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Panobinostat (Farydak): A Novel Option for the Treatment of Relapsed Or Relapsed and Refractory Multiple Myeloma
Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow and the excessive production of a monoclonal immunoglobulin. In the United States, MM comprises approximately 10% of all hematological malignancies, making it the nation’s second most common hematological malignancy.2,3 Men have a slightly higher risk of developing MM than women. The condition appears, on average, at the age of 62 years in men and 61 years in women. Predisposing factors to developing MM include, but are not limited to, environmental exposures to pesticides and herbicides; occupational exposures; ionizing radiation; and a hereditary predisposition, with an increased risk when MM has affected at least two relatives.1
Both MM cells and normal plasma cells are produced by terminally differentiated B-lymphocytes. Following differentiation, normal plasma cells typically die within days or weeks, but MM cells demonstrate prolonged survival. Multiple myeloma cells secrete cytokines, such as interleukin (IL)-1, IL-6, tumor necrosis factor-alpha, and the receptor for activation of nuclear factor kappa B ligand (RANK-L), which promote cellular survival, clonal growth, and treatment resistance. Multiple myeloma is associated with genetic abnormalities that may prevent normal cellular differentiation and apoptosis, further prolonging the survival of myeloma cells.4
Patients with MM may present with an array of clinical features, including hypercalcemia, renal dysfunction, anemia, and bone pain, commonly referred to by the acronym CRAB. Renal injury can develop secondary to the monoclonal light chain protein produced by MM cells.5 Moreover, the high protein load can overwhelm normal protein reabsorption mechanisms, leading to renal tubular injury. Malignant plasma-cell proliferation and infiltration into bone marrow disrupts normal hematopoiesis, which may lead to anemia.1 Hypercalcemia and bone pain may occur in patients with MM secondary to calcium mobilization from the bone and the formation of osteolytic lesions, respectively. The secretion of IL-1, IL-6, and IL-6 receptors from myeloma cells promotes osteoclast function and decreases osteoblastic activity, leading to bone weakening, pain, and potential pathological fractures.
Multiple myeloma remains incurable, and virtually all patients will experience relapse despite efficacious first-line treatment.1 Commonly used therapeutic options include proteasome inhibitors, such as bortezomib (Velcade, Millenium Pharmaceuticals) and carfilzomib (Kyprolis, Onyx Pharmaceuticals); immunomodulatory drugs, such as lenalidomide (Revlimid, Celgene) and thalidomide (Thalomid, Celgene); and chemotherapy, such as melphalan.3 Depending on patient-specific factors, these medications may be used as monotherapy or as combination therapy, possibly with a corticosteroid, such as dexamethasone. As patients relapse or become refractory to common antimyeloma agents, novel options for previously treated patients become increasingly important.
One novel antimyeloma therapeutic target focuses on the modulation of epigenetic mechanisms through the inhibition of histone deacetylase. Vorinostat (Zolinza, Merck), a histone deacetylase inhibitor, demonstrated in vitro activity against myeloma cells6 and was also found to be well tolerated when given in combination with bortezomib in phase 1 studies.7,8 A randomized, double-blind, placebo-controlled, phase 3 clinical trial evaluated the safety and efficacy of vorinostat in combination with bortezomib for the treatment of patients with relapsed or refractory MM.9 Although the addition of vorinostat to bortezomib statistically prolonged progression-free survival (PFS) in this trial, the clinical relevance of the difference in PFS between the bortezomib and placebo groups was unclear, putting into question the clinical utility of vorinostat.9
In February 2015, the Food and Drug Administration approved panobinostat (Farydak, Novartis Pharmaceuticals), another histone deacetylase inhibitor, for the treatment of MM in combination with bortezomib and dexamethasone in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent.10
MECHANISM OF ACTION
Panobinostat is a potent inhibitor of histone deacetylase, which is responsible for the regulation of gene transcription, cellular differentiation, cell-cycle progression, and apoptosis.11
The inhibition of histone deacetylase prevents the deacetylation of histone and nonhistone proteins. This results in changes in both gene transcription and protein activity. In MM cells, the inhibition of histone deacetylation damages DNA and upregulates proteins that promote apoptosis and cell-cycle arrest. Despite its unique mechanism of action, panobinostat lacks therapeutic activity as monotherapy in patients with MM.12 Instead, antimyeloma synergistic activity has been demonstrated when panobinostat is used in combination with bortezomib and dexamethasone.13,14
The chemical structure of panobinostat is shown in
After oral administration, the peak concentration (Cmax) of panobinostat is reached within two hours. The plasma Cmax and the area under the curve from zero to 48 hours (AUC0–48) of panobinostat were approximately 44% and 16% lower, respectively, compared with fasting conditions when oral panobinostat was taken 30 minutes after a high-fat meal. In vitro, approximately 90% of the drug is bound to human plasma proteins; plasma protein-binding is independent of the drug’s concentration. Panobinostat is a substrate of P-glycoprotein and is extensively metabolized via reduction, hydrolysis, oxidation, and glucuronidation.
