The Lynx Group

Emerging Therapies and New Approaches in the “Double-Refractory” Setting in Myeloma

September 2013, Vol 4, No 7

Chicago, IL—Advances in the understanding of the biology of multiple myeloma and the identification of new drugs have resulted in improved management of myeloma, including for disease refractory to the recent proteasome inhibitors and immunomodulatory agents that have been added to the treatment of patients with myeloma.

New therapeutic strategies are needed in this challenging population, said Robert Z. Orlowski, PhD, MD, Professor, Department of Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, TX, at the 2013 American Society of Clinical Oncology annual meeting.

Double-Refractory Setting

Carfilzomib (Kyprolis) and pomalidomide (Pomalyst) have demonstrated benefit in the double-refractory setting, resulting in their recent approval by the US Food and Drug Administration (FDA) for patients with myeloma. In patients with relapsed and/or refractory myeloma, carfilzomib was associated with a 15.4% overall response rate (ORR) and a median response duration of 7.8 months. The median overall survival (OS) was 15.6 months in the overall population and 11.9 months in the double-refractory subgroup.

Pomalidomide has been shown to be active against double-refractory mye­loma in phase 2 and 3 trials. The ORR was 31%, progression-free survival (PFS) was 3.8 months, and OS was 13.8 months in patients with relapsed and/or refractory myeloma who received pomalidomide and weekly dexamethasone (Decadron).

In one phase 3 clinical trial, patients were randomized to pomalidomide and low-dose dexamethasone or to single-agent high-dose dexamethasone. In patients with double-refractory disease, the median PFS was 3.2 months in the pomalidomide arm versus 1.7 months in the high-dose dexamethasone arm (P <.001); median OS was not reached in the pomalidomide arm versus 7.4 months in the high-dose dexamethasone arm (P <.001), said Dr Orlowski.

KSP Inhibitor

A novel treatment strategy targets kinesin spindle protein (KSP) in patients with myeloma, said Dr Orlowski. ARRY-520 is a potent, highly selective KSP inhibitor that was studied in a phase 2 trial as a single agent (cohort 1) and in combination with low-dose dexamethasone (cohort 2). After a median treatment time of 3.9 months, the ORR was 22% and the median response duration was 5.4 months. In cohort 1, 53% of patients had disease refractory to bortezomib and 75% had disease refractory to lenalidomide. Of the 32 patients in cohort 1 with assessable response, ORR was 16%; of these, 16% had partial responses.

Daratumumab

Daratumumab is an investigational human monoclonal antibody that has received “breakthrough therapy” designation from the FDA for the treatment of patients with myeloma who have received at least 3 previous lines of therapy or patients with myeloma that is “double refractory” to a proteasome inhibitor and an immunomodulatory agent. A phase 1/2 dose-escalation study of 32 patients with relapsed myeloma showed at least a minimal response in 8 of the 12 patients who received ≥4 mg/kg of daratumumab, with no major safety issues.

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