Recently, the FDA approved a new treatment for multiple myeloma previously treated with one to three lines of therapy: daratumumab (Darzalex®, Janssen) in combination with carfilzomib and dexamethasone. In this interview, Meletios Dimopoulos, MD, principal investigator of the phase 3 CANDOR trial, which served as the basis for the approval, speaks with i3 Health regarding the benefits and adverse events of this new therapeutic combination, as well as additional advances in the treatment of relapsed/refractory myeloma.
How does daratumumab/carfilzomib/dexamethasone (DKd) compare with other options for relapsed or refractory multiple myeloma?
Meletios A. Dimopoulos, MD: Well, the major concern today in patients with relapsed myeloma, especially after one line of therapy, is that there is an increasing number of patients with myeloma who receive lenalidomide as maintenance or continuous treatment, so we try to develop regimens that may be effective in this subset of patients. So far, the regimens that we have are associated with a median progression-free survival ranging from 10 months to 14 months. With the CANDOR trial, which evaluated and compared the triplet therapy of daratumumab, carfilzomib, and dexamethasone versus carfilzomib and dexamethasone, we saw that the progression-free survival overall was significantly increased in favor of the triplet, and this improvement was even more pronounced in patients who were progressing on lenalidomide. So this is one area where DKd is associated with a significant improvement, with a progression-free survival that is expected to exceed 20 months. If you compare with other studies––which of course we don't want to do, but sometimes we need to see it that way––there is a significant improvement in the outcome of patients who progress on lenalidomide, so I believe this is one of the strengths of this study. The other is that we have now a new combination that could be given to patients who progress on lenalidomide or other drugs and who need an effective salvage regimen.
What adverse events are of particular concern with this regimen, and how are they best managed?
Dr. Dimopoulos: We know that when we administer carfilzomib, we have a small percentage of patients who may develop cardiovascular side effects, meaning hypertension, and less often, in some patients, a decrease of the left ventricular ejection fraction, a form of reversible cardiomyopathy. Also, some patients may develop an increase in creatinine. On the other hand, we know that whenever we add the daratumumab to a regimen, these patients are at high risk for developing neutropenia and infections. So the major concerns, despite the fact that they occur in the minority of patients, are the cardiovascular toxicity and the infections. Of course, as we get more familiar with the use of a regimen, we learn how to best mitigate these complications, for example, by using antibiotic prophylaxis, by being more alert for the possibility of an infection, and also by trying to adjust the dose if we see any sign of cardiovascular toxicity.
Which of the latest research advances looks the most promising in the treatment of relapsed/refractory multiple myeloma?
Dr. Dimopoulos: There are several drugs and combinations that have been approved for the treatment of myeloma in the last few years, particularly in the relapsed/refractory setting. The combination of DKd is one of them. On the other hand, we have now the possibility of using other immunological therapies. We now have an anti-BCMA antibody-drug conjugate, belantamab mafodotin, which has been approved for the treatment of myeloma. We have the bispecific T-cell engager treatments (BiTEs) that also are active in myeloma, and also the immunologic approach with the use of chimeric antigen receptor (CAR) T cells; several different companies have their own products. In addition, there is the potential role of selinexor, an oral antimyeloma drug that has a unique mechanism of action and can be active in some patients who have failed multiple other regimens.
What advice can you offer to hematologist-oncologists and other members of the cancer care team as they treat patients with relapsed/refractory multiple myeloma?
Dr. Dimopoulos: Today, we have multiple combinations that can be effective in the second line, the third line, and also beyond, so there is a real positive prospect for the treatment of myeloma that we have today, with many more treatment options than we used to have even three or four years ago. We expect that this will improve the overall survival of myeloma patients and that some of these treatment options or drugs may be used earlier in the course of the disease, as we have seen with the case of daratumumab: it was first established in far advanced disease, then subsequently in combination with other agents early in the course of the disease, and now we have evidence from clinical trials that adding daratumumab to the front-line combinations can improve progression-free survival and overall survival, both in younger and also in older patients with myeloma.
About Dr. Dimopoulos
Meletios A. Dimopoulos, MD, is a Professor of Hematology/Medical Oncology and Chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine in Athens, Greece. He is also Chairman of the Greek Myeloma Study Group and the Balkan Myeloma Study Group. Dr. Dimopoulos specializes in the treatment of hematologic malignancies, with particular expertise in multiple myeloma and other plasma cell dyscrasias. He serves on the scientific advisory boards of the International Myeloma Foundation, the International Waldenstrom's Macroglobulinemia Foundation, and the Multiple Myeloma Research Foundation. He is also an Associate Editor of Current Hematologic Malignancy Reports and is an editorial board member or reviewer of several other journals, including The New England Journal of Medicine, the Journal of Clinical Oncology, Blood, and Leukemia and Lymphoma. Dr. Dimopoulos has authored over 1,000 publications in peer-reviewed journals.
For More Information
Dimopoulos M, Quach H, Mateos MV, et al (2020). Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet, 396(10245):186-197. DOI:10.1016/S0140-6736(20)30734-0
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.