Approximately 40% of the hepatic elimination of panobinostat occurs through the CYP3A enzyme pathway. In addition, CYP2D6 and CYP2C19 play a minor role in panobinostat metabolism. In vitro, the glucuronidation of panobinostat occurs via uridine diphosphate glucuronosyltrans-ferase (UGT) 1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT2B4. After administration, 29% to 51% of the panobinostat dose is excreted via the urine, and 44% to 77% is excreted via the feces. Less than 2.5% is excreted as unchanged drug in the urine and less than 3.5% in the feces.
PANORAMA 1 was a multicenter, randomized, placebo-controlled, double-blind, phase 3 study evaluating patients with relapsed or relapsed and refractory MM. To be included, patients had to have received from one to three prior treatment regimens; had to have an Eastern Cooperative Oncology Group (ECOG) status of 2 or less; and had to be at least 18 years of age. A total of 768 subjects were randomly assigned to receive panobinostat, bortezomib, and dexamethasone (n = 387) or bortezomib, dexamethasone, and placebo (n = 381). The study consisted of two treatment phases: eight three-week cycles and four six-week cycles, for a maximum duration of 12 weeks. In the first treatment phase, panobinostat 20 mg or placebo was administered three times weekly for the first two weeks of each cycle. Bortezomib 1.3 mg/m2 was given on days 1, 4, 8, and 11 of each cycle, and dexamethasone was administered on the day patients received bortezomib and the day after that. The primary efficacy outcome was PFS; secondary outcomes included overall survival (OS) and safety.16
Patients in the panobinostat arm had significantly longer PFS compared with patients in the placebo group: 11.99 months and 8.08 months, respectively (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.52–0.76; P < 0.001). According to preliminary results, however, there was no statistically significant difference in median OS between the panobinostat group and the placebo group (33.64 months versus 30.39 months, respectively; HR, 0.87; 95% CI, 0.69–1.10; P = 0.26).16 A final analysis of the OS data also found no significant difference between the panobinostat-treated patients and those given placebo (40.3 months versus 35.8 months, respectively; HR, 0.94; 95% CI, 0.78–1.14; P = 0.5435).17
Patients more commonly discontinued treatment because of adverse events (AEs) in the panobinostat group (34%) compared with the placebo group (17%). Grade-3 or grade-4 AEs occurred in 96% of the patients in the panobinostat arm and in 82% of the patients in the placebo arm. The AEs associated with panobinostat in this study are detailed in
The authors concluded that the addition of panobinostat to bortezomib and dexamethasone improved PFS in patients with relapsed or relapsed and refractory MM, but this benefit did not translate to a significant increase in OS.16
PANORAMA 2 was a phase 2, multi-center, single-arm, open-label trial evaluating combination therapy with panobinostat, bortezomib, and dexamethasone in adults with relapsed and bortezomib-refractory MM. To be eligible, the participants had to have received at least two previous lines of therapy and to have been exposed to an immunomodulatory drug. Other inclusion criteria included being 18 years of age or older, an ECOG performance status of 2 or less, and having measurable disease (defined as an M protein concentration of 10 g/L or greater or a urine M protein concentration of at least 200 mg per 24 hours).
Like the previous PANORAMA study, PANORAMA 2 included two treatment phases. The first phase consisted of eight three-week cycles of panobinostat 20 mg three times weekly in weeks 1 and 2. Bortezomib 1.3 mg/m2 was administered twice weekly in weeks 1 and 2 of each cycle. Dexamethasone 20 mg was given four times weekly for the first two weeks of each cycle and was administered on the day of and the day after bortezomib administration. If the subjects demonstrated a clinical benefit during the first phase, they continued therapy in the second phase. The second phase consisted of six-week cycles of panobinostat three times weekly, bortezomib once weekly, and dexamethasone on the days of and the days after bortezomib in weeks 1, 2, 4, and 5. This phase lasted until the subjects experienced disease progression, toxicity, or death, or until they withdrew their consent to be in the study.
