A. Keith Stewart, MB, ChB: The standard of care in the United States has become a 3-drug combination involving a proteasome inhibitor, usually bortezomib, with an immune modulator, usually lenalidomide, and that has become the de facto standard for younger and increasingly for elderly patients. We are seeing an encroachment on that with the drug carfilzomib, which has some unique toxicity issues. The issues that we worry about with carfilzomib, which can be substituted for bortezomib, are that it has a low but real incidence of cardiovascular events by which we most commonly see some congestive heart failure, hypertension, and shortness of breath. These tend to be serious in 3% to 5% of patients. So, for the vast majority of patients, it is not a concern.
But as patients get older, particularly we are more conservative in using that drug because of those issues. We are more aggressive at managing hypertension, and we are more selective in which patients we will put on those drugs. For example, we would probably not treat patients with cardiac amyloidosis. We would probably not treat patients with a known history of congestive heart failure, atrial fibrillation, or severe hypertension, with carfilzomib as 1 example. However, I would emphasize that it is a well-tolerated drug for most people. It is highly effective, and I think it’s rapidly becoming a more attractive option, particularly in our younger, healthier population.
Some recent studies have suggested that in addition to the usual 3 drugs that we use, a fourth drug can be added. One study in particular, the ALCYONE study, compared melphalan/bortezomib/prednisone alone versus the same 3 drugs with daratumumab. It showed distinct advantages in response rate, depth of response, and particularly MRD-negativity—which became part of the FDA label in the approval—and increased progression-free survival. This 4-drug cocktail is probably going to transform the way we think about treating myeloma. In the United States, melphalan will not be used. But the combination of 4 drugs—a proteasome inhibitor, an IMiD, a steroid, and a monoclonal antibody such as daratumumab—are likely to be highly effective.
There are other 4-drug combinations being explored. The combination of carfilzomib/lenalidomide/daratumumab and bortezomib/lenalidomide and elotuzumab, another monoclonal antibody, are now in clinical trials. We’re watching quite carefully to see if the addition of a 4-drug always improves outcomes, and particularly we are paying attention to whether it also increases toxicity. Most of these studies are still in the clinical trial phase, and we’re waiting for the results to become available.
There are also studies in which only 2 drugs, like lenalidomide/dexamethasone, are combined with daratumumab. One study called MAIA will be reported later this year in more elderly patients, who are probably not inclined to go to transplant, to see if that 3-drug cocktail is particularly effective.
Daratumumab, when combined with these other chemotherapy agents, is a highly effective drug. There are some limitations due to the convenience of employing the drug. It’s well tolerated. There is a high instance of infusion reactions with the first infusion, and as a consequence it is given very slowly. It can be a 7- or even 8-hour infusion on the first day, which can provide some difficulties for community practices in particular, keeping a single patient in the bed or in a chair for the entire day.
For this infusion, no inconvenience can be overcome. There are some studies now suggesting you can shorten the duration of infusion. There are some studies coming in which subcutaneous daratumumab is being employed instead of intravenous infusions. Beyond the initial first day of infusional reaction, it’s essentially a very well tolerated drug and quite easy for our patients to take. It is given once a week for the first 8 weeks, then once every 2 weeks for 16 weeks, and then once monthly. So, after the first 6 months of therapy, it’s really just a monthly infusion with very limited toxicity and a much shorter infusion time.
If we begin to use daratumumab in the frontline setting, we have to address what will happen at relapse. Is this a drug that we can use again like we do with rituximab in lymphoma? Or is it a drug that we would replace with a different monoclonal antibody, perhaps targeting a different surface marker such as BCMA? BCMA has become a very popular target in myeloma and there are already some monoclonal antibodies that are showing high efficacy in treating patients in relapse. So, 1 strategy would be to use daratumumab initially, even as part of maintenance therapy, and when the patient relapses, to switch to something targeting the BCMA cell surface marker.