Paul G. Richardson, MD: Now we’re going to change gears a little bit, and in the second part of our conversation, we are going to move now into relapsed and refractory multiple myeloma. I was going to ask Nina to talk to us about how she considers what regimen to use in the relapsed/refractory setting; when do you pull the trigger on relapsed disease; how do you think about rate of progression; distinction between lines of therapy, classes of therapy; what’s early versus late relapse, what does that mean to you; and most importantly, what about the molecular characteristics of relapse? Nina, walk us through this forest of information.

Nina Shah, MD: For most of those, one of the best things about keeping people on maintenance or observing them closely is that you can find out when they progress. There are 2 ways that people progress or relapse. I like to use the word progress because relapse, by definition, is just a reappearance from CR [complete response] and protein, and I don’t think that’s a reason to treat someone necessarily. But if they have a true progression, which is progression by bone marrow, progression by M protein, light chains, or by progressive disease based on imaging, then they need to be treated. Although, not all progressions are the same. There’s the biochemical progression, which is your IMWG [International Myeloma Working Group] met criteria of 0.5 g/dL on the M protein or 25%, or an increase of at least 100 m/L on light chains. Especially now, our patients are getting to those normal light chains and normal M protein numbers with our new therapies, so we see that, and it’s not that much tumor burden.

Then there’s the clinical progression. Someone shows up with a new fracture, a new plasmacytoma, new renal insufficiency, or you haven’t seen them in a while, and they show up and now their light chains have grown crazy and now they’re creatinine is a little abnormal. Overall, those are the 2 flavors of progression that you have if you had to categorize them.

What are the biochemical progressions? I think those people have time, usually. I think it’s worth it to then—and I used to be a little worse about this, but now I’m much more consistent—when you see the biochemical progression, make sure it’s confirmed by the next blood test. I have gotten away from the 24-hour UPEP [urine protein electrophoresis] as I am not a fan. But that’s OK, I hope no one gets on my case! However, I always get the blood test. Specifically, that’s the time you need to send them for imaging, to set the bone marrow up, you must look for clonal evolution. All these things are important because they tell you what urgency you must treat the patient. If there’s nothing new on PET [positron emission tomography] and it’s 15% on the bone marrow and it’s just numbers, you can think about a clinical trial, and you should because there are clinical trials for the 1 to 3 priors that are open. Specifically, there are CAR [chimeric antigen receptor] T trials open, etc. In the absence of clinical trials, I think there are myriad options. I think we’re going to discuss those later. However, there are a lot of options you can think about.

Next, there’s the people who need treatment right away. They come in with a new fracture, they have a new plasmacytoma, they might need radiation. As soon as you manage what the acute issue is, those people should get treated right away because they will have progression and clinical progression, and you want to prevent morbidity at this time. Overall, that’s how I think about if I’m going to start treatment or not. The people who have the biochemical progression at the 0.5 g/dL, you can wait. I would say once you get to 1.0 g/dL, you should probably start treating them. Notably, that moment that they hit the 0.5 g/dL, they can consider doing all their whole work-up like we talked about.

As far as thinking about what you’re going to do about the agents, we have our classes of agents, and most people have been exposed to lenalidomide either in induction or with maintenance therapy, and many of them will have been exposed to a proteasome inhibitor [PI]. As such, those are your classes that you’ve already been exposed to, and now your choices are, “OK, do I use a CD38 antibody, which is a new class, and do I combine it with a new IMiD [immunomodulatory imide drug], or do I try to re-expose these people to something they’ve had before?” For example, perhaps someone had bortezomib as an induction therapy and they weren’t refractory to it, they had their cycles, they went to transplant, and it’s been a while. You can consider treating those people again.

Finally, I want to talk a little bit about the molecular aspects of it. I think if ASH [the American Society Hematology annual meeting] of 2019 taught us anything, it’s that we have a biomarker to treat for the first time, which is [translocation] 11;14. For those people specifically, it’s not a wrong choice to give them venetoclax, even early in the first progression, because people can do well even on venetoclax/dexamethasone alone. I know that’s not FDA approved, but this is one of those few times where you can try to get at the core of their disease and think about what else they may have. The reason that it’s also important to do that bone marrow biopsy, is maybe you’re going to find out something new. Perhaps, the patient will have a new deletion 17p, or a new deletion 16q? Whatever it is, that’s going to help you decide how aggressive you need to be.

Ultimately, the patient’s clinical picture is the most important. Did they progress quickly after transplant? Did they progress years and years after transplant? Those things help you to understand how aggressive this is and how aggressive you need to be to maintain the goals of efficacy and quality of life.

Paul G. Richardson, MD: I think that’s an excellent point. I want to pick up on a nice point you made about t[11;14). I’m wondering if we are going to see 2 types of t(11;14), because I’m not sold that it’s a standard risk feature. I’ve been struck by what we’ve seen by the t(11;14) biology, and the clue perhaps lies in plasma cell leukemia, which is enriched for t(11;14). I agree with you, Nina, that there’s value to engaging venetoclax early. My challenge is when venetoclax fails in the t(11;14) patient over time, then what happens? We have the clear data that the non-t(11;14) can see Pandora’s box emerge and the disease behaves extremely badly. The fact is that your outcomes can be poor. Nonetheless, I agree with you. I think t(11;14) is a fascinating area, and I’m hopeful we’ll have an approval for t(11;14) in this year to help us with this because from a community practice perspective, having that approval can only be a good thing, particularly in the t(11;14) subset in BCL2 overexpressors.

The 17p always make me feel uncomfortable. I just wondered, Nina in terms of your approach, how do you think about that if you see that emerge? What guns do you then bring to bear?

Nina Shah, MD: I get aggressive with these people because if you stop therapy for 3 weeks for example, their disease is going to grow. As such, you must find something that they can get on quickly. Sometimes if they’ve presented with high burden of disease, you might even consider like high-dose Cytoxan [cyclophosphamide] and get them reduced, and then get them on to something that they haven’t seen, such as daratumumab or carfilzomib. Nonetheless, it is really challenging. We’ve all said this before, but all 17p deletions are not the same thing. There might be 1, there might be 2 deletions, we don’t know, and sometimes we don’t take the time to find out because that’s just not how we get the bone marrow. Overall, not all 17p deletions are the same. However, when I see it, and especially if I see it new, I know that there’s been some badness going on in the evolution in that bone marrow.

Paul G. Richardson, MD: I think it remains a fundamental challenge. I’m struck by, for example, something I am going to ask David about. I think we’ve got new drugs like selinexor and the data from Boston, which tell us that regarding 17p, you’ve got some new guns in the cupboard that we can deploy if we need to.

Transcript edited for clarity.