PANORAMA-3: Panobinostat can be safely combined with subcutaneous bortezomib

While significant progress has been made in the long-term management of multiple myeloma, novel treatment options are needed to improve the duration of response (DoR) in patients with relapsed and/or refractory multiple myeloma (RRMM).¹

Histone deacetylation (HDAC) is part of myeloma cell cycle progression and DNA repair. Inhibitors of HDAC have been studied in combination with other established and novel treatments. Panobinostat is an orally available pan-deacetylase inhibitor, approved for RRMM in combination with bortezomib and dexamethasone (PVd) in 2015 in both the U.S. and the EU, based on the results of the phase III PANORAMA-1 study (NCT01023308).² However, it was approved with a warning for severe diarrhea and cardiac events.³

A real-world study recently analyzed the adverse drug reactions reported with panobinostat during the 2 years following its approval. They found that gastrointestinal adverse events (AEs) were the most frequently reported to the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System and that there was a statistically significant increase in the risk of experiencing an adverse drug reaction with panobinostat than what was initially reported in the clinical trials.⁴

Panobinostat was approved only in combination with intravenous bortezomib, a proteasome inhibitor, which has been associated with AEs that include peripheral neuropathy, gastrointestinal symptoms, and transient thrombocytopenia.^1,2

Overall, there were two non-exclusive potential approaches to improve the safety profile of PVd combination without risking its efficacy in RRMM: to test alternative dosing schedules of panobinostat, and to administer bortezomib subcutaneously, which exhibits a more favorable toxicity profile with similar efficacy.²

In January 2021, Jacob Laubach et al. published in Lancet Oncology the efficacy and safety preliminary results of three different dosing regimens of oral panobinostat combined with subcutaneous bortezomib and oral dexamethasone in an open-label, randomized, multi-center phase II study in patients with RRMM (PANORAMA-3, NCT02654990).¹ 

Study design¹

In PANORAMA-3, patients (N = 248) aged 18 years or older have been recruited from 71 hospitals and medical centers in 21 countries.¹ Eligible patients had received 1–4 prior lines of therapy. Patients were ineligible if they had previously received antimyeloma chemotherapy or medication up to 2 weeks before the study began or if they were refractory to bortezomib.

The primary endpoint was overall response rate (ORR) after all patients had completed up to eight treatment cycles.

Secondary efficacy endpoints included:

• ORR throughout the study
• DoR
• Progression-free survival (PFS)

Patients (N = 248) were randomly assigned (1:1:1) to receive one of three treatment regimens in 21-day cycles (14 days on, 7 days off) until disease progression or unacceptable toxicity:

• Panobinostat 20 mg three times weekly (n = 82), the approved dosing schedule
• Panobinostat 20 mg twice weekly (n = 83)
• Panobinostat 10 mg three times weekly (n = 83)

Dosing and scheduling for subcutaneous bortezomib and oral dexamethasone were based on patient age and were the same in each panobinostat arm:

• Bortezomib 1.3 mg/m² subcutaneous administration twice weekly or weekly, depending on patients’ age
• Dexamethasone 20 mg pre- and 24 hours after bortezomib; 10 mg for patients > 75 years

Statistical analyses

Primary analysis occurred when all patients had completed up to eight cycles of treatment. Interim analyses were performed when approximately 120 patients (40 per group) had been treated for up to eight cycles. Final analyses will be carried out when all patients have¹:

• Completed a 3-year survival follow-up, and/or
• Discontinued from the study

Results¹

Characteristics of the patients enrolled include:

• Median age (range): 66.5 (59.0–73.0)
• Relapsed at baseline: 68%
• Relapsed or relapsed and refractory at baseline: 32%
• Prior stem cell transplantation: 36%
• A median of two prior lines of treatment (interquartile range, 1.0–2.0) that mainly consisted of immunomodulatory drugs (> 99%), steroids (97%), and proteasome inhibitors (74%)

After a median follow-up of 14.7 months, the investigators reported lower response rates and shorter remission with panobinostat at 10 mg. When comparing the two treatment arms that used 20 mg panobinositat, both seemed to achieve similar response rates, although the three times weekly group achieved longer remissions, which could translate into higher survival outcomes with longer follow-up. However, this study was not designed for statistical comparisons between arms.

Please see Table 1 for results by selected primary and secondary endpoints.

Table 1. Primary and secondary endpoint results by treatment arm¹

Adverse Events

More than 75% of patients experienced a Grade ≥ 3 AE, irrespective of the dose of panobinostat. The majority were considered treatment-related, and in 21.8% and 24.1% of patients, these led to treatment discontinuation in the arms with higher doses of panobinostat (three times weekly and twice weekly, respectively). Cases of treatment discontinuation due to AEs decreased to 11.3% with panobinostat at the 10 mg dose.

Diarrhea, nausea, fatigue, thrombocytopenia, and anemia were some of the most frequently reported AEs across arms. Please see Table 2 for a summary of AEs grouped by primary system organ class.

Table 2. Summary of adverse events by treatment arm¹

Conclusion

In the RRMM setting, there is an urgent need for drugs that can overcome resistance to previous therapies and produce clinically meaningful responses in patients who progress after multiple lines of therapy.

In PANORAMA-3, patients treated with panobinostat plus bortezomib plus dexamethasone experienced ORRs from 50.6% to 65.1%, despite having received a median of two previous lines of therapy and 68% of all patients having previous bortezomib exposure.

Although there was greater toxicity associated with the 20 mg doses of panobinostat than the 10 mg dose, the safety profile was favorable compared with the PANORAMA-1 trial, and the antitumor activity was preserved. This finding suggests that the use of subcutaneous bortezomib meaningfully improves tolerability and patient outcomes with the triplet PVd. Previous trials of panobinostat plus bortezomib plus dexamethasone in patients with RRMM have demonstrated similar results, lending support to the consistency and reproducibility of these findings.