The study’s primary endpoint was the overall response rate (ORR). Secondary outcomes included PFS, OS, the time to response, the duration of response, an evaluation of minimal response, and an evaluation of the safety and tolerability of the combination regimen.
The results demonstrated a 34.5% ORR; one patient (1.8%) had a near-complete response and 18 patients (32.7%) had a partial response. The median time to a response and the median duration of the response were 1.4 months and 6.0 months, respectively. Median PFS was 5.4 months. With a median follow-up period of 8.3 months, median OS had not been reached. Select AEs associated with panobinostat in this study are listed in
The investigators concluded that the results supported further investigation of the role of panobinostat in combination with bortezomib and dexamethasone for the treatment of patients with advanced relapsed and refractory MM.
The most common AEs associated with panobinostat include diarrhea, peripheral edema, nausea, vomiting, fatigue, pyrexia, and loss of appetite. Laboratory abnormalities such as hypophosphatemia, hypokalemia, hyponatremia, and serum creatinine elevations may also occur at rates of 40% or more. Hematological abnormalities, such as thrombocytopenia, neutropenia, leukopenia, lymphopenia, and anemia, may occur at incidences higher than 60%. Other possible serious AEs that may occur with panobinostat include life-threatening gastrointestinal and pulmonary hemorrhage and hepatotoxicity.
It is recommended that clinicians monitor platelets during therapy and offer transfusion support to patients to mitigate the risk of hemorrhage. Liver-function tests should be monitored during panobinostat therapy, and doses should be adjusted based on the occurrence of abnormalities.
Warnings and Precautions15
The label for panobinostat includes boxed warnings regarding the potential for severe diarrhea and cardiac toxicities.
Severe diarrhea may warrant the use of antidiarrheal medications, reduction of the panobinostat dose, temporary interruption of therapy, and/or permanent discontinuation of panobinostat.
Cardiac toxicities in patients taking panobinostat have included severe arrhythmias, echocardiogram (ECG) changes, and QT prolongation. These events may be exacerbated by electrolyte abnormalities. Evaluation of electrolytes and ECG results is recommended at baseline and periodically throughout treatment with panobinostat.
Use in Specific Populations15
Pregnancy and Lactation
Panobinostat can cause fetal harm when administered to pregnant women. If panobinostat is used during pregnancy or if a woman becomes pregnant while taking the drug, she should be appraised of the potential hazard to the fetus. It is not known whether panobinostat is excreted in human milk.
Women and Men of Reproductive Potential
Pregnancy testing should be performed in women of childbearing potential before starting treatment with panobinostat and intermittently during treatment with the drug. Women of reproductive potential should be advised to avoid becoming pregnant while taking panobinostat. Sexually active women of reproductive potential should be advised to use effective contraception while taking panobinostat and for at least one month after the last dose of the drug. Sexually active men should be advised to use condoms while on treatment and for three months after their last dose of panobinostat.
Geriatric and Pediatric Use
In clinical trials of panobinostat in patients with MM, 42% of patients were 65 years of age or older. Patients older than 65 years of age had a higher frequency of selected AEs and of discontinuation of treatment because of AEs. The incidence of deaths not related to disease progression was 9% in patients 65 years of age or older compared with 5% in patients younger than 65 years of age. Patients older than 65 should be monitored for toxicity more frequently, especially for gastrointestinal toxicity, myelosuppression, and cardiac toxicity.
The safety and efficacy of panobinostat in children have not been established.
The safety and efficacy of panobinostat have not been evaluated in patients with hepatic impairment. The starting dose of panobinostat should be reduced in patients with mild or moderate hepatic impairment. The use of panobinostat should be avoided in patients with severe hepatic impairment. Patients with hepatic impairment should be monitored frequently for AEs.
Mild to severe renal impairment did not affect the plasma exposure of panobinostat in clinical trials. Panobinostat has not been studied in patients with end-stage renal disease or in patients on dialysis. The dialyzability of panobinostat is unknown.
The concomitant use of panobinostat and drugs that prolong the QT interval—such as moxifloxacin, clarithromycin, methadone, and chloroquine, as well as antiarrhythmic drugs, such as amiodarone, disopyramide, procainamide, quinidine, and sotalol—should be avoided because panobinostat may also prolong the QT interval. Although serotonin receptor antagonists, such as ondansetron and dolasetron, are known to increase the risk for QT prolongation, they may be coadministered with panobinostat in conjunction with ECG monitoring.
