Novel Combos Thrive in Myeloma, But Challenges Remain

James Weitzman, MD

The frontline and relapsed/refractory settings in multiple myeloma have dramatically shifted with the additions of monoclonal antibodies, proteasome inhibitors, and immunomodulatory drugs (IMiDs), but a number of treatment-related challenges remain, explained James Weitzman, MD.

“It's incredible how far we've come and how many agents we have that can treat [patients with myeloma],” said Weitzman. “It's amazing for our patients because we have so many options. We have a standard of care, which is great. Now, we're trying to stay ahead of the data and stay caught up with the guidelines.”

Following the approvals of several of these therapies, alone and in combination, Weitzman said other questions have come into the paradigm, specifically related to seeking out agents that are best to pair with one another, determining the optimal sequence of treatments, what the appropriate strategy is for patients who relapse, and defining options for those with penta-refractory disease, and others.

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Multiple Myeloma, Weitzman, a medical oncologist at Emerson Hospital and Waltham Cancer Center of Massachusetts General Cancer Center, discussed progress in the multiple myeloma treatment paradigm and what challenges remain.

OncLive: How would you define the state of multiple myeloma treatment?

Weitzman: Myeloma [treatment] has changed immensely. When I was in fellowship 12 years ago, there were 2 or 3 drugs [available for patients with myeloma]. We were still using melphalan upfront and a lot of steroids. Then, we started using thalidomide (Thalomid).

Since I graduated fellowship and have since been in practice, the field has added new IMiDs; we now have 3 of them. We're also using proteasome inhibitors and monoclonal antibodies, and [we continue to get] new [treatment] improvements.

What are some of the major advances in this space?

Some of the major advances have been in the frontline setting. Adding daratumumab, one of the new monoclonal antibodies, is really going to revolutionize myeloma. People are saying [it is similar to adding rituximab] to the lymphoma world. The addition of monoclonal antibodies is really going to change the way we treat patients.

What research that was presented at the 2019 ASH Annual Meeting do you find particularly exciting?

I'm getting excited about the upfront data, which is the best chance we have [at long-term remissions] when we first see a patient. [Research will show] whether we're going to use a different monoclonal antibody, a different proteasome inhibitor, and [what the optimal combination is] with all of these agents. That is the most exciting part to me.

How do you apply the information from clinical trials to your practice?

We need to stay a step ahead and give the patients the best treatments out there. What agents do we use in the frontline setting? How do we combine them? Upon relapse, do we treat patients immediately or do we wait for them to have symptomatic relapse? What agents do we use, and when can we reuse them? What agents combine with each other and have synergy? It is so challenging yet so exciting. We're all learning as we go along and finding ways to improve outcomes for all of our patients.

What are the biggest remaining challenges in myeloma?

The penta-refractory group is the most challenging. Penta-refractory patients have progressed on 2 IMiDs—usually lenalidomide (Revlimid) and pomalidomide (Pomalyst)—2 proteasome inhibitors—carfilzomib (Kyprolis) and bortezomib (Velcade)—and daratumumab (Darzalex). These patients have very few options. Do we go back and reuse some of the old drugs in different combinations? There are also some newer drugs that we are getting familiar with.

Are you seeing a lot of patients with penta-refractory disease?

Yes and, in a way, that's a good sign because it means these patients are living long enough to get through third-, fourth-, fifth-line therapies. With a lot of the laboratory tests we have, we are catching relapses earlier. We are able to switch [therapies] a little sooner before patients get symptomatic and become difficult to treat. We're finding ways to keep sequencing drugs and keep recycling drugs. More and more, we're seeing patients who are penta-refractory and are really hard to treat. That is a big unmet need in myeloma right now.

When treating patients with relapsed/refractory disease, have you been reusing drugs?

This is where the art of medicine comes in. You go back and, a lot of times, I'll graph out what regimens [the patient] has had in the past. I'll make a second chart where I graph out their light chains, immunoglobulin, or monoclonal spike, and find out if they were truly refractory to these [drugs] or if they were partially refractory.

I'll definitely reuse drugs. I try and use a drug that [the patient] is not refractory to. If they've been without [the drug] for 6 months, I'll reuse it and maybe combine it with a different agent because we know there is synergy. If this IMiD didn't work well with this proteasome inhibitor, perhaps the IMiD will work well with a monoclonal antibody. I use [drugs] in different ways because we have these agents and we're going to reuse them.

What ongoing research in multiple myeloma would you like to highlight?

We spoke a lot about frontline [myeloma treatment]. Using the lymphoma analogy, [ongoing research efforts are] taking the 4 best drugs and putting them upfront. In the second-line setting, we have some great agents available.

A lot of the research is focusing on these penta-refractory, multiple relapse patients who are still feeling good and are still in good health. How can we target their myeloma? That's where we'll get into the BCMA-directed therapies, such as CAR T-cell therapy, novel monoclonal antibodies, and new IMiDs. This field is going to keep exploding.

What advice do you have for community oncologists who are treating patients with multiple myeloma?

Get familiar with all these agents. There are so many studies out there. [Myeloma] has become such a subspecialty. Reach out to a colleague if you haven't used one of these drugs or if you haven't used a pair of agents together. There are so many different ways to give the drugs in terms of timing. You could give it as a weekly or twice-weekly regimen. Do you pair it with something? When do you reduce the dose? How do you reduce the dose? What adverse events are unique to each drug? It's important to utilize your colleagues, as well as experts in the community and at the big centers.