Frontline Options Evolving in Newly Diagnosed Myeloma

Bita Fakhri, MD, MPH

The field of newly diagnosed multiple myeloma has evolved to demonstrate that triplet regimens are better than doublets; however, more data are required before quadruplets become the standard of care, according to Bita Fakhri, MD, MPH.

Within the current landscape, the challenge is deciding which combination of agents is most effective yet also tolerable as induction therapy.

In May 2018, the FDA approved frontline daratumumab (Darzalex) in combination with bortezomib (Velcade), melphalan, and prednisone (VMP) for the treatment of patients with newly diagnosed disease who are ineligible for stem cell transplant. The decision was based on phase III findings from the ALCYONE study.

In the trial, daratumumab plus VMP was associated with a 50% reduction in the risk of progression or death compared with VMP alone. However, despite these statistically significant results, US hematologists have shown skepticism toward the 4-drug regimen because VMP is mostly utilized in Europe.

However, in the United States, bortezomib, lenalidomide (Revlimid), and dexamethasone (VRd) is a commonly used regimen. Early data with carfilzomib (Kyprolis), moreover, has demonstrated a potential opportunity to replace bortezomib as the go-to proteasome inhibitor in this combination based on phase II data.

Fakhri, a professor of medicine in the Division of Hematology/Oncology at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, said disease and patient characteristics can be used to determine the optimal regimen.

OncLive: Please provide an overview of your presentation.

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Fakhri shared her insight on the treatment of patients with newly diagnosed multiple myeloma.Fakhri: My presentation focused on frontline treatment options for patients with newly diagnosed multiple myeloma. I tried to provide an overview on what has been used historically in multiple myeloma, and how the field has evolved over the last few years. Doublet regimens have become triplet regimens. VRd, which is a combination of lenalidomide, bortezomib, and dexamethasone, is a very common regimen in the United States.

Please discuss the use of carfilzomib in the induction setting.

Based on disease characteristics and patient characteristics, we can definitely come up with different regimens. Another accepted triplet is KRd, which is carfilzomib with lenalidomide and dexamethasone. This is preferred in the high-risk population. After that, I spoke about data from the past year, moving into quadruplet therapy. It is not commonly used yet, but there is one 4-drug regimen that is FDA approved. Currently, we use 2 factors to pick a regimen for a patient: transplant eligibility versus ineligibility and disease characteristics in terms of genomics. In transplant-ineligible patients, the use of KRd is not universally endorsed. There is the risk of pulmonary toxicity. At the same time, we have really good phase II data, particularly in the relapsed/refractory space. There was a trial looking at carfilzomib, lenalidomide, and dexamethasone. It showed prominent improvement in progression-free and overall survival for patients with relapsed/refractory multiple myeloma.

There is a frontline approval for VMP and daratumumab. While this might not have a significant impact in the United States, how does this open the door for future trials with daratumumab?

Based on the data in this setting, it makes perfect sense to choose KRd as induction therapy for relapsed patients. One other thing that is extremely important is the toxicity profile. Bortezomib is known for causing debilitating neuropathy, so if you have a patient who already has bad neuropathy, you would want to avoid that drug.There was a recent study looking at daratumumab plus VMP versus VMP alone. The study had outstanding results, meeting all of its efficacy endpoints. The PFS at about 16 months was significantly better in the daratumumab with VMP group. The objective response rate (ORR) was also much higher.

Did you address any other frontline regimens?

What is the biggest takeaway?

VMP is a very European regimen and is not often utilized by American physicians. However, there is an old notion that elderly and frail patients cannot tolerate combination therapy, and we're seeing that isn't true. Not only did they benefit, but it seemed to very tolerable. The toxicity profiles were similar compared with the younger population. There were 2 other abstracts I wanted to mention. One of them was a phase I daratumumab and KRd trial, which showed very good ORR. It was difficult to draw any real conclusion from it, though, because it was [a small study of] only 21 patients. We'll wait for the data to mature. There was another abstract with elotuzumab (Empliciti) and KRd in the upfront setting. The ORR was high, but so was the toxicity. Triplet regimens remain as the standard of care. The field still needs to answer the question of what the right induction therapy should be for each patient population. The 4-drug regimen results are very interesting, but we need to learn more. I don't use them outside of clinical trials. I'm curious to see how the field moves on.