The results of studies presented at ASCO 2014 highlight 2 novel drug classes that showed strong activity in multiple myeloma (MM), representing potential advances in relapsed or refractory disease.
Panobinostat Extends Survival
In the phase 3 PANORAMA-1 trial, the addition of the oral pan-histone deacetylase (HDAC) inhibitor panobinostat to a bortezomib regimen led to a significant increase in median progression-free survival (PFS).
“The primary end point was met (P <.001), with a clinically relevant increase in median progression-free survival of approximately 4 months,” said Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston.
PANORAMA-1 was an international, randomized, double-blind, placebo-controlled, phase 3 trial of 768 patients with MM who had received 1 to 3 previous lines of treatment but who were not bortezomib-refractory. The patients were randomized to panobinostat or to placebo, each in combination with intravenous bortezomib and dexamethasone. After 8 cycles of therapy, responders continued to receive fewer doses of bortezomib plus dexamethasone.
The overall response rate (ORR) was similar between the arms, but the combination almost doubled the rate of complete and near-complete responses (27.6% vs 15.7%, respectively; P = .006).
The median PFS improved significantly, from 8.1 months with placebo to 12 months with panobinostat, a 37% reduction in risk (P <.001). After 28 months of follow-up, the median overall survival remained comparable—33.6 months with panobinostat and 30.4 months with placebo.
“These results confirm the efficacy of panobinostat, bortezomib, and dexamethasone that was previously observed in the PANORAMA-2 trial with patients who were heavily pretreated and bortezomib-refractory,” Dr Richardson noted.
Treatment with panobinostat led to more thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia or fatigue, but <5% of patients discontinued treatment as a result of adverse events.
Based on these data, the manufacturer has submitted a New Drug Application to the US Food and Drug Administration (FDA). In May, the FDA granted a priority review status to panobinostat. Other panobinostat-containing combinations and additional HDAC inhibitors are currently in clinical trials.
Anti-CD38 Monoclonal Antibodies
Impressive data from small, earlyphase studies were presented for 2 monoclonal antibodies that target the CD38 protein—SAR650984 and daratumumab.
SAR650984 a New Antibody
A phase 1b study evaluated the combination of SAR650984 and lenalidomide plus dexamethasone in 31 patients with highly refractory MM who had received 6 previous treatments, showing strong antitumor activity and good tolerability, according to Thomas G. Martin III, MD, of the University of San Francisco.
“SAR650984 in combination with lenalidomide and dexamethasone showed encouraging signs of activity in this heavily pretreated population,” Dr Martin reported.
The trial explored 3 different dose levels of SAR650984. The ORR was 58%, but this rose to 63% among patients receiving the highest dose (10 mg/kg given every other week), with 25% of patients achieving a very good partial response. The response rates by previous treatments are shown in the Table.
“Upwards of one third of patients had more than a 90% reduction in M protein value,” Dr Martin added. “In patients achieving a very good partial response, very few patients have come off therapy. This is still early in therapy…so I am hoping over time that these responses continue to improve and to deepen.”
Daratumumab as a Single Agent
Antitumor activity for daratumumab, used as a single agent, was shown in a phase 2 study of 50 heavily pretreated patients with relapsed or refractory disease. A total of 30 patients received 8 mg/kg and 20 patients received 16 mg/kg for 8 weekly doses, followed by 8 doses twice monthly and then monthly dosing for up to 24 months.
The ORR with daratumumab was 35% with the 16-mg/kg dose and 10% with the lower dose, reported Henk M. Lokhorst, MD, of University Medical Center Utrecht, the Netherlands.
“All patients who achieved a partial response or better at 16 mg/kg and who had bone marrow involvement cleared bone marrow progenitor cells after daratumumab treatment,” Dr Lokhorst noted.
Median PFS was 23 weeks in the 16-mg/kg group and 15 weeks in the 8-mg/kg cohort, at a median follow-up of <15 weeks.
“The median PFS estimate in the 16-mg/kg group is rather immature,” Dr Lokhorst said. “The current median PFS in this group is 23 weeks, which is also the longest follow-up of any patient in this cohort.”
The drug was well tolerated, and no severe infusion-related reactions were seen. Daratumumab is being evaluated in combination with lenalidomide plus dexamethasone in phase 3 trials.