As a substrate of cytochrome P450 3A4 (CYP3A4), panobinostat is prone to interactions with medications that are strong inhibitors or inducers of the CYP3A4 metabolic pathway. The dose of panobinostat should be reduced to 10 mg when it is coadministered with strong CYP3A4 inhibitors, including, but not limited to, clarithromycin, itraconazole, voriconazole, and conivaptan. Patients taking panobinostat should also be instructed to avoid grapefruit and grapefruit juice, which may also inhibit CYP3A4. The coadministration of strong CYP3A4 inducers with panobinostat was shown to decrease systemic exposure of panobinostat by approximately 70%. It is recommended, therefore, that clinicians avoid concomitant administration of panobinostat and strong CYP3A4 inducers.
Panobinostat inhibits CYP2D6 and may increase plasma concentrations of CYP2D6 substrates, such as metoprolol, atomoxetine, nebivolol, perphenazine, venlafaxine, and dextromethorphan. Concomitant use of panobinostat and CYP2D6 substrates should be avoided, but if this is not possible, patients should be monitored for adverse events related to the CYP2D6 substrate.
DOSAGE AND ADMINISTRATION15
Panobinostat is available as 10-mg, 15-mg, and 20-mg capsules. The initial dosing schedule is 20 mg once every other day for three doses per week (on days 1, 3, 5, 8, 10, and 12) of weeks 1 and 2 of each 21-day cycle for eight cycles. Panobinostat may be continued for an additional eight cycles for patients who experience a clinical benefit, provided they have no unresolved severe or medically significant toxicities or adverse effects secondary to the medication. The recommended dosing schedule is detailed in
Panobinostat is available in blister packs containing six capsules of 10 mg, 15 mg, or 20 mg each––enough for one cycle of treatment.15 The average wholesale price per package is $8,800, meaning that the cost of an entire treatment spanning 16 cycles (48 weeks) would be $140,800.19
P&T COMMITTEE CONSIDERATIONS
Panobinostat is the first histone deacetylase inhibitor approved for the treatment of patients with relapsed or relapsed and refractory MM.10 As an oral agent, it may improve adherence, since a visit to an infusion clinic is not required for the drug’s administration. Panobinostat may be continued if a patient is hospitalized, assuming that he or she is not admitted secondary to toxicities associated with panobinostat and that no contraindications to treatment exist.15
Panobinostat is a category 1 recommendation in the National Comprehensive Cancer Network (NCCN) MM guidelines. NCCN has recommended that the combination regimen of panobinostat, bortezomib, and dexamethasone is a potential treatment option for patients who have previously treated MM and who have received at least two previous treatment regimens that included bortezomib and an immunomodulatory agent.3 Given the growing number of treatment options for relapsed or relapsed and refractory MM patients, a panobinostat-containing regimen may be a viable option in those patients who may be intolerable to or have contraindications to other possible treatment regimens in this setting.
Panobinostat, a histone deacetylase inhibitor, has no therapeutic effect when used alone in multiple myeloma patients.12 It demonstrates antimyeloma synergistic activity, however, when administered with bortezomib and dexamethasone.13,14 It has been approved as part of combination therapy with those two agents for the treatment of patients with MM who have received at least two prior regimens, including bortezomib and an immunomodulatory agent.15 The combination of panobinostat, bortezomib, and dexamethasone was associated with prolonged PFS in two pivotal trials,16–18 but this benefit did not translate to a significant improvement in OS.16,17 Nevertheless, with its novel mechanism of action, panobinostat may be a useful option for the multidrug treatment of MM patients who no longer benefit from other therapies.
Figure and Tables
Chemical Structure of Panobinostat
Selected Adverse Events Associated With Panobinostat in Pivotal Clinical Trials
|Peripheral neuropathy||61||17||< 1||NR||NR||NR|
NR = not reported.
