Dr. Ajay Nooka: Absolutely. A 66-year-old man with ISS stage three, R-ISS stage three IgG lambda myeloma was diagnosed in 2017. He presented initially with anemia and multiple lytic lesions. The initial FISH results showed a gain of 1q, deletion of 1p, and deletion 13q. Next slide, please. Patient received induction therapy for our standard of care with VRD, went for an immediate autotransplant in first remission, and received LEN maintenance given the absence of significant high-risk features, but patient behaved like a high-risk disease where the patient progressed after four months. So, when he progressed, he relapsed on hypercalcemia and renal failure, received CyBorD for six cycles, and then went on to receive bortezomib maintenance. He relapsed with extramedullary disease two years after. And at that point, for his EMD, causing a mass effect, he got radiation therapy and then was started on Daratumumab, Pomalyst, and dexamethasone. He experienced a second relapse with a new extramedullary disease seven months later. This time, he was treated with radiation therapy and was continued on carfilzomib, Cytoxan, and dexamethasone. The patient relapsed again as an extramedullary disease, this time within the mesentery and present with GI bleeding. He received bridging therapy with Xpovio, carfilzomib, dexamethasone, and he had stable disease. At this time, the plan was made to take him for a CAR T, and leukapheresis was done. And he received bb2121 with lymphodepletion Flu-Cy. And he achieved a VGPR, and he had resolution of all the extramedullary disease on a follow-up PET-CT. He developed grade 2 CRS, for which he received cetuximab. And now, patient experienced a relapse with new extramedullary disease to the mandible and clavicle six months later, and he was started on teclistamab. Next slide, please. So, he achieved a very rapid VGPR and resolution of the extramedullary disease a month later. There was no CRS observed. There's no ICANS observed. He continues on the weekly treatment.

Dr. Sagar Lonial: all right, good. So that's a nice setup, I think, for our next discussion, which is really talking about the Wild West now with all the new potential drugs and treatments that we have. So, Doctor Kauffman, before we get to sort of the menu of what we may have, can you tell me a little bit about testing we do in a relapse patient, and particularly whether or not there's imaging in that now in 2023?

Dr. Jonathan L. Kaufman: Right. So standard testing is the standard myeloma lapse to get a sense of disease burden. Probably not at every relapse, but certainly I think at first relapse we should do a bone marrow biopsy to identify both disease burden, get a sense of has there been cytogenetic progression, essentially. And this is another opportunity for us to do sequencing. The sequencing we might not use in that moment, but we could potentially learn things that down the line we could use. And so, I think that's the pathologic evaluation. And then the question from an imaging evaluation, certainly a patient with high-risk disease, this is a patient where we should get a PET scan. And my standard is for all relapsing patients is to get a PET scan. So, there are some patients who are relapsing, or where you don't need to run into treatment. And doing a PET scan can be very helpful to decide whether you need to do a treatment now or you can- to observe. But so, doing a PET scan helps us identify, is there new bone disease? Is there new FDG avid bone disease? And does the patient have extramedullary disease?

Dr. Sagar Lonial: And I think- I know that Doctor Joseph is going to catch us up on some of the treatments here. But before we get there, I want to ask you two both, when we think about biochemical relapse, I think there's sort of a knee-jerk response to I see something, let's do something. Is that- how do you all approach biochemical relapse in terms of do something or watch and wait? How do you make those kinds of decisions?

Dr. Ajay Nooka: I think you bring a great point. So, the clinical trials use the criteria for enrollment, and that is allowing for us to have new drugs. But in reality, does every patient that has a slow biochemical relapse need to be treated? Is it a knee-jerk reaction? The answer is no. I have patients who I've waited for four years before I changed the treatment. So, the key I always tell the patients when they get what it is, you get to squeeze the benefit of the current regimen all the way before you throw that away and you never use it again. So that's my take on how to approach this.

Dr. Jonathan L. Kaufman: I think that's an excellent point. And this is really the- where having experience and making decisions and having collaborators is really helpful. I have patients who meet the IMWG criteria for PD on a certain regimen. But certain times, you can continue that regimen. And if you're monitoring closely and you know what you're looking for, and they have a negative PET and they don't have symptoms and they don't have anemia, then in a large part you can observe that patient while on the same treatment or observe the relapse on the same treatment. I don't think that's a common thing that I do. The other thing that I've had happen is I've had a treatment clearly stop working and I've stopped that treatment and I don't necessarily run into the next therapy. I have a recent patient who progressed on daratumumab and pomalidomide, and we stopped therapy for clear progression, and we didn't have to start treating him for another year. So, I think careful observation, understanding the symptoms of myeloma. This is probably not something you're doing in somebody with high-risk disease or previously presented with a pathologic fracture or previously presented with AKI, but there are certain patients where you can do that.

Dr. Sagar Lonial: So, I wanted Doctor Joseph to weigh in on where she doesn't feel comfortable doing that. So, I think you started that list, but-

Dr. Nisha Joseph: Yes, sure. I mean I think- what I was thinking of is the pace of the biochemical progression. So, I think what could also be really helpful is time. So, if someone's progressing but it's very slow, fine, we're comfortable watching it. If we're seeing that evolve, obviously this is not going to work. So, and the crab is around the corner. So, I think that time can also be really helpful.