JOURNAL ARTICLE

Bortezomib, lenalidomide, and dexamethasone with panobinostat for front-line treatment of patients with multiple myeloma who are eligible for transplantation: a phase 1 trial

Elisabet E Manasanch, Jatin J Shah, Hans C Lee, Donna M Weber, Sheeba K Thomas, Behrang Amini, Lei Feng, Zuzana Berkova, Michelle Hildebrandt, Robert Z Orlowski
Lancet Haematology 2018, 5 (12): e628-e640
30501870

BACKGROUND: Bortezomib with lenalidomide and dexamethasone (VRd) is a standard regimen for the front-line treatment of multiple myeloma. Panobinostat is approved in combination with bortezomib and dexamethasone in patients with myeloma who 'have been given at least two previous regimens including bortezomib and an immunomodulatory agent. We aimed to determine the maximum tolerated dose of a new regimen combining VRd with panobinostat in patients with newly diagnosed multiple myeloma.

METHODS: In this phase 1 study, we enrolled patients from the University of Texas MD Anderson Cancer Center (Houston, TX, USA) with newly diagnosed multiple myeloma who were aged 18 years or older and eligible for autologous stem-cell transplant (ASCT) according to International Myeloma Working Group 2014 diagnostic criteria. Participants were allocated either to the dose-escalation cohort or the dose-expansion cohort. In the dose-escalation cohort, in a 3 + 3 design, patients were treated in cycles of 21 days with bortezomib (1·3 mg/m2 , subcutaneously) on days 1, 4, 8, 11; lenalidomide (25 mg, orally) on days 1-14; dexamethasone (20 mg, orally) on days 1, 2, 4, 5, 8, 9, 11, and 12; and escalating doses of panobinostat (10-20 mg, orally) on days 1, 3, 5, 8, 10, and 12. The dose level exceeded the maximum tolerated dose if at any given dose more than one of three patients, or two of six patients, had a dose-limiting toxic event. In the dose-expansion cohort, patients were given the maximum tolerated dose of the drug combination as determined from the dose-escalation cohort. Patients could proceed with upfront ASCT after two to four cycles of initial therapy or store their stem cells and proceed with a delayed ASCT approach. Patients with delayed ASCT could continue therapy for up to eight cycles, followed by maintenance with lenalidomide, dexamethasone, and panobinostat at their last tolerated dose for up to 2 years. The primary objective was to determine the maximum tolerated dose of VRd with panobinostat. Safety was assessed in all patients who completed at least one cycle of therapy. This trial is registered with ClinicalTrials.gov, number NCT01440582, and is no longer recruiting participants.

FINDINGS: Between Feb 18, 2013, and June 8, 2016, 55 patients were identified as eligible for enrolment. The dose-escalation cohort comprised 12 participants. The first three (25%) patients at dose level 1 (panobinostat 10 mg) did not encounter dose-limiting toxicity. Of six (50%) patients at dose level 2 (panobinostat 15 mg), two (33%) had dose-limiting toxic events during cycle 1; one (17%) had grade 4 thrombocytopenia with bleeding and the other had grade 3 diarrhoea, thus exceeding the maximum tolerated dose. Because the maximum tolerated dose had been exceeded, three more patients were accrued to dose level 1 and these patients did not experience dose-limiting toxic events. Dose level 1 (21 day cycles of bortezomib 1·3 mg/m2 subcutaneously on days 1, 4, 8, 11; lenalidomide 25 mg orally on days 1-14; dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, 12; and panobinostat 10 mg orally on days 1, 3, 5, 8, 10 and 12) was established as the maximum tolerated dose.

INTERPRETATION: The combination of VRd with panobinostat 10 mg is safe and effective in patients who are newly diagnosed with multiple myeloma and who are transplant eligible. Further studies in large randomised controlled settings are needed to confirm these results.

FUNDING: Novartis and MD Anderson Cancer Center Support Grant.

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