Panobinostat, Bortezomib, and Dexamethasone Dosing Schedules
Panobinostat Dose Adjustments for Toxicity
|Grade 3 ANC 750–1,000 mm3||Maintain dose; no dose adjustment required.|
|Two or more episodes Grade 3 (ANC 500–750 mm3)||Hold until ANC is ≥ 1,000 mm3|
|Grade 3 (ANC < 1,000 mm3) with NF||Hold until NF resolves and ANC ≥ 1,000 mm3. Resume at lower dose.|
|Grade 4 (ANC < 500 mm3)||Hold until ANC is ≥ 1,000 mm3 and resume at a lower dose.|
|Grade 3 or 4 neutropenia||Growth factor support or dose reduction. If neutropenia unresolved or severe infection occurs despite growth factor support or dose reduction, discontinue panobinostat.|
|Grade 3 (platelets < 50,000 mm3)||No dose adjustment required; platelets should be monitored weekly.|
|Grade 3 (platelets < 50,000 mm3) with bleeding||Hold panobinostat; weekly platelet monitoring until platelets are ≥ 50,000 mm3 and then resume at lower dose.|
|Grade 4 (platelets < 25,000 mm3)||Hold panobinostat; weekly platelet monitoring until platelets are ≥ 50,000 mm3 and then resume at lower dose.|
|Severe thrombocytopenia||May require platelet transfusion. If platelet count does not improve despite transfusion or dose reduction, discontinue panobinostat.|
|Grade 3 (hemoglobin < 8 g/dL)||Hold until hemoglobin ≥ 10 g/dL and resume at lower dose.|
|QTcF increase to ≥ 480 msec||Hold and correct electrolyte abnormalities, if present. If no resolution in QT prolongation, permanently discontinue.|
|Grade 2 (moderate diarrhea; 4 to 6 stools/day)||Hold panobinostat until diarrhea resolves and then resume at same dose.|
|Grade 3 (severe diarrhea; ≥ 7 stools/day, IV fluids or hospitalization required)||Hold panobinostat until diarrhea resolves and then resume at a lower dose.|
|Grade 4 (life-threatening)||Discontinue permanently.|
|Severe nausea (grade 3 or 4)||Hold panobinostat until nausea/vomiting resolves and then resume at a lower dose.|
|Severe/life-threatening vomiting (grade 3 or 4)||Hold panobinostat until nausea/vomiting resolves and then resume at a lower dose.|
ANC = absolute neutrophil count; NF = neutropenic fever.
- Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;634:1046–1060.
- Siegel R, Ma K, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9–29.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), Multiple Myeloma, Version 2.2015. September 30, 2014. Available at: http://szpiczak.org/lang/aktualnosci/komunikaty/pdf/rok_2014/myeloma_for_physicians.pdf. Accessed September 29, 2015.
- Mahindra A, Hideshima T, Anderson KC. Multiple myeloma: biology of the disease. Blood Rev 2010;24;(suppl 1):S5–S11.
- Eleutherakis-Papaiakovou V, Bamias A, Gika D, et al. Renal failure in multiple myeloma: incidence correlations, and prognostic significance. Leuk Lymphoma 2007;48:337–341.
- Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA 2004;101:540–545.
- Badros A, Buger AM, Philip S, et al. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 2009;15:5250–5257.
- Weber DM, Graef T, Hussein M, et al. Phase I trial of vorinostat combined with bortezomib for the treatment of relapsing and/or refractory multiple myeloma. Clin Lymphoma Myeloma Leuk 2012;12:319–324.
- Dimopolous M, Siegel DS, Lional S, et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomized, double-blind study. Lancet Oncol 2013;14:1129–1140.
- Food and Drug Administration. FDA approves Farydak for treatment of multiple myeloma. February
232015;Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435296.htm. Accessed September 30, 2015.
- Andreu-Vieyra CV, Berenson JR. The potential of panobinostat as a treatment option in patients with relapsed and refractory multiple myeloma. Ther Adv Hematol 2014;5:197–210.
- Wolf JL, Siegel D, Godschmidt H, et al. A phase II trial of the pan-deacetylase inhibitor panobinostat as a single agent in advanced relapsed/refractory multiple myeloma. Leuk Lymphoma 2012;53:1820–1823.
- Ocio EM, Vilanova D, Atadja P, et al.
In vitroand in vivorationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica 2010;95:794–803.
- Catley L, Weisberg E, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 2006;108:3441–3449.
- Farydak (panobinostat) prescribing information East Hanover, New Jersey: Novartis Pharmaceuticals Corporation. February 2015;Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2015/205353s000lbl.pdf. Accessed March 21, 2016.
- San-Miguel JF, Hungria VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomized, double-blind phase 3 trial. Lancet Oncol 2014;15:1195–1206.
San-Miguel JF, Hungria VTM, Yoon S-S, et al. Final analysis of overall survival from the phase 3 Panorama 1 trial of panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. Poster presented at American Society of Hematology (ASH) 57th Annual Meeting & Exposition Orlando, Florida December 5–8 2015Available at: https://ash.confex.com/ash/2015/webprogram/Paper79871.html. Accessed March 21, 2016.
- Richardson PG, Schlossman RL, Alsina M, et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood 2013;122:2331–2337.
- Red Book Online Ann Arbor, Michigan: Truven Health Analytics. Available at: www.micromedexsolutions.com. Accessed April 8, 2016.