Beyond Kyprolis And Pomalyst: What Is Next On The Horizon?
Published: Apr 23, 2013 1:47 pm
Within the past nine months, two new agents have been approved for the treatment of relapsed multiple myeloma.
In July 2012, a second generation proteasome inhibitor, Kyprolis (carfilzomib), was approved for patients with relapsed/refractory disease. In February of this year, Pomalyst (pomalidomide) was approved for use in similar patients.
These two agents, with dexamethasone (Decadron) or in combination with other drugs, should further broaden the armamentarium for the treatment of myeloma as we continue to strive to make myeloma a chronic disease.
Rather than dwell on the advantages of these two agents, which are substantial, let us examine what is in the future for the treatment of multiple myeloma.
There are currently three agents being studied for the treatment of myeloma that are in Phase 3 clinical trials, the penultimate clinical trial format that may lead to approval by the U.S. Food and Drug Administration (FDA): elotuzumab, ixazomib (MLN9708), and panobinostat (Farydak).
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The most promising ongoing Phase 3 trials in myeloma are investigating elotuzumab or ixazomib in combination with Revlimid (lenalidomide) and dexamethasone.
The first of these trials is investigating the monoclonal antibody elotuzumab in combination with Revlimid and dexamethasone, compared to Revlimid and dexamethasone alone, in relapsed and refractory myeloma. The study has completed the trial accrual, and we await the preliminary results.
The side effects of this combination have been quite minimal, and the Phase 2 results were very promising. If the Phase 3 results are positive, we may see FDA approval of this agent in 2014, which would make elotuzumab the first monoclonal antibody to be approved for the treatment of myeloma. Monoclonal antibodies are a mainstay of treatment for lymphoma and chronic lymphocytic leukemia.
The second promising trial is investigating the third generation oral proteasome inhibitor ixazomib plus Revlimid and dexamethasone, compared to Revlimid and dexamethasone alone, in relapsed and refractory myeloma. Ixazomib allows for an all oral regimen of a proteasome inhibitor, immunomodulatory drug (Revlimid), and dexamethasone. In Phase 2 trials of this combination, response rates were robust and the side effect profile of ixazomib showed less neuropathy (pain, tingling, and loss of sensation in the extremities) than Velcade (bortezomib). FDA approval of ixazomib is not projected until 2015.
Panobinostat is a histone deacetylase inhibitor (HDAC) that interferes with DNA in tumor cells. It is being studied in combination with Velcade and dexamethasone, compared to Velcade and dexamethasone alone. It is not clear if the trial will be a positive trial. A recent trial with the same class drug, Zolinza (vorinostat), was not positive in Phase 3 testing.
Along with Zolinza, perifosine is another myeloma drug that looked promising in Phase 2 trials but did not prove efficacious in a larger Phase 3 trial. Perifosine is an AKT inhibitor, which means that it blocks one of the enzyme pathways in myeloma cells. The Phase 3 trial of perifosine in combination with Velcade and dexamethasone, compared to Velcade and dexamethasone alone, was recently closed at the interim analysis for lack of significant efficacy.
There are some other agents that are not as advanced in clinical trials. These agents will probably not be considered for approval until 2015 or later.
The first is another third generation oral proteasome inhibitor called oprozomib. This agent is currently in Phase 2 trials and appears to be effective. The earlier trials with this agent demonstrated moderate gastrointestinal side effects. The drug delivery system was modified, and the current formulation is much better tolerated.
Daratumumab, a monoclonal antibody directed against a surface protein on virtually all myeloma cells (CD38), has very high potential. Over the last 20 years, a number of monoclonal antibodies have been developed. However, virtually none of these monoclonal antibodies has anti-myeloma activity by itself. Elotuzumab, as mentioned above, is effective in combination, yet has minimal single-agent activity. Daratumumab shows activity as a single agent in early studies. This would allow for its use alone, with no requirement for combination with other agents. This may be an ideal agent for maintenance therapy after induction treatment or transplant.
Finally, although this discussion focuses primarily on these agents in the relapse setting, it should be noted that once evaluated in the relapse setting, these agents will ultimately be evaluated in newly diagnosed patients. Thus is the case with an on-going Phase 3 clinical trial of elotuzumab plus Revlimid and dexamethasone, compared to Revlimid and dexamethasone alone, in the frontline treatment of myeloma. Also, once approved, many of these agents have increased efficacy when combined with different class drugs. For example, Kyprolis, Revlimid, and dexamethasone is a very potent regimen for relapse and frontline therapy.
In summary, the future pipeline for myeloma agents is very promising. Although myeloma is only 1 percent of all cancers, six of the 21 agents approved over the past 12 years to treat cancer have been for myeloma, and more myeloma agents appear on the horizon. Soon, we truly will be able to state with confidence that myeloma is a chronic disease with multiple treatment options that can control the disease for years.
Dr. David H. Vesole is Co-Chief of the Myeloma Division and Director of Myeloma Research at The John Theurer Cancer Center at Hackensack University Medical Center. Dr. Vesole writes a quarterly column for The Myeloma Beacon.
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