New agents extend progression-free survival in double refractory myeloma
Dr Jonathan Kaufman - Winship Cancer Institute of Emory University, Atlanta, USA
Today I was asked to talk about the management of patients with relapsed and refractory disease, specifically the really challenging subset of patients with what we call double refractory myeloma, that is refractory to our current agents, the proteasome inhibitors like bortezomib and IMiDs like lenalidomide.
What options are available?
In the United States there are currently two medications approved for use in this setting. One is the next generation proteasome inhibitor called carfilzomib. In the pivotal study with carfilzomib there were 266 patients treated and these patients all had had prior bortezomib and lenalidomide and were refractory and in that setting there was about a 24% response rate and those patients who responded had a median duration of response of about 8 months. And the other very promising agent also recently approved, or approved in the past year or so in the United States, is pomalidomide which is the next generation IMiD from thalidomide and lenalidomide. Pomalidomide in combination with dexamethasone was shown to be superior to single agent pomalidomide in a randomised phase II study, response rates around 30% and, again, median duration of response of around 8 months. There was a large international study that compared pomalidomide, low dose dexamethasone and high doses of dexamethasone and, again, very similar response rates, about 30% of patients respond, again this is a refractory setting, clearly superior from response rate, time to progression, progression free survival and overall survival compared to dexamethasone alone.
So those are the two new medications available for patients with what we call double refractory disease that are both approved in the United States, I believe pomalidomide is approved in the United Kingdom and around Europe and carfilzomib is waiting for approval based on their large phase III study. It’s not been reported yet, that phase III study looked at a combination of carfilzomib plus lenalidomide dexamethasone and in a randomised fashion compared that to lenalidomide and dexamethasone alone and we’re waiting for those results. Assuming or if those results are positive I would assume that we would start to see approvals outside the United States for carfilzomib.
Then there are a whole host of investigational agents and probably the most exciting class of investigational agents in myeloma is the monoclonal antibodies. In lymphoma we’ve been using monoclonal antibodies for going on 20 years but in myeloma we have yet to see an effective monoclonal antibody. The one that is the most developed is a medication called elotuzumab. Elotuzumab is a monoclonal antibody against a cell surface glycoprotein that we now know is SLAMF7. SLAMF7 is only on plasma cells and somewhat on NK cells and it appears that elotuzumab works through the induction of ADCC and we know that lenalidomide upregulates ADCC as an immune mechanism. So the study that we did we combined elotuzumab with lenalidomide and dexamethasone and we saw excellent results, response rates in the 90% range, progression free survival in the 30 month range which are far superior to what we would have predicted with lenalidomide and dexamethasone alone. So, again, elotuzumab len-dex has moved forward with the phase III study to try to truly establish this as an effective therapy and we’re waiting on those results.
Then there are two drugs, both targeting anti-CD38, one drug called daratumumab and another one that we know as SAR, and both of those drugs as single agents have activity against refractory myeloma. So we’re waiting on further development of those monoclonal antibodies.
With the proteasome inhibitors, particularly bortezomib, the major toxicity that limited us from using these medications for a long time was the development of peripheral neuropathy. Fortunately carfilzomib has very little peripheral neuropathy and essentially no painful peripheral neuropathy. So that has really established carfilzomib as a medication that could potentially be used for a long period of time. There are uncommon or, quite frankly, rare side effects with carfilzomib, including cardiac problems, shortness of breath and so forth, that are not in a lot of patients but it’s the type of thing that people, as they use this medication for the first time, need to be conscientious of as a possibility.
From a pomalidomide standpoint, pomalidomide, as an IMiD that’s similar to lenalidomide, has toxicity very similar to lenalidomide in that the most common toxicity is hematologic in nature – myelosuppression, thrombocytopenia, neutropenia and anaemia. In a large part can be managed and predicted and dose reductions really manage those toxicities.
The other side effect that we noted, and it’s hard to really tease out whether it’s specifically related to pomalidomide or it’s related to the combination with dexamethasone, or because these are refractory myeloma patients, is our frequent infections and pneumonia. So, again, that’s something to be conscientious about with pomalidomide. The other thing you have to mention, it’s just like any time we use the IMiDs, thalidomide, lenalidomide and pomalidomide, we always have to think about DVT prophylaxis and any time we use any of the IMiDs in any circumstance we always at least think about DVT prophylaxis and for the standard risk patients use aspirin and for patients who are high risk, immobile, have a history of DVT, we’ll need more aggressive anticoagulation.
What message would you give to doctors?
In terms of what’s to be positive about in myeloma, where we previously would have predicted that patients with double refractory myeloma would live less than one year, now we know with these new agents, these new combinations of agents, patients are living much longer and living, quite frankly, better lives because of better control of their myeloma.