Subcutaneous Bortezomib Combo Improves Tolerability for Patients with Relapsed/Refractory Multiple Myeloma

January 19, 2021
Matthew Fowler

Data published in The Lancet found a favorable tolerability profile for the subcutaneous formulation of bortezomib when compared with previous trials of the combination panobinostat plus dexamethasone and intravenous bortezomib in myeloma.

As compared with previous trials using intravenous bortezomib, data suggest that the subcutaneous formulation of the agent added to the regimen of panobinostat (Farydak) plus dexamethasone improves tolerability for patients with relapsed or refractory multiple myeloma, according to data published in The Lancet.

The regimen that was examined in the randomized phase 2 PANORAMA 3 trial (NCT02654990) improved tolerability for patients with this disease when examined versus intravenous bortezomib.

“Although there was greater toxicity associated with the 20 mg dose of panobinostat (either three times weekly or twice weekly) compared with the 10 mg three times weekly dose, the safety profile was favourable compared with the PANORAMA 1 trial [NCT01023308], and antitumour activity was preserved,” wrote the investigators who were led by Jacob P. Laubach, MD. “This finding suggests that the use of subcutaneous bortezomib, along with weekly bortezomib from the onset of treatment among older patients and for all patients beyond 4 cycles of treatment, meaningfully improves tolerability and patient outcomes.”

Participants (n = 248) were recruited from April 27, 2016 to January 17, 2019 and were randomly assigned to 3 different dosage groups; 82 patients were treated with 20 mg panobinostat 3 times weekly, 83 with 20 mg panobinostat 2 times weekly, and 83 with 10 mg panobinostat 3 times weekly.

Responses were measured after up to 8 cycles of treatment, with an overall response rate of 62.2% (95% CI 50.8%-72.7%) for the panobinostat 20 mg, 3 times weekly group; 65.1% (95% CI, 53.8%-75.2%) for the 20 mg, 2 times weekly group; and 50.6% (95% CI, 39.4%-61.8%) for the 10 mg, 3 times weekly group.

Grade 3/4 adverse events (AEs) were measured in each of the 3 groups, occurring in 91% of patients in the panobinostat 20 mg, 3 times weekly group; 83% of patients in the 20 mg, 2 times weekly group; and 75% of patients in the 10 mg, 3 times weekly group. The. Most common grade 3/4 AE was thrombocytopenia, which occurred in 42%, 31%, and 24% of patients from each group, respectively.

Serious adverse events also occurred in each group, at rates of 54%, 48%, and 44%, respectively. The most common serious AE was pneumonia, present in 12%, 12%, and 11% of patients from each group, respectively. There were 14 total deaths during the study, with none deemed to be related to treatment.

“This study included the panobinostat 20 mg twice weekly dose to ascertain whether administration of 20 mg at a reduced frequency compared with the standard dose (20 mg 3 times weekly, 2 weeks on and 1 week off) would preserve efficacy but reduce toxicity,” wrote the investigators. “The regimen with the highest dose and frequency of panobinostat administration (20 mg 3z times weekly) had the greatest efficacy but, as expected, was associated with a modestly increased rate of grade 3 or worse adverse events.”

The investigators acknowledged that a potential limitation of the study was that it was not powered to make statistical comparison between each of the treatment groups. Because of this and the fact that few patients had previous monoclonal antibody therapy, the current mainstay for relapsed and newly diagnosed multiple myeloma, the investigators admitted it is not possible to draw firm conclusions about the activity of the combination of panobinostat plus bortezomib and dexamethasone for patients previously exposed to CD38-targeting therapy, such as daratumumab (Darzalex).

Reference:

Laubach JP, Schjesvold F, Mariz M, et al. Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study. Lancet. 2021;22(1):142-154. doi: 10.1016/ S1470-2045(20)30680-X.