Multiple Myeloma: Treatment Options for First Relapse

Nina Shah, MD: Ola, can you briefly outline the available treatment options line by line for patients who are in their first relapse, especially looking at patients who are lenalidomide naїve or sensitive vs refractory and then those who are lenalidomide and bortezomib refractory? What are the available treatment options?

Ola Landgren, MD, PhD: I recently looked at the NCCN [National Comprehensive Cancer Network] Guidelines. When I counted last time, there were 40 or 41 different combinations, so I’m not going to go through the whole list. But if you think about patients who are naїve or sensitive to lenalidomide, there are probably quite few in the United States these days because we often use IMiDs [immunomodulatory imide drugs] up front and lenalidomide maintenance either alone or in combination with others.

But if a patient has been treated with an IMiD and for some reason the therapy has been stopped, you could still see a patient who’s at least probably going to be sensitive. It’s probably not called naїve because you gave it in the past. In such a patient, I’d consider using a combination with Revlimid. It’s interesting to look at a lot of the registrational trials done a couple of years ago. They usually had lenalidomide as part of the backbone, and most of these studies were done outside the United States. We all see that same thing.

When it comes to patients who are refractory based on the definition of the International Myeloma Working Group, if a patient is nonresponsive on therapy or within 60 days has a rise in the markers, we’ll call that refractory. But of course, when we start looking at the details, if you have a patient on a lower dose of a drug and that phenomenon happens, does that mean that patient is truly refractory? What if you had given a higher dose? All clinicians and experts know that’s not exactly the same thing. But the definitions by the international guidelines are set the way they are.

It makes sense to switch to another drug. But if you look at how drugs have been developed and approved by the FDA, pomalidomide was approved as a line after lenalidomide, so it’s an IMiD going to another IMiD. But then we have all these other classes of drugs. We already touched on that. You can use a CD38-targeted antibody, for example, with carfilzomib. You have the option of going to another IMiD, such as pomalidomide, in combination with other drugs, or you could go IMiD-free if you want. Whatever you pick, you’ll probably go back to the other approach later. It’s almost like going through the whole alphabet. It’s a matter of what order you will sort your letters.

Nina Shah, MD: We often talk about the alphabet soup of myeloma options. Sagar, Ola brought up that there are a lot of options. There are a lot of factors in the patient options. It’s not just the treatment options. What factors do you take into consideration when you’re choosing that first relapse therapy? There’s frailty, comorbidities, risk assessment, what they’ve had before, prior therapies, lifestyle, and quality of life. What factors are important to you when you choose a regimen for that first relapse?

Sagar Lonial, MD, FACP: There are some that can have an influence on that. Obviously, performance status is 1 of the bigger ones. The tempo of relapse, as Josh brought up earlier, is an important one to take into consideration. To me, one of the most important is how long their previous remission was.

We just presented data at ASH [American Society of Hematology Annual Meeting]. Our standard had been daratumumab-pomalidomide for all first relapse, and if you look at patients who relapsed within 2 years of diagnosis, they seem to gain less benefit from daratumumab-pomalidomide than those who relapsed after 2 years from diagnosis. That’s now a discriminator. We don’t know that using something different will be better, but we know that what we have with available therapy isn’t as good as we want. We want it to be better. Some patients want to take pills and not see us as often. Others live far away. Co-pays play into that. Those are all variables that we take into account. As Ola suggested, the advantage is that in first relapse, you have a long laundry list of options. When you get to second and third relapse, that list becomes a little more narrow, so the choice of flexibility becomes a little less.

Nina Shah, MD: If you were going to choose between a bortezomib-dexamethasone or carfilzomib-dexamethasone backbone, how do you make that decision? Because the combination is the question that a lot of us have.

Sagar Lonial, MD, FACP: In first relapse, we tend to go with carfilzomib as part of the backbone if that’s what we’re going to do. In myeloma we have 3 backbones. It’s like Alien. We have an IMiD, we have a PI [proteasome inhibitor], and we have an anti-CD38. In first relapse, if they’re not CD38 exposed, as Josh said earlier, that becomes the primary backbone. Then it’s a matter of whether you’re adding an IMiD or a PI to it.

Nina Shah, MD: There are a lot of interesting things talking about bortezomib vs carfilzomib, because a lot of people will have had their VRd [bortezomib, lenalidomide, dexamethasone], gone to transplant, and not see bortezomib for a long time. We’re loath to repeat it sometimes, but it’s something you can repeat because the person isn’t refractory to that. That’s something I have to remind myself of.

Josh, is there a time that you would ever choose a doublet vs a triplet at the first relapse? What’s your general standard of care or approach?

Joshua Richter, MD: There’s been an evolution in this. The reality is that in a day and age where we used to give full-dose doublets, I’d far prefer a dose-adjusted triplet. I don’t give doublets to almost anyone, except for extremely rare occasions. The only doublet I can think of that I’ve been giving is belantamab-dexamethasone in the later line, and even there you don’t need the dexamethasone. If we look to our colleagues in Europe in the ALCYONE trial, we look at the transplant-ineligible and the older and frailer. They’re getting quadruplets, and they’ve figured out a way that you can dose attenuate and provide supportive care to give a quadruplet. If the Europeans can give a quadruplet, in the United States, we can build ourselves up to giving triplets to everyone.

Nina Shah, MD: Yes, that’s definitely an evolution that we’ve gone through.

Transcript Edited for Clarity