/2 trial [40]. For the first 8 cycles, patients received panobinostat 10 mg on days 1, 3, 5, 8, 10, and 12 of 21-day cycles in combination with lenalidomide 25 mg on days 1-14, subcutaneous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. In subsequent maintenance cycles, lenalidomide and panobinostat were administered as tolerated, and dexamethasone 20 mg was administered weekly. Patients could undergo stem cell transplant after cycle 4. In total, 52 newly diagnosed patients who had a median age of 60 years (median, 40-79 years) were enrolled. At the time of data cutoff, 26 patients had received an autologous stem cell transplant, 1 received an allogeneic stem cell transplant, 10 chose to delay stem cell transplant, 8 were pending stem cell collection, and the remaining 7 withdrew from the study. After 4 cycles of treatment, the ORR was 94%, which included 46% stringent CR, CR, or near CR, 21% VGPR, and 27% PR. Additionally, 54% of patients tested negative for minimal residual disease. The combination was very well tolerated; the common grade 3/4 AEs included thrombocytopenia (36%), neutropenia (14%), fatigue (12%), and anemia (10%). 6.0 Conclusions DACi inhibit DACs that target histone and nonhistone proteins, resulting in death of MM cells via epigenetic modification and inhibition of the aggresome pathway. Panobinostat, a pan-DACi, has shown significant clinical benefit and is the first DACi approved for the treatment of MM. It is approved for use in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory MM who have received ≥ 2 prior regimens including bortezomib and an IMiD. Although clinical benefit from panobinostat-bortezomib-dexamethasone treatment has been shown, effective management of hematological and gastrointestinal toxicity is necessary to optimize outcomes. Use of subcutaneous, weekly bortezomib may improve the tolerability of the regimen. Panobinostat is also being studied in combination with other novel agents. HDAC6-selective inhibitors ricolinostat and ACY-241 are currently being studied in combination with dexamethasone and bortezomib or an IMiD for the treatment of relapsed and refractory MM. HDAC6- selective inhibitors may reduce off-target toxicity and improve tolerability compared with pan-DACi’s. 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