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Crowd at ASCO 2015
©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.” end hematology article

*Information in the abstract differs from that presented at the meeting.


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