©ASCO/Rodney White
CHICAGO—Combination regimens including the histone deacetylase inhibitor panobinostat can produce durable responses and prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to research presented at the 2015 ASCO Annual Meeting.
In a phase 2 trial, panobinostat plus lenalidomide and dexamethasone produced durable responses, even in high-risk, lenalidomide-refractory MM patients.
In a phase 3 trial, panobinostat in combination with bortezomib and dexamethasone led to a 7.8-month improvement in median PFS over placebo-bortezomib-dexamethasone in patients with relapsed or relapsed and refractory MM who had received 2 or more prior regimens.
Both studies were sponsored by Novartis, the company developing panobinostat.
PANORAMA-1 substudy
PANORAMA-1 was a phase 3, randomized, double-blind, placebo-controlled trial of 768 MM patients. Overall, panobinostat in combination with bortezomib and dexamethasone led to a clinically relevant and statistically significant increase in PFS of about 4 months compared to placebo-bortezomib-dexamethasone.
At ASCO, Jesús San Miguel, MD, of Clínica Universidad de Navarra in Pamplona, Spain, presented the results of an exploratory analysis of 147 patients in this trial (abstract 8526*).
The patients had relapsed or relapsed and refractory MM and had received 2 or more prior regimens, including bortezomib and an immunomodulatory agent (IMiD).
Disease and treatment characteristics were as follows:
| Panobinostat
(n=73) |
Placebo (n=74) | |
| Disease
characteristics, n (%) |
||
| Relapsed | 39 (53) | 30 (41) |
| Relapsed/refractory | 34 (47) | 43 (58) |
| Prior
therapies, n (%) |
||
| Bortezomib | 73 (100) | 74 (100) |
| Lenalidomide | 28 (38) | 37 (50) |
| Thalidomide | 63 (86) | 50 (68) |
| Bortezomib
+ lenalidomide |
28 (38) | 37 (50) |
| Bortezomib
+ dexamethasone |
69 (95) | 74 (100) |
| Prior
autologous transplant, n (%) |
54 (74) | 47 (64) |
| Median
prior lines of therapy (range) |
3 (2-4) | 3 (2-3) |
The median PFS was 12.5 months in the panobinostat arm, compared to 4.7 months in the placebo arm. Treatment with panobinostat also led to an increase in complete/near complete response rates (21.9% vs 8.1%) and overall response rate (58.9% vs 39.2%).
Common grade 3/4 non-hematologic adverse events in the panobinostat arm and placebo arm, respectively, included diarrhea (33.3% vs 15.1%), asthenia/fatigue (26.4% vs 13.7%), and peripheral neuropathy (16.7% vs 6.8%).
The most common grade 3/4 hematologic abnormalities in the panobinostat arm and placebo arm, respectively, were thrombocytopenia (68.1% vs 44.4%), lymphopenia (48.6% vs 49.3%), and neutropenia (40.3% vs 16.4%).
The percentage of on-treatment deaths was similar between the treatment arms (6.9% vs 6.8%).
“These data provide physicians with a better understanding of the clinical use of panobinostat, an HDAC inhibitor, a promising new drug class for this difficult-to-treat patient population with a high unmet need,” Dr San Miguel said.
Phase 2 trial
Ajai Chari, MD, of Mount Sinai Medical Center in New York, presented the results of a phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in patients with relapsed/refractory MM (abstract 8528*).
There were 20 evaluable patients with a median age of 64 (range, 51-75). They had received a median of 3 prior therapies (range, 1-10). Prior regimens were as follows:
| Prior
therapy |
Exposed/Refractory, n (%) |
| Dexamethasone | 20 (100)/9
(45) |
| Thalidomide | 6 (30)/2
(10) |
| Lenalidomide |
20 (100)/15 (75) |
| Pomalidomide | 7 (35)/7
(35) |
| Bortezomib | 20 (100)/9
(45) |
| Carfilzomib | 6 (30)/6
(30) |
| Autologous
transplant |
15 (75) |
For this study, patients received panobinostat (20 mg on days 1, 3, 5, 15, 17, and 19), lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, and 15).
The overall response rate was 45%. This included 1 complete response, 3 very good partial responses, 5 partial responses, and 8 minimal responses. Two patients had stable disease, and 1 progressed.
Among lenalidomide-refractory patients (n=16), the overall response rate was 38%. This included 3 very good partial responses, 3 partial responses, and 7 minimal responses. Two patients had stable disease, and 1 progressed.
The median PFS was 6.5 months overall and among lenalidomide-refractory patients.
Grade 3/4 toxicities were primarily hematologic, including neutropenia (55%), thrombocytopenia (40%), and anemia (5%). Grade 3/4 non-hematologic adverse events included infections (n=4), diarrhea (n=3), pulmonary emboli (n=2), neck pain (n=1), QTc prolongation (n=1), fatigue (n=1), and weight loss (n=1).
“In relapsed/refractory MM patients, panobinostat in combination with lenalidomide and dexamethasone demonstrated durable responses comparable to other recently approved agents, even in lenalidomide-refractory patients with high-risk molecular findings,” Dr Chari said.
“In notable contrast to PANORAMA-1 results, this completely oral regimen is well-tolerated, with no grade 3/4 [gastrointestinal] toxicities and primarily expected hematologic toxicities.”
*Information in the abstract differs from that presented at the meeting.