Optimal Combinations, Sequences Being Explored in Multiple Myeloma

For patients with multiple myeloma, there are a variety of agents now available that are being investigated in different approaches or sequences, according to Adam Waxman, MD.

A key class of agents with which researchers are aiming to improve patient outcomes, said Waxman, are second-generation proteasome inhibitors, including carfilzomib (Kyprolis) and ixazomib (Ninlaro). Additionally, monoclonal antibodies, such as daratumumab (Darzalex) and elotuzumab (Empliciti), are being explored as part of 4-drug regimens.

“With these emerging therapies, we have personalized treatments,” said Waxman. “We are never going to find a specific best treatment for everyone as it is a personalized disease. We need to look further at different combinations, sequencing, and new therapies.”

OncLive: Please provide an overview of your lecture.

In an interview during the 2017 OncLive^® State of the Science Summit on Hematologic Malignancies^TM, Waxman, internist at the University of Pennsylvania, discussed emerging regimens for patients with multiple myeloma.Waxman: We discussed early relapse therapies, the many new treatments, and important randomized phase III trials for patients with multiple myeloma. We focused on second- generation proteasome inhibitors, such as carfilzomib and ixazomib, as well as the monoclonal antibodies elotuzumab and daratumumab. We looked at the randomized data for patients who are receiving somewhere between their first- and third-line of therapy after initial therapy.

We are attempting to investigate these different trials to make sense of how to better select different therapies during different times of treatment. There are 7 or 8 different randomized trials primarily using the same 2 control arms of bortezomib (Velcade)/dexamethasone and lenalidomide (Revlimid)/dexamethasone.

What are some factors to consider when sequencing therapies for patients who relapse?

[With] triplets versus doublets in therapy for multiple myeloma, we are finding that we tend to see higher progression-free survival rates, and, in some cases, [improved] overall survival when patients are in their early relapse. Of course, with important attention being placed on different drug toxicities, it is important to be careful when selecting patients who will receive triplet therapy.This is part of the art of treating this disease because there are no multistage randomized trials where a patient is randomized to different sequences.

We are trying to figure this out by looking primarily at patient level factors. Most importantly, what were their responses to previous therapies and what treatments were the patients on at time of relapse? This is important because we have additional evidence on maintenance therapy. Many patients are going to have their first relapse while they are actively receiving maintenance bortezomib or lenalidomide. We know that giving the same drug is not going to be as effective as switching to something else to get longer responses.

It is important think about the toxicity profiles. A patient who already has peripheral neuropathy should not receive a bortezomib- or ixazomib-based regimen. There are more toxicities, such as hematological toxicities, in the daratumumab combinations than we see in either of the drugs alone. This is an individualization and personalization of the care we are giving to patients, as well as an increase of convenience of the regimen.

Ixazomib is convenient for patients because they do not have to come into the office every week [to receive treatment]. Other drugs, such as carfilzomib, require patients to come in twice a week and a daratumumab infusion could be 4 to 8 hours long.

Subcutaneous therapy is being explored in myeloma. Is daratumumab being looked at in this method?

What ongoing trials in the field are you looking forward to seeing the results of?

It is important to understand these personal characteristics. Has the patient received prior therapies? There is also emerging information discussing what molecular findings may help us to predict some of these responses. It is difficult to use these in patients who we are seeing in the clinic to make those decisions, but, hopefully, we will have more molecular markers in the future. Yes. We are now developing subcutaneous daratumumab, which would change the convenience issue, since this is only a 30-minute injection with fewer toxicities. It is a very exciting drug to have in the clinic.Multiple myeloma is an area where we are having emerging therapies and important clinical trials. With new exciting drugs, including immunoconjugates, we are working in the earlier disease course to redefine therapy.

Is chimeric antigen receptor (CAR) T-cell therapy being looked at for patients who have early relapse?

We have 2 randomized trials that are currently investigating the use of carfilzomib in the initial setting. Recently, at the 2017 ASCO Annual Meeting, there were early phase Ib data on quadruplet therapy in upfront myeloma. Further studies are investigating combinations where we have found that 3-drug regimens are better than 2-drug regimens. We are also investigating if 4 drugs are better than 3 drugs, which are exciting studies for the earlier management of the disease.Primarily in the studies being conducted at the University of Pennsylvania, we are working on patients who have received multiple lines of therapy before using CAR T-cell therapy. It could be used earlier as we have emerging information on the safety and efficacy. The idea of moving them earlier in therapy is going to be an important question to be answered.