Safety and Efficacy of Daratumumab in Multiple Myeloma

Transcript:Shaji Kumar, MD: Daratumumab has been studied as a single agent in patients with relapsed and refractory myeloma, in two separate studies. A combined analysis of the studies was presented at the ASH meeting last year. The first study, which is called GEN501, looked at two different dose levels: 8 mg/kg and 16 mg/kg of daratumumab. And patients with relapsed/refractory myeloma were studied in that trial. The SIRIUS trial, which was recently published again, looked at two different doses and then proceeded to add additional patients at 16-mg/kg dose. Between the two trials, a total of 148 patients were studied at the 16-mg/kg dose.

Overall, the response rate was roughly about 31% in patients who have been heavily pretreated. And it’s very important to consider that over 90% of these patients have been treated with a proteasome inhibitor or an immunomodulatory drug. About 85% of these patients had seen both those drugs and were refractory to both those drugs. And nearly two-thirds of the patients were refractory to a proteasome inhibitor, an immunomodulatory drug, and an alkylator drug. So, this was a very heavily pretreated patient group that had seen a median of three prior lines of therapy. In this group of people, an [the] overall response rate was 30%.

Among the patients who had a response to therapy, a median duration of response was a little over seven months. So, what this data shows us is that this agent, by virtue of the fact that it’s working through a different mechanism, is able to overcome the drug resistance to commonly used classes of drugs. And these are the results which led to its approval in use in patients with relapsed/refractory disease. The median progression-free survival in this daratumumab 16-mg/kg combined analysis was roughly about a year, and the median overall survival for these patients was roughly about 19 months. These patients with relapsed disease did not really have a good chance of response. The patients who were responding also had prolonged response and significant improvement in their overall survival compared to what you would have expected for that group of patients.

An additional analysis that was performed also looked at the outcomes based on what degree of response these patients had. So, in the patients who had a complete response with therapy, the median progression-free survival and the overall survival was not reached. And the patients who had a partial response to therapy also had significantly better overall survival and PFS compared to the patients who did not respond or had lesser degrees of response.

Peter Voorhees, MD: The most common adverse events seen with daratumumab therapy are the infusion-related reactions. The infusion-related reactions with daratumumab appear to be somewhat unique. They almost manifest as a severe seasonal allergy—type of episode in some patients. They may start to have watery eyes, runny nose, nasal congestion, a tickle in the back of the throat—perhaps associated with a cough—and in some more severe cases, you may see wheezing and some shortness of breath. The reason why we think that may be the case is there are basophiles lining the nasopharyngeal passages and upper respiratory tree, which have CD38 on them. And degranulation of these things may mediate some of the effects that we’re seeing. The premedications with the Montelukast—as well as the corticosteroid, the acetaminophen, and the H1 blocker—do seem to help mitigate that.

If you do start to see some of these symptoms emerging in your patient, you need to stop the infusion and let things simmer back down to normal, and then restart the infusion at half the rate to prevent the adverse infusion-related reaction from getting worse. We will see infusion reactions in about 40% to 50% of patients that are treated with daratumumab. This is a dose one phenomenon. If you see it with the first dose, that does not translate into infusion-related reactions with dose two and beyond. They are very infrequently seen. And, at most, 3% of patients and even less with dose three and beyond.

As far as other side effects of daratumumab are concerned, you may see very modest effects on blood counts, modest leucopenia, very modest thrombocytopenia, but those things have been seen. In addition to that, daratumumab will bind to red blood cells, so red blood cells have CD38 at very low levels on their cell surface. You do not see hemolysis as a result of this engagement. However, with the indirect Coombs test, or indirect anti-globulin test, the screen of the type will turn positive when you start daratumumab therapy, and it will remain positive for 6 months after the last dose. This is not necessarily an adverse event as much as it is a logistical issue.

So, typically, what we’ll make sure that we do is get a type and screen before patients start daratumumab therapy. We also get a red blood cell phenotype. This will allow us to make it easier to transfuse these patients once they start daratumumab and their screens become positive. In addition to that, we have our patients carry a card in their wallets basically explaining that they are on daratumumab, and it also lists what their blood type is in case they have to get transfused at a center that may be less familiar with the effects of daratumumab on transfusions.

Transcript Edited for Clarity