PANORAMA 1 is an important step in the development of HDAC inhibition as part of combination therapy for the long-term control of multiple myeloma.
—Philip McCarthy, MD
Melphalan, prednisone, and thalidomide (Thalomid), or MPT, was a widely accepted regimen in newly diagnosed multiple myeloma when the E1A06 trial was launched, noted Philip McCarthy, MD, Director of the Blood and Marrow Transplant Program at the Roswell Park Cancer Institute, Buffalo, New York. E1A06 compared MPT with melphalan, prednisone, plus lenalidomide (Revlimid), or MPR, in non–transplant-eligible, elderly patients (median age: 75.7 years).1 Both inductions were continued for 12 28-day cycles, with daily thalidomide (MPT-T) or lenalidomide (MPR-R) maintenance, respectively, continued until progression or relapse.
There was no difference in progression-free or overall survival between the two arms, but there was improved quality of life for the MPR-R arm. Nearly half the patients were off therapy at the end of induction and 9% remain on therapy at a median follow-up of 41 months. The second primary malignancy rate was 9.5% for MPT-T and 5.3% for MPR-R, he noted.
“What can we learn from this study? The progression-free survival and overall survival were inferior to that seen in MM 015, which examined MPR-R vs MPR vs melphalan/prednisone alone.2 This likely was due to the lower MPR-R melphalan dose and the older age population in E1A06,” Dr. McCarthy indicated.
The incidence of secondary primary malignancies in this study confirms the risk of the combined use of lower-dose melphalan with immunomodulatory drugs, which was reported in a recent meta-analysis.3 Another recent study, MM 020, demonstrated a superior progression-free survival and a trend toward overall survival benefit with continuous lenalidomide and low-dose dexamethasone until disease progression vs 18 months of lenalidomide/dexamethasone vs MPT.4
“Thus, the E1A06 study confirms the need for improved regimens with sustained tolerability for long-term disease control in multiple myeloma,” Dr. McCarthy concluded. “We are seeing the end of MPT and MPR as standard induction therapies for the non–transplant-eligible myeloma patient. Newer, better tolerated and more effective regimens incorporating [immunomodulatory drugs], proteasome inhibitors and potentially other novel agents such as antibodies will be studied as investigators attempt to control multiple myeloma long-term, with the goal of cure.”
Histone deacetylases (HDACs) modify chromatin, leading to gene-expression changes, which can result in aberrant cell-proliferation changes, in particular, multiple myeloma. HDAC inhibition results in epigenetic and chromatin changes, leading to diminished cell proliferation. Panobinostat inhibits various HDAC enzymes, with low-concentration activity against class I, II, and IV HDAC enzymes, which are involved in histone and transcription factor function, protein chaperoning, and tubulin formation.
PANORAMA 1 was a randomized, double blind phase III study of panobinostat or placebo plus bortezomib (Velcade) and dexamethasone in relapsed and refractory multiple myeloma patients. The study demonstrated that the panobinostat combination was superior.5 The progression-free survival for the panobinostat, bortezomib, dexamethasone arm was 12 months vs 8.1 months for bortezomib/dexamethasone plus placebo (P < .0001). There is no difference in overall survival at this time, Dr. McCarthy noted.
“What have we learned from this study? The study generated a 4-month gain in progression-free survival, which is greater than the 1-month difference in the VANTAGE 088 trial that compared vorinostat [Zolinza], bortezomib, dexamethasone with bortezomib/dexamethasone in relapsed/refractory patients.6 The combined complete response plus near complete response rate was higher in the study arm,” he pointed out.
“Bortezomib-refractory patients were not eligible for this study, so we do not know if panobinostat plus bortezomib/dexamethasone would have reversed this resistance,” he indicated. “The bortezomib was given intravenously, whereas subcutaneous administration is now standard,” he added.
Dr. McCarthy further pointed out that there were approximately twice the adverse events on the experimental arm, whereas there were twice as many cases of disease progression on the control arm. The adverse events were thrombocytopenia, fatigue, and gastrointestinal toxicity as well as a small increase in hemorrhagic events.
Questions remain, he said. “For example, could the schedule be modified to decrease these adverse events? Can this combination be utilized upfront to enhance efficacy?” While further research may provide answers, he called the PANORAMA 1 trial “an important step in the development of HDAC inhibition as part of combination therapy for the long-term control of multiple myeloma.” ■
Disclosure: Dr. McCarthy reported no potential conflicts of interest.
1. Richardson PG, Hungria VT, Yoon S, et al: Panorama 1. ASCO Annual Meeting. Abstract 8510. Presented June 2, 2014.
2. Palumbo A, Hajek R, Delforge M, et al: Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366:1759-1769, 2012.
3. Palumbo A, Bringhen S, Kumar SK, et al: Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma. Lancet Oncol 15:333-342, 2014.
4. Facon T, Dimopoulos MA, Dispenzieri A, et al: Initial phase 3 results of the first (frontline investigation of lenalidomide + dexamethasone versus standard thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma patients ineligible for stem cell transplantation. 2013 American Society of Hematology Annual Meeting. Abstract 2. Presented December 8, 2013.
5. Stewart AK, Jacobus SJ, Fonseca R, et al: E1A06. ASCO Annual Meeting. Abstract 8511. Presented June 1, 2014.
6. Dimopoulos M, Siegel DS, Lonial S, et al: Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088). Lancet Oncol 14:1129-1140, 2013.
At the 2014 ASCO Annual Meeting, one phase III trial confirmed the promise of a novel agent in advanced multiple myeloma, while another cooperative group trial returned some rather surprising results in newly diagnosed myeloma patients.
Panobinostat Doubles Response, Prolongs Remission