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Adding Pan-Deacetylase Inhibitor Panobinostat to Bortezomib and Dexamethasone Improves Progression-Free Survival in Relapsed Myeloma

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Key Points

  • Adding panobinostat to bortezomib/dexamethasone significantly increased progression-free survival in patients with relapsed or relapsed and refractory disease.
  • Follow-up for overall survival is ongoing.

In the phase III PANORAMA1 trial reported in The Lancet Oncology, San-Miguel and colleagues found that adding the pan-deacetylase inhibitor panobinostat to bortezomib (Velcade) and dexamethasone improved progression-free survival in patients with relapsed or relapsed and refractory multiple myeloma.

Study Details

In this double-blind trial, 768 patients from 215 centers in 34 countries who had relapsed or relapsed and refractory myeloma and who had received one to three previous treatments were randomly assigned between January 2010 and February 2012 to receive panobinostat, bortezomib, and dexamethasone (n = 387) or placebo, bortezomib, and dexamethasone (n = 381). Regimens consisted of 21-day cycles of panobinostat 20 mg on days 1, 3, 5, 8, 10, and 12, bortezomib 1.3 mg/m² on days 1, 4, 8, and 11, and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Randomization was stratified by number of previous treatment lines and previous use of bortezomib. Patients with primary refractory or bortezomib-refractory myeloma were not eligible. Crossover was not permitted. The primary endpoint was progression-free survival.

The panobinostat and placebo groups were generally balanced for age (median 63 years in both, 58% in both < 65 years), sex (52% and 54% male), ethnicity (64% and 66% white, 33% and 27% Asian, 1% and 4% black), Eastern Cooperative Oncology Group performance status (0 in 45% and 43%, 1 in 49% in both), creatinine clearance (60-89 mL/min in 68% and 65%, ≥ 90 mL/min in 31% and 34%), International Staging System stage (I in 40% in both, II in 27% and 24%, III in 20% and 23%), myeloma characteristics (relapsed in 64% and 62%, relapsed and refractory in 35% and 37%), previous autologous stem cell transplantation (56% and 59%), and previous treatment lines (one in 51% and 52%, two in 32% and 28%, three in 17% and 20%).

Previous treatments included bortezomib in 44% and 42%, lenalidomide (Revlimid) in 19% and 22%, thalidomide (Thalomid) in 53% and 49%, oral melphalan in 30% and 27%, cyclophosphamide in 47% and 44%, dexamethasone in 80% and 83%, bortezomib plus immunomodulatory drug in 24% and 26%, and bortezomib plus dexamethasone in 38% in both.

Improved Progression-Free Survival

Median follow-up was 6.47 months (interquartile range = 1.81–13.47 months) in the panobinostat group and 5.59 months (interquartile range = 2.14–11.30 months) in the placebo group. Median progression-free survival was 11.99 months (95% confidence interval [CI] = 10.33–12.94) in the panobinostat group vs 8.08 months (95% CI = 7.56–9.23) in the placebo group (hazard ratio [HR] = 0.63, P < .0001). The hazard ratio for progression-free survival was similar on multivariate analysis (HR = 0.58, P < .0001). Two-year progression-free survival was 20.6% vs 8.4%.

The progression-free survival benefit of panobinostat was observed across most prespecified subgroups, including patients with relapsed and refractory disease (HR = 0.54), those with stage II and III disease (HR = 0.61), those aged ≥ 65 years (HR = 0.72), and those with prior use of bortezomib (HR = 0.58).

Survival and Response

Overall survival data were not mature at the time of reporting. Median overall survival was 33.64 months (95% CI = 31.34 months–not estimable) vs 30.39 months (95% CI = 26.87 months–not estimable; HR = 0.87, P = .26). Objective response was observed in 60.7% vs 54.6% of patients (P = .09), including complete or near complete response rates of 27.6% vs 15.7% (P = .00006). Median time to response was 1.51 vs 2.00 months.  Median duration of response (partial response or better) was 13.14 vs 10.87 months. Among patients with at least near complete response, median progression-free survival was 19.38 vs 15.21 months.

Toxicity

The most common nonhematologic adverse events of any grade in the panobinostat group were diarrhea (68% vs 42% in the placebo group), peripheral neuropathy (61% vs 67%), and asthenia/fatigue (57% vs 41%). The most common grade 3 or 4 events were diarrhea (25% vs 8%), asthenia/fatigue (24% vs 12%), peripheral neuropathy (18% vs 15%), and pneumonia (13% vs 11%). Grade 3 or 4 hematologic adverse events included thrombocytopenia in 67% vs 31%, lymphopenia in 53% vs 40%, neutropenia in 35% vs 11%, and anemia in 18% vs 19%.

Serious adverse events occurred in 60% vs 42% of patients in the placebo group. Dose modifications were required for panobinostat in 51% of patients, bortezomib in 61%, and dexamethasone in 24% in the panobinostat group and for placebo in 23%, bortezomib in 42%, and dexamethasone in 17% of the placebo group. Discontinuation of treatment due to adverse events occurred in 36% vs 20%. Grade 3 or 4 adverse events led to discontinuation in 25% vs 13%, with the most common events being diarrhea (4%), peripheral neuropathy (4%), asthenia/fatigue (6%), thrombocytopenia (2%), and pneumonia (1%) in the panobinostat group and fatigue (3%), pneumonia (2%), peripheral neuropathy (2%), and diarrhea (2%) in the placebo group.

A total of 11 deaths were considered possibly related to study treatment in the panobinostat group, consisting of 7 due to infection, 2 to hemorrhage, 1 to myocardial infarction, and 1 to cerebrovascular accident. A total of seven deaths in the placebo group were considered possibly related to treatment, consisting of four due to infection, one to hemorrhage, one to pulmonary embolism, and one to cardiac arrest.

The investigators concluded: “Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow-up will be necessary to determine whether there is any effect on overall survival.”

Jesús F. San-Miguel, MD, of Clinica Universidad de Navarra-CIMA, Pamplona, is the corresponding author for The Lancet Oncology article.

The study was funded by Novartis Pharmaceuticals. For full disclosures of the study authors, visit www.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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