Shaji Kumar, MD, discusses ixazomib, daratumumab triplets, denosumab, and CAR T-cell therapy in multiple myeloma.
Shaji Kumar, MD
In the last few months, the FDA has approved a third daratumumab (Darzalex) triplet for multiple myeloma, and accepted a supplemental biologics license application for denosumab (Xgeva) for the prevention of skeletal-related events in patients with multiple myeloma. In July, Amgen announced it submitted supplemental New Drug Applications in the United States and Europe, based on data from 2 phase III studies showing carfilzomib (Kyprolis) improves overall survival (OS) for patients with relapsed/refractory multiple myeloma.
These developments come on the heels of a novel study which recently opened at Memorial Sloan Kettering Cancer Center exploring emerging chimeric antigen receptor (CAR) T-cell therapies that target B-cell Maturation Antigen (BCMA).
Additionally, investigators are currently evaluating ixazomib (Ninlaro)the first oral proteasome inhibitor introduced in the clinical setting — in patients with newly diagnosed multiple myeloma, which may provide an entirely oral option in the treatment landscape.
In an interview withTargeted Oncology,Shaji Kumar, MD, professor of Medicine, Mayo Clinic, discussed ixazomib, daratumumab triplets, denosumab, and CAR T-cell therapy in multiple myeloma.
TARGETED ONCOLOGY:Please provide an overview of your study of ixazomib, lenalidomide, and dexamethasone.
Kumar:The combination of a proteasome inhibitor and an immunomodulatory drug remains the current standard for the initial therapy of multiple myeloma. The combination of bortezomib (Velcade) and lenalidomide (Revlimid) has shown improved OS and has become the most commonly used treatment in the United States, and its use is increasing around the world.
Ixazomib is the first oral proteasome inhibitor introduced in the clinic and is currently approved for use in relapse myeloma in combination with lenalidomide and dexamethasone. Given the results we have seen with the bortezomib/lenalidomide/dexamethasone combination, this ixazomib/lenalidomide/dexamethasone combination was studied in the newly diagnosed setting as well. It gives the opportunity to use a completely oral initial therapy in myeloma.
The initial phase I/II study that was done enrolled 66 patients, the early part of which included dose-escalation of the ixazomib in combination with standard doses of lenalidomide and dexamethasone. The study results were originally published almost 2 years ago, and that had immediate follow-up of 14 months. It showed the regimen to be quite effective and also well tolerated.
The current analysis actually focuses on the long-term outcomes with a median follow-up of 55 months. It enrolls 42 patients out of the 66 who did not go to a stem cell transplant but continued on therapy with ixazomib. Out of the 42, there were 25 patients who got ixazomib maintenance as a single agent after the 12 months of induction therapy.
TARGETED ONCOLOGY:What were the findings?
Kumar:Overall, what we found was that amongst these 42 patients, the response rate was about 80%, including about 63% of the patients with a very good partial response or better. The toxicity was very well managed, and in the maintenance portion, there were hardly any new toxicities that we encounteredprimarily hematologic-like anemia. There were no cumulative hematological toxicities with long-term ixazomib maintenance, and there was a deepening of response with about 8 of the 25 patients going from a very good partial response to a complete response.
The triplet regimen appears to be quite effective initial therapy for patients with newly diagnosed myeloma. It offers the ability to use a completely oral therapy and also appears to be quite effective with manageable toxicity. Most importantly, the patients can continue on maintenance therapy with ixazomib long-term without any additional toxicity, while at the same time improving the efficacy.
TARGETED ONCOLOGY:What would you like community oncologists to take away from these findings?
Kumar:The field of myeloma is moving forward. We are getting more and more exciting initial therapy regimens for treating newly-diagnosed myeloma. This is the first one that is completely oral. So, the question for the myeloma field moving forward is how do we keep making the initial therapy even better? One of the options is to change each of the class of drugs to something that is more efficacious. The other option is to add new drugs to these triplet regimens.
TARGETED ONCOLOGY:The FDA recently approved the third daratumumab triplet for multiple myeloma, what impact do you think this will have?
