Effective use of panobinostat in combination with other active agents in myeloma in a novel five‐drug combination: Case report and interesting observations
Authors: Archana M. Rajan, Francis K. Buadi, Vincent Rajkumar
Journal: American Journal of Hematology (2015)

To the Editor: Multiple myeloma (MM) is a clonal plasma cell proliferative disorder characterized by hypercalcemia, anemia, renal dysfunction, and osteolytic bone lesions 1. The treatment of MM is rapidly changing with the arrival of several active new agents 2. New drugs that have entered the market in the last few years and have shown promise in various ongoing trials worldwide include carfilzomib, pomalidomide, and panobinostat. With the advent of these drugs, comes a multitude of new combinations that can be tailored to suit each individual patient's needs whether they are newly diagnosed, experiencing relapses off treatment, or are refractory to commonly used treatment regimens. Most treatment regimens in MM are doublets or triplets derived from the five major active classes of agents, namely, alkylators, anthracyclines, corticosteroids, proteasome inhibitors, and immunomodulatory agents. Despite the remarkable role these combinations have played in improvement of overall survival in MM, most patients eventually relapse, and drugs with new mechanisms of action, and combinations that utilize these drugs are needed. Panobinostat is a new treatment option that has emerged for the treatment of relapsed and refractory MM. It was approved by the United States Food and Drug Administration (FDA) in 2015 for use in patients with MM who have received at least two previous treatments including bortezomib and an immunomodulatory agent. The FDA approval was based on improved progression-free survival (PFS) in the Panorama1 trial that compared panobinostat plus bortezomib/dexamethasone to placebo plus bortezomib/dexamethasone 3. In this trial, the median PFS was significantly longer with the use of panobinostat, 12 months versus 8.1 months, P < 0.001, respectively. Panobinostat is a non-selective histone deacetylase (HDAC) inhibitor that results in increased acetylation of histone proteins thereby inducing cell cycle arrest and/or apoptosis of the tumor cells via multiple pathways. In addition, it has an inhibitory effect on the aggresome pathway which functions as an alternative protein degradation mechanism in the cell that may in part be responsible for the resistance to proteasome inhibitors. Although panobinostat has no significant single-agent activity, the Panorama trial demonstrates synergistic activity in combination with bortezomib in patients with relapsed refractory MM. It is therefore a novel agent with a unique mechanism of action that can be combined with other active drugs and incorporated into rational drug combinations. Three major factors significantly curtail the use of panobinostat in MM. First is the risk of severe Grade 3 or higher diarrhea (seven or more loose stools or need for hospitalization) that occurred in ∼26% of patients treated in the Panorama 1 trial 3. Second, panobinostat is a drug that needs a partner drug for efficacy since it has minimal single-agent activity in MM. In the schedule used in combination with panobinostat, bortezomib has the unfortunate side effect of severe neuropathy; in the Panorama 1 trial Grade 3 or higher neuropathy was seen in 18% 3. Third, the efficacy results in combination with bortezomib-dexamethasone are underwhelming. There was minimal improvement in response rates, only modest prolongation of PFS, and no improvement in overall survival. We report on a patient with relapsed and refractory MM treated with a novel five-drug regimen incorporating panobinostat that has the potential to overcome these three limitations of the drug. The patient is a 56-year-old male who was diagnosed with IgG kappa (Durie-Salmon Stage 3A, International Staging System (ISS) Stage III MM in 2004. He presented with severe back pain. Plain radiographic imaging showed pathologic compressions fractures at T7, T8, T10, and T11. Initial workup showed hemoglobin 11.1 g/dL, serum calcium 9.2 mg/dL, serum creatinine 1.1 mg/dL, serum lactate dehydrogenase 141 U/L, beta-2 microglobulin 5.33 mcg/L, and serum albumin 4.3 g/dL. He had a serum monoclonal (M) protein spike of 5.5 g/dL (IgG kappa). Quantitative immunoglobulin levels were IgG 9,750 mg/dL, IgA 26 mg/dL, and