Monoclonal Antibody Therapy in Myeloma

Transcript:Shaji Kumar, MD: Immunotherapeutic approaches have really come to fruition in myeloma in the past couple of years with the introduction of two monoclonal antibodies, both of which have been approved by FDA in the past year for treatment of multiple myeloma. Elotuzumab is a monoclonal antibody that is directed against SLAMF7, a protein on myeloma cells. Currently, elotuzumab is approved for treatment of multiple myeloma patients who have had at least 1 to 3 prior therapies and have relapsed after the last treatment. It is approved in combination with lenalidomide and dexamethasone, and this is based on the results of a phase III trial, which looked at the combination of elotuzumab, lenalidomide, and dexamethasone, comparing it to lenalidomide and dexamethasone in patients with relapsed myeloma. And that trial showed that there’s a significant improvement in progression-free survival by using elotuzumab, leading to its approval in that particular group of patients.

Daratumumab is the second monoclonal antibody that has gone through clinical trials and has recently been approved. In contrast with elotuzumab, this targets a different protein called, CD38, on the multiple myeloma cells. Daratumumab has been approved on the basis of a single-arm trial, unlike elotuzumab, which was approved on the basis of a randomized phase III trial. Daratumumab is currently approved for treatment of multiple myeloma that has progressed after 3 prior lines of therapy, or multiple myeloma that is refractory to both a proteasome inhibitor and an immunomodulatory drug. Daratumumab is approved as a single agent for use in multiple myeloma, in contrast with elotuzumab which is approved in combination with lenalidomide and dexamethasone.

Patients with multiple myeloma go through a variety of different treatments over their disease course. Now, one of the things that has dramatically changed the outcome of patients with myeloma, in the past decade, has been the introduction of proteasome inhibitors, the first one of which was, bortezomib, and immunomodulatory drugs, the first one which was, thalidomide, and then lenalidomide, and most recently, pomalidomide. Now, these are probably the two most effective classes of drugs that we have in multiple myeloma today. And one of the most common initial treatments of multiple myeloma is to use a combination of a proteasome inhibitor and an immunomodulatory drug.

Once patients become refractory to both these classes of drugs, or a drug from each of those classes, the outcome of patients from that time point tends to be relatively poor. In fact, there was a study that was done looking at a large group of patients from multiple countries, where we looked at what the survival of patients is after they become refractory to one drug from each of those classes. And it seemed like the progression-free survival was roughly about 5 months, and overall survival was about 9 months from the time patients became refractory to both those classes of drugs. Now, clearly this data is about 7 to 8 years old, and the outcome of patients has since improved because of the introduction of new therapies.

So, patients who are double-refractory to both, a proteasome inhibitor and an immunomodulatory drug, tend to have poor outcomes. These patients really need new therapies that belong to a different class of drugs in order for us to be able to bring the myeloma under control again.

Peter Voorhees, MD: A cycle of daratumumab monotherapy is 4-weeks long, and for the first 2 cycles, the daratumumab is administered once weekly. For cycles 3 through 6, the antibody is administered once every 2 weeks on days 1 and 15. For cycle number 7, it’s administered on day 1 once every 4 weeks. The dose of daratumumab is 16 mg/kg. Elotuzumab is administered in combination with lenalidomide and dexamethasone. Again, the cycle is 4-weeks long. Lenalidomide is administered on days 1 through 21 of the cycle. The dexamethasone is given on a once weekly basis. Elotuzumab is administered at 10 mg/kg IV once weekly for the first 2 cycles and then it’s administered once every 2 weeks for cycles 3 and beyond. And, just like with daratumumab, treatment is until disease progression.

There is a real risk of infusion-related reactions, particularly with daratumumab. In the initial studies, the rates of infusion-related reactions were on the order of 40% to 50%. Because of this, premedications are certainly required. With regards to daratumumab, patients are treated with diphenhydramine, or Benadryl. They receive a dose of acetaminophen, or Tylenol, as well as a dose of dexamethasone, or other corticosteroid-equivalent, prior to each dose of therapy. As it turns out, it appears as though activation of basophiles in the nasopharyngeal tract and upper respiratory tract may be responsible for some of the unique infusion reactions that you see with daratumumab. And there’s increasing anecdotal evidence to suggest that a dose of montelukast, or, Singulair, administered the day before the first infusion and the day of the first infusion, can mitigate some of the infusion-related reactions that we do see with daratumumab, making it easier to administer on a single day.

The rates of infusion-related reactions with elotuzumab are far less than that of daratumumab, approximately 10%. In both cases, the infusion-related reactions typically are grade 1 or 2 in severity. Grade 3 is very rare. Grades 4 and 5 typically are never seen. And the other important thing to recognize is that the infusion-related reactions are really a first-dose phenomenon. You very rarely will see an infusion reaction with the second dose, and beyond. As far as premedications for elotuzumab, typically patients are pretreated with a dose of corticosteroid. So a dose of dexamethasone of 28 mg is given 3 to 24 hours prior to administration of elotuzumab. An additional 8 mg dose of IV dexamethasone was administered within 30 to 60 minutes of the elotuzumab. They also received acetaminophen/Tylenol. They got an H1 blocker such as diphenhydramine or Benadryl, as well as an H2 blocker like ranitidine, for example.

Transcript Edited for Clarity