Plethora of Novel Agents Transforming Outcomes in Multiple Myeloma

Rachid Baz, MD

Novel combination regimens that include daratumumab (Darzalex), the anti-CD38 monoclonal antibody, are on the rise and producing significantly improved outcomes for patients with multiple myeloma, although therapeutic sequencing challenge exists.

Findings of an open-label, phase Ib study presented at the 2017 ASCO Annual Meeting demonstrated that the addition of daratumumab to carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) in patients newly diagnosed with multiple myeloma was well tolerated and had durable responses as a frontline regimen. Treatment with daratumumab plus KRd yielded an overall response rate (ORR) of 100% in 21 response-evaluable patients; the 6-month progression-free survival rate also was 100%.

OncLive: What was the basis of your discussion on multiple myeloma?

How do you treat these 2 patient groups differently?

Rachid Baz, MD, associate member, head of the Myeloma Section at Moffitt Cancer Center, gave his presentation “Too Many Cooks in the Kitchen” with regard to the abundance of available therapies for patients with multiple myeloma during the 2017 OncLive^® State of the Science Summit™ on Hematologic Malignancies. In an interview, he spoke to the change in risk factors for select treatments, the impact of daratumumab, and the current sequencing questions among the field. Baz: Over the past few years, we have had a lot of new treatment options for patients with myeloma—certainly, those with newly diagnosed disease. I divided the talk into approaches for patients who are elderly or frail versus patients who are younger or fit. Traditionally, we separated patients based on their eligibility for stem cell transplant, although, we now rely more on frailty than age. Historically, we used to avoid alkylating agents, like melphalan, for patients who are eligible for transplant because of concern over difficulty mobilizing stem cells. You consider the elderly patients’ therapy to be traditionally melphalan-based. Now there is considerable evidence that melphalan is not a required treatment for the elderly and frail patients either.

But the most important determinant of outcomes in patients who are elderly and frail turns out to be fitness or frailty indicators [versus age]. For those patients who are considered to be frail, a doublet, such as dose-adjusted lenalidomide/dexamethasone, or a weekly SC bortezomib (Velcade)/dexamethasone approach would be very reasonable. For a patient who is of intermediate fitness, a bortezomib/ lenalidomide/dexamethasone (VRd) regimen would be appropriate.

We have seen a lot of promise with daratumumab for patients with multiple myeloma. What does the future hold for it?

For the young and fit patients, typically the standard of care is bortezomib/dexamethasone/lenalidomide. Some of the emerging trials that are coming up are challenging that data for the future, so [we are] looking at the combination of carfilzomib/lenalidomide and incorporating a monoclonal antibody into upfront treatment. It is an exciting time definitely for patients with myeloma. We have more effective therapies and less toxic therapies, too. The key thing is to look at the data in patients with advanced myeloma. Daratumumab, as a single agent, has 30% activity, considerable activity. It has very little toxicity, and importantly, the toxicity is not overlapping with some of the other existing myeloma therapies. When we got to the triplet of bortezomib/lenalidomide/dexamethasone up front for young and fit patients, a quadruplet was too toxic if you added traditional or conventional therapies. However, when you get to monoclonal antibodies being added, it has the potential to make a big difference without adding too much toxicity. There are ongoing studies looking at daratumumab in addition to VRd.

What other exciting studies can we expect to read out this year?

There are also studies looking at the addition of daratumumab to lenalidomide/dexamethasone up front comparing that to lenalidomide/dexamethasone alone. Even for patients who are considered to be frail, incorporating daratumumab is not likely to add meaningful toxicity; it may have quite a beneficial effect on controlling myeloma. One of them is a comparison of carfilzomib, cyclophosphamide, and dexamethasone (KCd) versus KRd. If you think about the ENDEAVOR study in myeloma—comparing carfilzomib to bortezomib in the relapsed setting—carfilzomib turns out to be more efficacious with less neurotoxicity. It kind of makes sense to incorporate that in the upfront setting. Comparing KCd to KRd would be the new wave. That would be quite a bit interesting.

There are a couple of studies looking at the addition of elotuzumab (Empliciti) to the VRd backbone; that is interesting, too.

Anecdotally, how have you seen daratumumab impact quality of life or patient outcomes?

Are there any clear answers with sequencing therapies yet?

What are the pivotal messages from your lecture for community oncologists?

There is an intergroup study comparing KRd to VRd, which should hopefully establish that maybe KRd would be the standard of care. This is because KRd is not neurotoxic; it is at least as good, if not better. That type of treatment may likely be introduced in the upfront setting pretty soon. It has made a tremendous difference. Initially, it was approved as a single agent and we were already using it. But in combination, the POLLUX and CASTOR data are perhaps not typically what I currently use in practice. I am more likely to do a combination with pomalidomide (Pomalyst) and daratumumab; some say that data have shown that this is a considerably efficacious regimen. We have had a lot of patients with very aggressive disease refractory to other therapy and salvage them with this kind of regimen, with very impressive responses. [Daratumumab has] certainly made a big difference for patients’ lives. I don’t think we have a problem with “too many cooks in the kitchen.” The reality is, this is one of those situations where it is not a problem—it’s a good thing to have and it’s good for patients. Where we need more guidance is where each agent fits in the sequence and sequencing, but perhaps studies will guide us [to those answers] in the future. Overall, having more active agents for patients is a good thing, considering those therapies don’t cure patients. Having more available therapies makes them live longer, better, and healthier. The key thing is that there’s a lot to consider for almost any instance in myeloma. There are still a lot of very good unanswered questions. Even though upfront treatment is quite good, we can do quite better, as a community, for our patients. This is definitely the number-one thing to consider.

The second part is to look at frailty, instead of age, as a main determinant of when I use VRd or lenalidomide/dexamethasone and who the patient who can undergo transplant is. Fortunately, we have a very good relationship with community doctors in the area and they have good access to us, so we can communicate better and try to educate when we have a new trial and so forth.