IgM 6 mg/dL. The serum free light chain (FLC) assay showed kappa 48.7 mg/dL, lambda <0.04 mg/dL, and kappa:lambda ratio >1036.2. Urine M-spike was 137 mg/24 hr. On further work up bone marrow biopsy showed 70–80% clonal plasma cells. Conventional metaphase cytogenetics revealed complex hyperdiploid karyotype with trisomy 3, 4, 5, 9, 11, 15, 21, and 19; in addition, there was an imbalanced rearrangement with breakpoints at 4p12 and 8q24.1. Fluorescent in situ hybridization (FISH) results were not available. Details of therapy are listed chronologically in Supporting Information Table S1. One week after the diagnosis was confirmed, he was started on lenalidomide and dexamethasone (Rd) as initial therapy. Although the best response to Rd was a partial response (PR), his response was remarkably durable, and he took Rd for a total of 60 cycles. Early in the treatment course with Rd, autologous stem cells adequate for two transplants were collected and cryopreserved for future use. In July 2009, he had disease progression and underwent an autologous SCT with melphalan 200 mg/m2 using half of his previously collected stem cells. Day 100 evaluation post-transplant showed PR, and he opted not to receive maintenance therapy or a second autologous SCT. Subsequently he had multiple remissions and relapses (Supporting Information Table S1), and received a variety of treatment regimens, including a second autologous SCT in July 2013. As part of these regimens he received almost all known active drugs in MM including melphalan, cyclophosphamide, corticosteroids, doxorubicin, thalidomide, lenalidomide, bortezomib, and new active drugs carfilzomib, pomalidomide, and bendamustine. PFS with the first autologous SCT (no maintenance) was 12 months; PFS with the second autologous ASCT was 15 months (with maintenance). Disease progression occurred within 1 month with the last four regimens prior to starting on panobinostat. In April 2015, he was started on a quintuplet regimen of thalidomide, cyclophosphamide, bortezomib, dexamethasone, and low-dose panobinostat (10 mg three times a week). Thalidomide was used instead of other more potent immunomodulators since it causes less cytopenias, and the patient was transfusion dependent for platelets and red cells at that point. In addition, it was felt that the constipating effects of thalidomide may counteract the diarrhea associated with panobinostat. Although the patient tolerated the regimen reasonably well, and had no significant diarrhea, he had MM disease progression within 2 months. Up to this point he had received 15 treatment regimens for MM, with each new regimen being started due to disease progression on the previous regimen (Fig. 1). In June 2015, bortezomib was replaced with carfilzomib, and the dose of panobinostat was increased to full therapeutic dose (20 mg three times a week) (Supporting Information Table S2). This treatment regimen of dexamethasone, thalidomide, panobinostat, cyclophosphamide, and carfilzomib (DT-PACK) was administered due to clinical need, given the aggressive nature of the relapse and the lack of therapeutic options in this patient. He had a clinically significant response to the quintuplet regimen (Fig. 1), and although he continues to need transfusion support, as of October 2015, he remains on the same therapy without progression. In addition, he does not have diarrhea or neuropathy on this regimen. Serum monoclonal (M) protein level (g/dL) over time (calendar year) with each treatment regimen. Abbreviations: Rd, lenalidomide, dexamethasone; ASCT, autologous stem cell transplantation; PD, pomalidomide, dexamethasone; LBH/RAD001, panobinostat + everolimus; VCD, bortezomib, cyclophosphamide, dexamethasone; VDT-PACE, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide; VRD, bortezomib, lenalidomide, dexamethasone; KRD, carfilzomib, lenalidomide, dexamethasone; Benda, bendamustine; Mel + S-M, melphalan plus solumedrol; CRD, cyclophosphamide, lenalidomide, dexamethasone; CVRD, cyclophosphamide, bortezomib, lenalidomide, dexamethasone; CVTD, cyclophosphamide, bortezomib, thalidomide, dexamethasone; CVTD-Pano, cyclophosphamide, bortezomib, thalidomide, dexamethasone, panobinostat; DT-PACK, dexamethasone, thalidomide, panobinostat, cyclophosphamide, carfilzomib. Since almost all MM patients eventually become refractory to commonly used regimens it is imperative that we develop more