Here are course notes from the class I completed yesterday, Optimal Management Strategies and Novel Agents in Multiple Myeloma, specifically the section about clinical trials and new drug combination strategies:
At the present time, the novel agents we have discussed are used in combination with bortezomib or lenalidomide; additional new agents are being evaluated. Some of the more promising agents include heat shock protein 90 inhibitors, such as tanespimycin; monoclonal antibodies; new proteasome inhibitors, such as carfilzomib; new immunomodulatory derivatives, such as pomalidomide; and combinations with other histone deacetylase inhibitors, such as vorinostat, which is already marketed.
Elotuzumab, which targets SDF1, also called HuLuc63, together with lenalidomide and dexamethasone has shown some efficacy. With this regimen, up to 90% of patients are responding, but it should be cautioned that not all of these patients are truly refractory to lenalidomide.
Another monoclonal antibody regimen showing promise is CNTO 328, which is an anti-interleukin-6 antibody, combined with bortezomib. In patients who have received bortezomib approximately 25% to 30% are still achieving true responses with the combination regimen. Studies presented at ASH 2009 also looked at whether this regimen might be efficacious in upfront therapy. We and others are starting a protocol of bortezomib/melphalan/prednisone, as in the VISTA trial, with anti–interleukin-6.
Carfilzomib is also a proteasome inhibitor. In the 004 trial, carfilzomib resulted in 50% to 60% response rates in patients naive to bortezomib, whereas in the 003 trial of patients refractory to bortezomib response rates were 15% to 20%. Neuropathy is not commonly reported with carfilzomib; however, a flu-like cytokine release–type syndrome has been reported. It is encouraging that the toxicities from bortezomib and carfilzomib are not overlapping. Currently, there are ongoing trials of a combination of carfilzomib with lenalidomide and dexamethasone.
Pomalidomide is an interesting drug that has emerged in multiple myeloma. At the 2009 ASH meeting it was reported that lenalidomide-refractory patients, in other words patients progressing on their recent lenalidomide regimen, achieved a 30% to 40% response rate with pomalidomide. This agent is now going from phase I into phase II trials of myeloma amyloidosis and a variety of other diseases.
Vorinostat is also an interesting drug. It is a histone deacetylase inhibitor, and some data suggest that bortezomib resistance may involve histone deacetylase activity. Therefore it was hypothesized that bortezomib in combination with vorinostat might show activity in patients with relapsed/refractory myeloma. As reported at the 2009 ASH meeting, bortezomib plus vorinostat yielded a 30% to 40% response rate. This included refractory patients and patients who were heavily pretreated with bortezomib. An advantage of this drug is that it is FDA approved for treatment of cutaneous T-cell lymphoma; therefore, we are able to provide it to patients who did not respond to bortezomib, and it seems to be an efficacious agent in this setting.
I highlighted the final statement from these notes. Because vorinostat is already approved by the FDA for another cancer, some myeloma docs are using it “off label” in multiple myeloma patients, usually in combination with Velcade or Revlimid.
There are many, many reasons to stay positive about our future! Exercise, eat well and fight to preserve your lean muscle mass, so you can stay alive long enough for these new drugs to save the day!
And don’t forget to feel good and keep smiling! Pat