New MOAs in Multiple Myeloma Shine at ASH 2012
| Dec 10, 2012
Co-authored by Neesha Suvarna, PhD, Consultant
The multiple myeloma landscape is rapidly evolving, with the recent approval of Kyprolis (carfilzomib, Onyx) and the pending approval of pomalidomide (Celgene), both in the relapsed/refractory setting. We’ll see pivotal data for pomalidomide on Tuesday morning during ASH’s Late-Breaking Abstract session, but the first days of the conference have highlighted a few new mechanisms of action that are showing promising activity in multiple myeloma. Numerous other agents also are being investigated in the relapsed/refractory myeloma setting. Awareness of the changing myeloma landscape will be critical for anyone thinking about initiating new pivotal Phase III trials in this disease.
ARRY-520 (Array BioPharma) is a kinesin spindle protein inhibitor that is currently being developed in relapsed/refractory multiple myeloma patients. At ASH we saw the results of a dose-escalation study for ARRY-520 alone and in combination with dexamethasone (Shah, Abstract 449). The trial included highly relapsed patients who had failed prior Velcade and Revlimid and were heavily pretreated, with six to 10 prior regimens. The objective response rate (ORR) in the monotherapy arm was 16%, and in the combination arm the ORR was 22% (all partial responses). Considering these patients have failed so many prior treatment options, the 16% to 22% ORR is impressive; compare that with the 24% ORR achieved with Kyprolis monotherapy in patients with a median of five prior lines of therapy. Both the monotherapy and combination arms were very well-tolerated with low incidence of non-hematologic toxicities; neuropathy was not observed with ARRY-520 therapy. Most common hematologic toxicities for monotherapy included Grade 4 neutropenia (28%), thrombocytopenia (25%) and anemia (6%). In the combination arm, Grade 4 toxicities included neutropenia (38%), thrombocytopenia (19%) and anemia (5%). Biomarker studies identified AAG as a potential selection marker for response to ARRY-520, although this requires further confirmation, which is ongoing. Currently the drug is being evaluated in a new Phase I study in combination with Kyprolis or Velcade.
Another unique mechanism of action that has shown exciting results is elotuzumab (Abbott, BMS, Ono), which made its first splash at ASH 2011. Elotuzumab is a humanized monoclonal antibody against the surface glycoprotein CS1, which is expressed primarily on multiple myeloma cells. In a Phase II study, elotuzumab in combination with RevDex in relapsed/refractory patients demonstrated clinical activity with an ORR of 92% (including 14% CR) and 20.8-month median progression-free survival (PFS) in the 10 mg/kg dosing cohort (Richardson, Abstract 202). When compared with historical controls of RevDex in multiple myeloma, elotuzumab stands out with better response benefit and longer PFS, even in a more heavily pretreated patient population. Elotuzumab is currently being evaluated in combination with RevDex in two Phase III trials in first- and second-line myeloma.
Results were reported from a Phase I trial that evaluated the novel monoclonal antibody tabalumab (LY 2127399, Eli Lilly), which targets the membrane-bound and soluble B-cell activating factor (BAFF), a protein that is elevated in patients with multiple myeloma. The Phase I study evaluated the combination of tabalumab with Velcade (bortezomib, Millennium/Johnson & Johnson) in multiple myeloma patients who have relapsed after at least one prior therapy (Raje et al., Abstract 447). Of the 43 enrolled patients, the majority had received three or more prior therapies and almost all patients had relapsed after prior Velcade or an iMiD (Revlimid (lenalidomide, Celgene) or thalidomide); 75% had received prior Velcade. Overall the combination of tabalumab with Velcade/dexamethasone was very well-tolerated, with the most common Grade 3 or higher adverse events being thrombocytopenia (23%), pneumonia (10%) and peripheral sensory neuropathy (10%). The ORR was 45.8% and included two (4%) complete responders; an additional 21 patients achieved stable disease. The median time to progression (TTP) was 4.9 months, and duration of response was 7.3 months. It’s unclear at this time whether the responses seen can be attributed to tabalumab or to the Velcade combination partner; therefore, it will be key to gain better understanding of the trial patient population, especially the quality of their response to prior Velcade in order to assess the true value of this agent.