Panobinostat, Dexamethasone, Bortezomib Combo Effective in Heavily Pretreated MM Patients

The addition of panobinostat to bortezomib and dexamethasone improved progression-free survival (PFS) and duration of response compared with bortezomib and dexamethasone alone in patients with relapsed/refractory multiple myeloma (MM) who had been treated with two or more prior regimens (including bortezomib and an immunomodulatory drug [IMiD]) – providing guidance as to which patients would benefit more from the novel drug, according to the results of a subgroup analysis of the PANORAMA 1 trial by Paul G. Richardson, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues.

Panobinostat, a histone deacetylase inhibitor, was approved by the U.S. Food and Drug Administration in February 2015 in combination with bortezomib and dexamethasone for the treatment of multiple myeloma in patients who had received two or more prior therapies.

“The results from PANORAMA 1 clearly demonstrated that panobinostat increases the median PFS of patients with relapsed or relapsed/refractory MM when added to bortezomib and dexamethasone,” Dr. Richardson and colleagues wrote. “However, patients who progress following treatment with bortezomib and IMiDs have a poor prognosis.”

The goal of this analysis was to determine which patients would derive the most benefit from the panobinostat combination: those with prior IMiD treatment (n=485), prior bortezomib and IMiD treatment (n=193), or patients receiving two or more prior regimens (including bortezomib and an IMiD; n=147).

“As expected, patients in the groups with prior bortezomib plus an IMiD and ≥2 prior regimens including bortezomib and an IMiD were more heavily pretreated and demonstrated a longer time since diagnosis than did the patients in the prior IMiD group,” the authors reported.

As seen in TABLE 1, median PFS for the panobinostat combination was longer than that for patients receiving bortezomib/dexamethasone alone across all subgroups, but the increase was greatest among patients who had received ≥2 prior regimens.

Secondary endpoints of efficacy (including complete remission [CR] rate, time to response, duration of response, and time to progression) were also consistently improved among pre-treated, panobinostat-treated patients. “The rate of high-quality responses more than doubled [in these patients] across all subgroups, with a notable increase among patients with ≥2 prior regimens (21.9% vs. 8.1%; p=0.023),” Dr. Richardson and colleagues wrote.

Patients treated with panobinostat also had a longer duration of response than those treated with placebo, in combination with bortezomib and dexamethasone – particularly for patients who received prior IMiD + bortezomib: 11.99 months (95% CI 9.69-13.90) versus 8.31 months (95% CI 6.14-12.32). These heavily-pretreated patients also demonstrated a greater improvement in treatment-free interval (TFI) with panobinostat: 4.7 months versus 1.9 months.

Common grade 3 or 4 adverse events (AEs) and laboratory abnormalities in patients who received panobinostat across the subgroups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue (TABLE 2). Overall, the authors wrote, “the safety profile of the panobinostat combination was similar among the prior treatment subgroups.” However, the number of on-treatment deaths was higher among panobinostat-treated patients who had been received prior IMiDs than among patients in the placebo group (17 vs. 10).

“As treatment options for relapsed MM increase with the development of novel therapies and treatment combinations, it is critical to identify patient populations that derive the greatest benefit to aid physicians in treatment decisions,” Dr. Richardson and co-authors concluded. “Investigation of other novel panobinostat combinations continues, including combinations with carfilzomib, ixazomib, and lenalidomide, in order to identify new treatment alternatives for patients with limited options and provide additional insight on the safety profile of this novel agent.”


Reference

Richardson PG, Hungria VTM, Yoo SS, et al. Panobinostat plus bortezomib and dexamethasone in relapsed/relapsed and refractory myeloma: outcomes by prior treatment. Blood. 2015 December 2. [Epub ahead of print]

TABLE 1. Median Progression-Free Survival Among Treatment Groups
Prior treatment Events Median PFS, months (95% CI) Hazard ratio (95% CI)
PAN + BTZ + DEX Placebo + BTZ + DEX PAN + BTZ + DEX Placebo + BTZ + DEX
IMiD 132/245 171/240 12.3 (10.3-13.8) 7.4 (6.0-7.9) 0.54 (0.43-0.68)
BTZ + IMiD 57/94 72/99 10.6 (7.3-13.8) 5.8 (4.4-7.1) 0.52 (0.36-0.76)
≥2 Regimens (including bortezomib + IMiD) 44/73 54/74 12.5 (7.3-14.0) 4.7 (3.7-6.1) 0.47 (0.31-0.72)
PAN=panobinostat; BTZ=bortezomib; DEX=dexamethasone

TABLE 2. Most Common Grade 3 or 4 Adverse Events
Prior IMID Prior BTZ + IMiD ≥2 Prior Regimens, including BTZ + IMiD
Thrombocytopenia 162 (27%) 63 (69%) 49 (68%)
Lymphopenia 130 (54%) 97 (41%) 35 (49%)
Neutropenia 89 (37%) 33 (36%) 29 (40%)
Diarrhea 63 (26%) 28 (30%) 55 (76%)
Asthenia/fatigue 61 (25%) 23 (25%) 19 (26%)

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