Higher Dosing Schedules of Panobinostat Plus Subcutaneous Bortezomib Triplet Appears Promising in Relapsed/Refractory Myeloma

Jacob Laubach, MD, MPP

The combination of a 20-mg 3-times-weekly or twice-weekly dosing schedule of panobinostat (Farydak) with subcutaneous bortezomib (Velcade) plus dexamethasone (FVd) induced durable responses as treatment of patients with relapsed or refractory multiple myeloma and demonstrated an acceptable safety profile in the phase 2 PANORAMA 3 study (NCT02654490), according to findings presented during the 2020 ASH Annual Meeting.¹

After up to 8 cycles of treatment, findings showed that the objective response rates (ORRs) were 62.2%, 65.1%, and 50.6% in patients who received the triplet at the 20-mg 3-times-weekly dose, 20-mg twice-weekly dose, and 10-mg 3-times-weekly dose of panobinostat, respectively. The median time to response was 1 month, 2 months, and 3 months, respectively; the median DOR was 22 months (14–not estimable), 12 months, and 11 months, respectively.

Additionally, the rates of adverse events (AEs) at the highest panobinostat dose were lower than what was previously observed in the PANORAMA 1 dose with intravenous (IV) bortezomib, suggesting that the subcutaneous administration of the proteasome inhibitor improves tolerability versus the IV formulation, explained lead study author Jacob Laubach, MD, MPP. However, the 10-mg 3-times-weekly dosing regimen was the best tolerated of the 3 dosing schedules.

“This study supports the use of this 3-drug regimen with subcutaneous bortezomib in combination with panobinostat,” Laubach, clinical director of the Jerome Lipper Multiple Myeloma Center, senior physician, Dana-Farber Cancer Institute, and assistant professor of medicine, Harvard Medical School, said in a virtual poster presentation during the meeting. “The study supports the fact that panobinostat, bortezomib, and dexamethasone is an important treatment option for patients who have become refractory to standard agents, including [immunomodulatory drugs], proteasome inhibitors, and CD38 monoclonal antibodies, with the appropriate dose and schedule modifications to minimize toxicity.”

Previously, the results of the PANORAMA 1 trial showed a significant benefit in PFS with FVd compared with placebo and bortezomib/dexamethasone. However, AEs were more frequent with the panobinostat regimen (grade 3/4, 96% vs 82% with bortezomib/dexamethasone).²

PANORAMA 3 was an open-label, international, multicenter, phase 2 trial that randomized patients to receive 1 of 3 different dosing schedules of panobinostat and incorporated subcutaneous bortezomib/dexamethasone: panobinostat at 20 mg 3 times per week (n = 82), twice-weekly panobinostat at 20 mg (n = 83), and 10 mg of panobinostat at 3 times per week (n = 83).

For cycles 1 through 4, all patients younger than 75 years old received subcutaneous bortezomib at 1.3 mg/m2 twice-weekly and oral dexamethasone at 20 mg 4 times per week. Also for patients younger than 75 years old from cycle 5 onwards, and all patients older than age 75, received weekly bortezomib subcutaneously at 1.3 mg/m2 and oral dexamethasone at 20 mg twice weekly; patients older than 75 years were given dexamethasone at a 10-mg twice-weekly dose.

Treatment was administered until disease progression, death, discontinuation due to toxicity, or consent withdrawal.

To be eligible for enrollment, patients must have been at least 18 years old, had relapsed or relapsed/refractory myeloma per International Myeloma Working Group 2014 criteria, and previously received 1 to 4 prior lines of treatment, including an immunomodulatory agent. Patients who were refractory to bortezomib could not enroll on the study.

The primary end point was ORR after up to 8 cycles of therapy; secondary end points included ORR after all treatment cycles, best response, duration of response (DOR), time to response, progression-free survival (PFS) probability at 1 year, and safety.

Patients were enrolled at 71 sites across 21 countries. The median age was 66.5 years (range, 59.0-73.0); most patients (87%) were between the ages of 18 to 75 years old, and 86% were Caucasian. More than half (55%) were male, and the median time since diagnosis was 48.6 months (range, 29.9-73.7).

At baseline, 68% of patients had relapsed disease; 32% had relapsed/refractory disease. Seventeen percent of these patients were refractory to lenalidomide (Revlimid) while 2% were refractory to pomalidomide (Pomalyst).

