Effective use of panobinostat in combination with other active agents in myeloma in a novel 5-drug combination: Case Report and Interesting Observations

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, come 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 5 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 2 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 progression-free survival (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 (7 or more loose stools or need for hospitalization) that occurred in approximately 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 is 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 5-drug regimen incorporating panobinostat that has the potential to overcome these 3 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 11.1g/dL, serum calcium 9.2mg/dL, serum creatinine 1.1 mg/dl, serum lactate dehydrogenase 141 U/L, beta-2 microglobulin 5.33mcg/L, and serum albumin 4.3 g/dL. He had a serum monoclonal (M) protein spike of 5.5g/dL (IgG kappa). Quantitative immunoglobulin levels were IgG 9750 mg/dL, IgA 26mg/dL, and IgM 6mg/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 137mg/24 hours. 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 Table 1. 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 2 transplants were collected and cryopreserved for future use. In July 2009, he had disease progression and underwent an autologous SCT with melphalan 200mg/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 (Table 1), 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 4 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 (10mg 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 (Figure 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) (Table 2). 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 (Figure 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.

Table 1.

Regimens Used in Treatment, Best Response, and Clinical Course

Regimen Number	Regimen	M Spike Values (g/dL) at start of regimen	Best Response	Duration of Therapy*
1	Lenalidomide and Dexamethasone	M Spike = 5.5	Partial response	Oct 2004- Jun 2009 (60 Cycles)
2	Autologous transplantation with melphalan 200 mg/m conditioning	M Spike = 1.4	Partial response	July 29, 2009 (Day 0 transplant)
3	Pomalidomide and Dexamethasone	M Spike = 1.6	Partial response	July 2010 – May 2011 (9 cycles)
4	LBH/RAD001 protocol	M Spike = 2.6	Progression	May 2011 - Oct 2011 (2 cycles)
5	Bortezomib, Cyclophosphamide, Dexamethasone (VCD)	M spike = 3.1	Minimal response	Oct 2011 – April 2012 (8 cycles)
6	VDT-PACE	M Spike = 2.8	Partial Response	May 2012 (1 cycle)
7	Bortezomib, Lenalidomide, Dexamethasone (VRD)	M Spike = 2.4	Partial response	May 2012 – Sept 2012 (4 cycles)
8	VDT -PACE	M Spike = 1.9	Progression	Oct 2012 - Nov 2012 (1 cycle)
9	Carfilzomib, Lenalidomide and Dexamethasone	M Spike = 2.2	Progression	Nov 2012 - Jan 2013 (3 cycles)
10	Bendamustine	M spike = 3.4	Progression	Feb 2013 (1 cycle)
11	Intermediate dose Melphalan (40 mg/m2 intravenous) and methyl prednisolone	M Spike = 2.6	Partial response	March 2013 – Jun 2013 (3 cycles)
12	Autologous transplantation with BEAM conditioning	M Spike = 2.1	Partial response	July 26, 2013 (day 0)
13	Lenalidomide, Cyclophosphamide, Dexamethasone	M spike = 1.3	Partial response	Sept 2013 - Oct 2014 (14 cycles)
14	Lenalidomide, Cyclophosphamide, Dexamethasone, and Bortezomibt†	M spike = 0.9	Progression	Oct 2014 - Feb 2015 (4 cycles)
15	Thalidomide, Cyclophosphamide, Bortezomib, and Dexamethasone	M spike = 1.4	Progression	March 2015 - April 2015 (1 cycle)
	Thalidomide, Cyclophosphamide, Bortezomib, Dexamethasone, and Panobinostat (10mg)	M Spike = 2.1	Progression	May 2015 - June 2015 (2 cycles)
16	Thalidomide, Cyclophosphamide, Carfilzomib, Dexamethasone, and Panobinostat (20mg) (DT-PACK)	M spike = 2.1	Partial response	July 2015 - Sept 2015 (4 cycles)

^*Each new regimen was started due to because progression on the previous regimen with the possible exception of Melphalan-methylprednisolone which was given as a bridge to transplant.

^†Dexamethasone dose increased after 1^st cycle due to lack of response

LBH, panobinostat; RAD001, everolimus; VDT-PACE, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide; BEAM, carmustine, etoposide, cytarabine, melphalan;

Figure 1. Serum Monoclonal (M) protein level (gm/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

Table 2.

Dosing and Schedule of Dexamethasone, Thalidomide, Panobinostat, Cyclophosphamide, and Carfilzomib (DT-PACK) Combination Regimen

Dexamethasone 40mg/day oral once-daily with food on days 1,8,15 once weekly

Thalidomide 400mg/day oral once-daily days 1-28

Panobinostat 20 mg oral three times a week

Cyclophosphamide 300mg oral once-daily with food on days 1,8,15

Carfilzomib 27mg/m2/day IV infusion over 30 minutes days 1, 2, 8, 9, 15, 16

Cycle length = 28 days

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 3 treatment regimens, but achieved a PR following treatment with this 5-drug combination. The regimen is detailed in Table 2, 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 <.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 5-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 5 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.