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Oral Panobinostat and Dexamethasone Plus Subcutaneous Bortezomib for Patients With Relapsed or Refractory Multiple Myeloma


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The randomized phase II PANORAMA 3 trial found that when used in combination with subcutaneous bortezomib and oral dexamethasone, oral panobinostat produced higher response rates with 20-mg dosing regimens and lower toxicity with a 10-mg regimen. The safety profile also appeared to be better than that observed with the approved combination including intravenous bortezomib. These results were reported in The Lancet Oncology by Jacob P. Laubach, MD, and colleagues.

Jacob P. Laubach, MD

Jacob P. Laubach, MD

Study Details

The open-label trial included 248 patients with relapsed or relapsed and refractory disease from sites in 21 countries. Patients were randomly assigned 1:1:1 between April 2016 and January 2019 to receive oral panobinostat at 20 mg three times weekly (dose in the currently approved combination regimen including intravenous bortezomib; n = 82), 20 mg twice weekly (n = 83), or 10 mg three times weekly (n = 83) plus subcutaneous bortezomib and oral dexamethasone. All regimens were given in 21-day cycles (14 days on/7 days off). For cycles 1–4, all patients aged ≤ 75 years received bortezomib at 1.3 mg/m2 twice weekly and oral dexamethasone at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. For these patients from cycle 5, and thereafter and for all cycles in patients aged > 75 years, treatment was bortezomib at 1.3 mg/m2 once weekly and dexamethasone at 20 mg (10 mg for patients aged >75 years) on days 1, 2, 8, and 9. Treatment continued until disease progression or unacceptable toxicity. Patients had received one to four previous lines of therapy, including an immunomodulatory agent. The primary endpoint was overall response rate (partial response or better) after up to eight cycles in the intention-to-treat population.

Responses

Median duration of follow-up among all treatment groups was 14.7 months (interquartile range = 7.8­–24.1 months). After up to eight treatment cycles, partial response or better was observed in 51 patients (62.2%, 95% confidence interval [CI] = 50.8%­–72.7%) in the 20 mg three times weekly group, 54 patients (65.1%, 95% CI = 53.8%–75.2%) in the 20 mg twice weekly group, and 42 patients (50.6%, 95% CI = 39.4%–61.8%) in the 10 mg three times weekly group.

Median response durations were 22 months (95% CI = 13.9 months–not estimable), 12 months (95% CI = 8.8–21.3 months), and 11 months (95% CI = 6.2–14.5 months) in the three groups, respectively. Progression-free survival probability at 12 months was 53% (95% CI = 39%–64%), 51% (95% CI = 38%–63%), and 33% (95% CI = 20%–45%), respectively.

KEY POINTS

  • Response rates were higher with panobinostat 20-mg regimens.
  • Adverse event rates were lower with the 10-mg regimen.

Adverse Events

Grade 3 or 4 adverse events occurred in 91% of the 20 mg three times weekly group, 83% of the 20 mg twice weekly group, and 75% of the 10 mg three times weekly group. The most common, occurring in ≥ 20% of patients in any group, were thrombocytopenia (42%, 31%, and 24%), and neutropenia (23%, 16%, and 8%). Serious adverse events occurred in 54%, 48% and 44% of patients (considered treatment-related in 32%, 27%, and 18%). The most common, occurring in ≥ 10% of patients in any group, was pneumonia (12%, 12%, and 11%). Discontinuation of treatment due to adverse events occurred in 30%, 28%, and 15% of patients. No deaths were considered related to treatment.

As stated by the investigators, “The incidence of adverse events, including diarrhea, with the approved dose of panobinostat was lower than that observed with the same dosing regimen in the pivotal PANORAMA 1 study, in which patients received intravenous bortezomib.”

They concluded, “The safety profile of panobinostat 20 mg three times weekly was more favorable than in previous trials of this regimen with intravenous bortezomib, suggesting that subcutaneous bortezomib improves the tolerability of the panobinostat plus bortezomib plus dexamethasone regimen. The overall response rate was highest in the 20 mg three times weekly and 20 mg twice weekly groups, with 10 mg three times weekly best tolerated.”

Dr. Laubach, of Dana-Farber Cancer Institute, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Novartis Pharmaceuticals and Secura Bio. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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