Addition of Vorinostat to Bortezomib Achieves Modest Improvement in Progression-Free Survival in Relapsed/Refractory Multiple Myeloma

Meletios Dimopoulos, MD

Vorinostat added to bortezomib improved progression-free survival (PFS) compared with bortezomib plus placebo in patients with relapsed/refractory multiple myeloma, according to results of the phase III VANTAGE 088 trial presented at the 53rd Annual Meeting of ASH. The absolute improvement in PFS was modest but met the study’s primary endpoint.

“The combination of vorinostat plus bortezomib is active in patients with relapsed/ refractory multiple myeloma. Most patients will eventually relapse or become resistant to treatment. We are encouraged by the results of the investigational use of vorinostat in combination therapy in this difficult-to-treat patient population,” said lead author Meletios Dimopoulos, MD, professor and chairman of Clinical Therapeutics at the University of Athens School of Medicine, Greece.

Compared to the control arm, there was a 23% relative risk reduction in disease progression (P = .01) in the vorinostat-containing arm. Median PFS was 7.63 months with bortezomib plus vorinostat versus 6.83 months with bortezomib plus placebo. Time to progression was also improved with bortezomib plus vorinostat, with a relative risk reduction of 21% versus bortezomib plus placebo (P = .02). Objective response rate (ORR) was 56% in patients treated with bortezomib plus vorinostat versus 41% in the control arm (P <.0001). No improvement in overall survival (OS) has been reported to date, but data are still maturing.

Even though the improvement in PFS was modest—a median of about 25 days— Dimopoulos said that many of these patients are out of treatment options, and vorinostat provides another option for them.

Vorinostat is an oral histone deacetylase inhibitor approved for use in cutaneous T-cell lymphoma. The drug is also prescribed off-label for other hematological malignancies.

“

We are encouraged by the results of the investigational use of vorinostat in combination therapy in this difficult-to-treat patient population. ”

—Meletios Dimopoulos, MD

The international, multicenter, randomized, double-blind, placebo-controlled, phase III study (1 of the largest in multiple myeloma) enrolled 637 patients from 33 countries between January 2009 and January 2011. Only about 8% were from North America. Median age was 62 years, and 59% were male. Slightly more than half were white. Patients could have received 1 to 3 prior regimens, including stem cell transplantation; about 45% in the vorinostat-containing arm and 40% in the control arm received 1 prior regimen; 22% and 18%, respectively, received 3 prior regimens.

Patients were randomized to bortezomib plus vorinostat versus bortezomib plus placebo and were treated until disease progression, unacceptable toxicity, or study withdrawal.

A subgroup analysis showed that the combination of bortezomib/vorinostat significantly improved PFS in younger patients (aged < 65 y), patients who received 1 previous line of therapy, patients previously exposed to one of the IMiDs (immunomodulators), and patients with no prior exposure to bortezomib (P <.05 for all comparisons).

The rates of several adverse events were significantly higher in the vorinostat-containing arm. The most common adverse events reported were thrombocytopenia (45% in the vorinostat group and 24% in the placebo group with grade 3-4); diarrhea (17% vs 9%, respectively with grade 3-4); nausea (8% vs 4% with grade 3-4); vomiting (7% vs 4% with grade 3-4); and fatigue (17% vs 7% with grade 3-4). There was no difference between the 2 arms for discontinuation due to adverse events: 21% versus 22%, respectively.

David S. Siegel, MD, PhD

Salvage Setting

An open-label, single-arm, phase IIb study called VANTAGE 095 evaluated the investigational use of vorinostat plus bortezomib in bortezomibrefractory patients, as well as patients deemed refractory, intolerant, or ineligible for IMiD-based therapy regimens. Results reported at ASH by lead author David S. Siegel, MD, PhD, chief of the Multiple Myeloma Division at John Theurer Cancer Center in Hackensack, New Jersey, showed an ORR of 11% in this difficult-to-treat population.

The multicenter trial enrolled 143 patients from 41 centers in 12 countries; 136 patients were evaluable for efficacy. The study population was heavily pretreated, with a median of 4 prior lines of therapy (range, 2-17); 69% had received 4 or more prior regimens.

Treatment was with 21-day cycles of bortezomib plus oral vorinostat. Patients with no change in disease status after 4 cycles of treatment or progressive disease after 2 cycles were given oral dexamethasone on the day of and day after each dose of bortezomib.

Dimopoulos MA, Jagannath S, Yoon S-S, et al. Vantage 088: Vorinostat in combination with bortezomib in patients with relapsed/refractory multiple myeloma: results of a global, randomized phase III trial. Blood. (ASH Annual Meeting Abstracts) 2011;118(21, abstr 811).

Siegel DS, Dimopoulos MA, Yoon S-S, et al. Vantage 095: Vorinostat in combination with bortezomib in salvage multiple myeloma patients: final study results of a global phase IIB trial. Blood. (ASH Annual Meeting Abstracts) 2011;118(21, abstr 480).