Other baseline characteristics were similar between the 3 dosing groups, regarding ECOG performance status, number of prior lines of therapy, previous treatment regimens, cytogenetic abnormalities, and baseline disease status.

Additional data showed that the median number of treatment cycles completed in the 20-mg 3-times-weekly dose, 20-mg twice-weekly dose, and 10-mg 3-times-weekly doses were 9, 8, and 7 cycles, respectively.

In the 20-mg 3-times-weekly dose, the stringent complete response (sCR) rate was 1.2% (n = 1), the complete response (CR) rate was 3.7% (n = 3), the very good partial response (VGPR) rate was 24.4%, the partial response (PR) rate was 32.9%, and the minimal response rate was 8.5%. A total 18.3% of patients had stable disease (SD), 1 patient (1.2%) experienced disease progression (PD), and 9.8% of patients had unknown responses.

For the 20-mg twice-weekly dose, the sCR, CR, VGPR, and PR rates were 0%, 3.6% (n = 3), 28.9%, and 32.5%, respectively. Twelve percent of patients achieved a minimal response. The SD rate was 15.7%, and 1 patient (n = 1) experienced PD. Five patients (6.0%) had unknown responses.

Finally, in the 10-mg 3-times-weekly dose, the sCR rate was 4.8% (n = 4), the CR rate was 1.2% (n = 1), the VGPR rate was 19.3%, the PR rate was 25.3%, and the minimal response rate was 9.6%. SD was the best response in 30.1% of patients, and 3.6% of patients had PD. Five patients (6.0%) had unknown responses.

After all cycles, the ORR was 62.2%, 67.5%, and 53.0% at the 20-mg 3-times-weekly, 20-mg twice-weekly, and 10-mg 3-times-weekly doses, respectively.

At 1 year, the PFS probability was 53% in the 20-mg 3-times-weekly dose, 51% in the 20-mg twice-weekly dose, and 33% in the 10-mg 3-times-weekly dose.

Regarding safety, AEs were more common in the two 20-mg dosing schedules of panobinostat. Grade 3 or higher AEs occurred in 91.0%, 83.1%, and 75.0% of patients on the 20-mg 3-times-weekly dose, 20-mg twice-weekly dose, and 10-mg 3-times-weekly dose, respectively; AEs that led to discontinuation were 29.5%, 27.7%, and 15.0%, respectively.

Treatment-related AEs (TRAEs) occurred at 94.9% with the 20-mg 3-times-weekly dose, 96.4% with the 20-mg twice-weekly dose, and 91.3% with the 10-mg 3-times-weekly dose. Serious AEs occurred in 53.8%, 48.2%, and 43.8%, respectively.

On-treatment deaths were highest in the 10-mg 3-times-weekly arm (n = 6) compared with 5 in the 20-mg 3-times-weekly arm and 3 from patients who received the agent at 20-mg twice weekly. No deaths were causally related to treatment.

The most common TRAEs, occurring in at least 20% of patients in any arm, were also more common with either of the 20-mg regimens compared with the 10-mg regimen and included diarrhea, thrombocytopenia, fatigue, nausea, neutropenia, anemia, asthenia, and peripheral neuropathy. Similar rates were found regarding treatment-emergent AEs.

However, AEs of special interest included all-grade and grade 3 or higher severe hemorrhage and thrombocytopenia, seen with the 20-mg 3-times-weekly dose (all-grade 65.4%; grade 3 52.6%), 20-mg twice-weekly dose (55.4% and 37.3%, respectively), and 10-mg 3-times-weekly dose (38.8% and 28.8%). All-grade and grade 3 or higher severe diarrhea was another AE of special interest, also seen with the 20-mg 3-times-weekly dose (all-grade 66.7%; grade 3 11.5%), 20-mg twice-weekly dose (65.1% and 10.8%, respectively), and 10-mg 3-times-weekly dose (50.0% and 5.0%).

_References

1. _{Laubach JP, Schjesvold F, Mariz M, et al. Efficacy and safety of the panobinostat-bortezomib-dexamethasone combination in relapsed or relapsed/refractory multiple myeloma: results from the randomized PANORAMA 3 study. Presented at: 2020 ASH Annual Meeting and Exposition; December 4-8, 2020; virtual. Abstract 3201.}
2. _{San-Miguel J, Hungria VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195-1206. doi:10.1016/S1470-2045(14)70440-1}