Kumar:I think it is important for the field. The initial registration study was daratumumab with lenalidomide or with bortezomib. The problem is that the vast majority that relapse after the initial therapy often tend to be on one of these drugs for maintenance, the bortezomib or lenalidomide. Those are the kind of patients that are not included in the original registration study. The daratumumab/pomalidomide (Pomalyst)/dexamethasone combination gives us the opportunity to use the new triplet with 2 drugs which the patients have never seen before.
TARGETED ONCOLOGY:How do you see the field moving forward in the next 5 to 10 years?
Kumar:Four-drug combinations are currently being evaluateddaratumumab is an exciting new drug, one of the first monoclonal antibodies to be introduced for the treatment of myeloma. Based on the initial results, there is a phase III trial that looks at daratumumab/lenalidomide/dexamethasone that has completed accrual and we are waiting on the results of that. It could be another triplet where the proteasome inhibitor has been replaced with a monoclonal antibody. The other option is to add daratumumab—or elotuzumab (Empliciti), the other monoclonal antibody—to the triplet. Carfilzomib /lenalidomide/dexamethasone has been studied in combination with daratumumab. Elotuzumab has been combined with bortezomib lenalidomide and dexamethasone. Daratumumab is currently being studied in combination with ixazomib/lenalidomide/dexamethasone. And there others who are looking at adding cyclophosphamides to carfilzomib/lenalidomide/dexamethasone.
Essentially, the question is can we develop a quadruplet4 drugs from 4 different classes—that can potentially give us fast and deep responses and deep enough that we could potentially treat patients for a defined duration then stop therapy. I think that is where the field is headed.
TARGETED ONCOLOGY:What could be the potential impact of denosumab if approved?
Kumar:That I think remains to be seen. I think there are some important questions. The primary message from that phase III study is that denosumab is effective. It is as effective as zoledronic acid, which is what is currently being used. The question comes from the fact that we know, currently, that zoledronic acid does not necessarily need to be used on a monthly basis. Using reduced doses of zoledronic acid less frequently can also give excellent results.
The original studies that looked at the role of these phosphonates were in the context of treatments that were less effective than what we use today. With the very effective regimens that we have we can get the myeloma under control fast, the role of the phosphonates, or bone protective agents, I am predicting will be less important. Though, it will still be an important part, just less important than what we have though about it in past.
Then there is the question about price. If denosumab is as efficacious as zoledronic acid, would we be using something that is more expensive if we choose denosumab? For us to use that, there has to be some distinct advantages. One possibility is that the denosumab can be safely used in patients with renal failure or renal dysfunction. That is a place where denosumab has a clear advantage over the standard of care. The other question that we are trying to answer from the clinical trial is if using denosumab in patients with baseline renal insufficiency prevents any deterioration of the renal function compare to zoledronic acid which is fairly common in multiple myeloma.
More importantly, the denosumab trial showed an improvement in progression-free survival (PFS), even though the difference wasn’t as impressive in the subsequent analysis as it was in the primary analysis.
I think we would like to see some longer-term resultsboth in terms of the ability to prevent renal function deterioration as well as PFS—before I think it will get universally used instead of zoledronic acid.
TARGETED ONCOLOGY:Is there anything else happening in the space that is particularly exciting?
Kumar:I think a lot of interesting data is being presented. One of the most exciting is with CAR T cells. We saw some very impressive results in patients who have had a lot of prior therapies. Nearly all patients who had received the effective dose of the CAR T cells had a response, and a significant number of them had a complete response. Some of these responses have been durable, too, lasting a year beyond initial therapy. Obviously, it is a small proportion of patients that are selected for this particular study, but we want to see how generalizable this modality is. I think this provides a very convincing proof of principle, that CAR T cell-based approaches can be effective in myeloma. Now, we just need to find the antigens to go after, and what particular patients would benefit.
One other area of interest in the field right now is that of minimal residual disease (MRD) testing. A lot of the studies currently ongoing and being planned include MRD testing, either as a way of defining if we need to make therapy changes, or just comparing 2 different therapies as a surrogate endpoint instead of waiting for the PFS or the OS results to read out. We will probably see this in the next year or 2, being an integral part of myeloma care.