active, feasible, multi-drug combinations. In this case report, we describe a novel quintuplet regimen, DT-PACK that was effective in the treatment of a patient with highly refractory MM. He had previously been treated with 15 prior regimens, enumerated according to recommended guidelines 4. He failed to respond to the immediate prior three treatment regimens, but achieved a PR following treatment with this five-drug combination. The regimen is detailed in Supporting Information Table S2, and further investigation in clinical trials should be considered. The use of thalidomide in this combination was postulated as a strategic attempt to balance out the severe diarrheal effects of panobinostat with the gastrointestinal motility inhibiting effects of thalidomide. A similar effect was observed years ago when thalidomide was being investigated for the treatment of metastatic colon cancer. In that trial, although the combination of thalidomide plus irinotecan was not more effective, the use of thalidomide eliminated the diarrhea associated with irinotecan 5. Thalidomide can cause severe constipation and prophylactic laxatives/stool softeners are recommended routinely with thalidomide therapy 6. In a setting where an immunomodulatory agent is needed, if cytopenias or diarrhea are issues, it is reasonable to consider thalidomide (a much older immunomodulatory agent) rather than lenalidomide or pomalidomide. Neurotoxicity is a major adverse effect of bortezomib, especially in the recommended dosing schedule where the drug is given twice-weekly. Reduction in dose or dosing frequency can be tried to reduce the neurotoxicity 7, 8, but a more attractive option is to use a proteasome inhibitor with a much lower risk of neuropathy. In addition, carfilzomib may be more potent. The Endeavor trial found that carfilzomib plus dexamethasone had better response rates and PFS compared with bortezomib-dexamethasone (median PFS 18.7 months versus 9.4 months, HR = 0.53, 95 percent CI, 0.44–0.65) 9. Carfilzomib was also associated with fewer cases of peripheral neuropathy; the proportion of patients with grade ≥2 peripheral neuropathy was significantly higher in the bortezomib arm: 32% versus 6% (P < 0.0001). By using a more potent proteasome inhibitor that has less neurotoxicity, we can possibly maximize the synergy between a deacetylase inhibitor (panobinostat) and a proteasome inhibitor (carfilzomib). In summary, this case report describes a novel five-drug regimen that used at this dosage is feasible and effective. To our knowledge this is the first report of this regimen which was administered due to clinical need in a heavily pre-treated patient. This regimen has the potential to overcome some of the limitations of panobinostat as tested in the Panorama 1 trial. It may reduce the risk of diarrhea due to the addition of thalidomide, and reduce neurotoxicity by the substitution of carfilzomib for bortezomib. It also increases the chances of a response by using five active classes of drugs in combination; this case report is illustrative of the potential efficacy of this regimen. Finally, this patient is an excellent example of the type of major therapeutic advances that have occurred in MM. We now have numerous combinations that are feasible and tolerable. The use of such regimens in a sequential manner can not only prolong survival but also allows patients the opportunity to be treated with investigational agents and newer approved options as they become available. In this patient, we are hopeful that the response to the DT-PACK combination will enable disease control until monoclonal antibodies such as elotuzumab and daratumumab are approved for clinical use. Panobinostat is a newly approved drug, and we need additional studies to determine the best way to use the drug in a safe and effective manner. We recommend further testing of this regimen in clinical trials. By offering a less toxic option this strategy offers hope for the treatment of patients with refractory MM. Archana M. Rajan,1 Francis K. Buadi,2 Vincent Rajkumar2* 1Aureus University School of Medicine, Oranjestad, Aruba; 2Division of Hematology, Mayo Clinic, Rochester, Minnesota Additional Supporting Information may be found in the online version of this article. Supporting Table 1 Supporting Table 2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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