Compared with intravenous administration, subcutaneous bortezomib may improve the tolerability of a panobinostat, bortezomib, and dexamethasone combination among patients with relapsed or relapsed and refractory multiple myeloma (MM), according to research published in The Lancet Oncology.
While the introduction of proteasome inhibitors, including bortezomib, and immunomodulatory agents, such as lenalidomide, has markedly improved survival for patients with MM, most patients develop treatment resistance after multiple therapy lines. The 2015 approval of panobinostat, a pan-histone deacetylase inhibitor indicated for relapsed or relapsed and refractory MM, has improved survival further, though it has been associated with significant toxicity.
The current standard of care in MM may not reflect that of the period during which panobinostat received approval. Approval of subcutaneous bortezomib was granted after initiation of the trial leading to the approval of panobinostat, and elderly patients now receive fewer weekly treatment doses in the nonclinical trial setting. Therefore, researchers conducted an open-label, randomized, phase 2 trial (PANORAMA 3; ClinicalTrials.gov Identifier: NCT02654990) to “evaluate the efficacy and safety of  different dosing regimens of oral panobinostat, in combination with subcutaneous bortezomib and oral dexamethasone, and to assess the impact of attenuating bortezomib dosing frequency by age.” The study was conducted at 71 sites across 21 countries.
A total of 248 patients (aged 18 years or older) with relapsed or relapsed and refractory MM were randomly assigned to receive either panobinostat 20 mg 3 times weekly (82 patients; median age, 67 years; 51% men), panobinostat 20 mg twice weekly (83 patients; median age, 65 years; 53% men), or 10 mg panobinostat 3 times weekly (83 patients; median age, 66 years; 60% men) All patients had received 1 to 4 prior lines of therapy, and all regimens also included subcutaneous bortezomib and dexamethasone.
After up to 8 treatment cycles, the overall response rate was 62.2% among 51 of the 82 patients in the 20 mg 3 times weekly group, 65.1% among 54 of the 83 patients in the 20 mg twice weekly group, and 50.6% in 42 of the 83 patients in the 10 mg 3 times weekly group; complete responses were noted in 3 (4%), 3 (4%), and 1 (1%) of patients, respectively. The median durations of response were 22, 12, and 11 months, respectively.
Grades 3 or 4 adverse events were noted in 71 patients (91%) in the 20 mg 3 times weekly group, 69 patients (83%) in the 20 mg twice weekly group, and 60 (75%) patients in the 10 mg 3 times weekly group; 14 deaths were noted, including 5 in the 20 mg 3 times weekly group, 3 in the 20 mg twice weekly group, and 6 in the 10 mg 3 times weekly group. However, none of the deaths were considered treatment-related.
“[T]he use of subcutaneous bortezomib, along with weekly bortezomib from the onset of treatment among older patients and for all patients beyond four cycles of treatment, meaningfully improves tolerability and patient outcomes,” the authors concluded.
Disclosure: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
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 Oncol. Published online December 4, 2020. doi:10.1016/S1470-2045(20)30680-X