The selective histone deacetylase (HDAC) inhibitor panobinostat was safe and effective when used in combination with bortezomib and dexamethasone (RVD) in patients with newly diagnosed multiple myeloma (MM). The results from a phase I/II trial suggest that this panobinostat combination regimen could become a new option for induction therapy prior to autologous hematopoietic cell transplantation (AHCT) in transplant-eligible patients.
Lead author Jatin J. Shah, MD, from the Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center, presented the results at the 2015 ASH Annual Meeting.
Panobinostat was recently approved by the U.S. Food and Drug Administration, in combination with RVD, for the treatment of patients with relapsed myeloma based on results of the PANORAMA trial. In this trial, the panobinostat plus RVD combination nearly doubled complete response rates in relapsed patients compared with RVD alone.
Dr. Shah and colleagues examined whether panobinostat could be safely combined with bortezomib and dexamethasone in patients with newly diagnosed MM and assessed response rates in this patient population.
Forty-two patients were enrolled in the trial; all had newly diagnosed MM requiring therapy and were eligible for AHCT.
The median age among all patients was 60 years (range = 44-79 years). Most had low-grade myeloma (International Staging System [ISS] stage I = 28; ISS stage II = 10; ISS stage III = 4); 14 also had cytogenetically high-risk myeloma:
- 1 patient with t(4:14) and del17p
- 1 patient with del17p and 1q21
- 12 patients with only 1q21 amplification
The 21-day treatment cycles consisted of the following:
- Panobinostat: Induction therapy with 10 mg administered orally on days 1, 3, 5, 8, 10, and 12 for two weeks with one week of rest at the end of each cycle, followed by maintenance therapy with maximum tolerated dose (MTD; derived from induction phase) on days 1, 3, 5, 8, 10, and 12 of each cycle
- Bortezomib: Induction therapy with 1.3 mg/m2 administered subcutaneously on days 1, 4, 8, and 11 of cycles 1 through 8
- Dexamethasone: Induction therapy with 20 mg administered orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 1 through 8, followed by maintenance therapy with MTD on days 1, 8, 15, and 21 of each cycle
- Lenalidomide: Induction therapy with 25 mg administered orally on days 1 through 14 of every cycle, followed by maintenance therapy with MTD on days 1 through 21 of each cycle
Of the 42 enrolled patients, two had completed only one or two cycles of treatment and one patient was unevaluable for response. Dr. Shah presented data on 39 patients who had completed four cycles of treatment and were evaluable for efficacy.
Patients achieved a high overall response rate (ORR; including partial response [PR] or better) of 93 percent (TABLE). Notably, for 12 of the 14 high-risk patients who were evaluable for response, the ORR reached 100 percent.
Fifty-nine percent of patients (25 of 42) completed induction therapy and underwent consolidation with AHCT, while five patients completed induction therapy, came off study, and did not proceed to AHCT, Dr. Shah and colleagues reported. Among those who underwent transplant, eight patients chose a delayed transplant approach; six of these patients remained on trial with maintenance therapy (lenalidomide/dexamethasone/panobinostat), per study protocol.
"Two patients, neither with high-risk disease, progressed after cycles 10 and 11 with extramedullary disease and plasma cell leukemia/central nervous system involvement, respectively," Dr. Shah reported. "Four additional patients have completed two, three, and five cycles of therapy and are pending transplant."
The addition of panobinostat to RVD was safe, the authors noted. One patient developed a second primary malignancy while receiving panobinostat plus RVD – a newly diagnosed breast cancer during cycle nine of therapy.
"The side-effect profile demonstrated minimal gastrointestinal toxicity/diarrhea, and, overall, this was a well-tolerated combination," the authors concluded. Furthermore, "the combination of RVD plus panobinostat led to rapid disease control."
Shah JJ, Feng L, Manasanch EE, et al. Phase I/II trial of the efficacy and safety of combination therapy with lenalidomide/bortezomib/dexamethasone (RVD) and panobinostat in transplant-eligible patients with newly diagnosed multiple myeloma. Abstract #187. Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando, Florida.
|TABLE. Response Rates for Evaluable Patients|
|Overall (n=39)||High-risk disease (n=12)|
|Overall response rate (â‰¥partial response)||36 (93%)||12 (100%)|
|Complete response/near complete response||17 (44%)||6 (50%)|
|Very good partial response||10 (26%)||4 (33%)|
|Partial response||9 (23%)||2 (17%)|
|Stable disease||3 (8%)||N/A|