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Adequate Treatment Response in Transplant-Ineligible MM Patients


Raymond Thertulien, MD, PhD, discusses high-risk factors for patients with MM.

Ryan Haumschild, PharmD, MS, MBA: I want to pivot to high-risk. We hear people talk about high-risk multiple myeloma. Typically it’s the cytogenetics being brought to the table. That’s how we evaluate them. Dr Thertulien, talk to me about how you define patients with high-risk multiple myeloma and how you treat high-risk patients with multiple myeloma.

Raymond Thertulien, MD, PhD: That’s an excellent question. High-risk multiple myeloma is a moving target. There are some factors and characteristics of multiple myeloma that we all agree are high risk. There are others we will not necessarily disagree on, but we may not have a lot of data to back up the high-risk phenotype for multiple myeloma. We all have a hunch that patients who have those particular characteristics don’t do as well as patients who we call good risk or standard risk. If we look at the cytogenetics and we look at stratification 4;14, we all agree that’s high risk. Same with 14;16 and 17p deletion or TP53 mutation. We all agree that these are high risk. These were the factors that were used to define high risk in the MAIA trial. We also recognize that 1q amplification 1q21+ gain is also high risk. It’s 1 of the most common abnormalities considered high risk in multiple myeloma in the relapsed setting—up to 60%, and in diagnosis up to 40%. It’s considered high-risk. That wasn’t considered high risk in the MAIA trial, and I don’t think it was considered high risk in the SWOG-S0777 trial either.

Then you have other characteristics that are not well defined and not available to all of us, like the gene expression profiling that was developed in Arkansas, which is not widely available. The plasma [cell labeling] index developed at the Mayo [Clinic] isn’t widely available. All of these are considered high-risk. When you look at the NCCN [National Comprehensive Cancer Network] Guidelines and what they considered high risk, you have complex carrier type. We all agree that’s high risk. A carrier-type deletion 13 is considered high risk, but in FISH [fluorescence in situ hybridization] it’s not considered high risk. As I said, this is a moving target. We’ve known all along that hypodiploid [myeloma] is considered high-risk, but it doesn’t show in any of the trials where we analyze high-risk patients in subgroup analysis.

We have other things that we have to look at. We knew all along that high LDH [lactate dehydrogenase] is a bad characteristic of myeloma, but it doesn’t enter a lot of the previous trials. Now it’s been incorporated into our staging system. If somebody has ISS [International Staging System] 3, and you revise ISS3 that incorporates LDH, that’s high risk. That also incorporates a lot of psychogenetic abnormalities. I’m going to throw 1 out there, and I don’t know if my colleagues will agree. We’ve known that 1p deletion can be considered high risk. If you have a biallelic 1p deletion, that’s very high-risk myeloma, but it isn’t featured in the current trial. That’s why I say this is a moving target. We’re still learning what high risk means. Now we’re talking about ultra-high-risk multiple myeloma. We have some patients who get transplanted and relapse within 12 months of an aortic transplant. We start calling this patient ultra-high risk. This is where we have a need in our treatment armamentarium to address these high-risk features.

Ryan Haumschild, PharmD, MS, MBA: You gave us a lot to think about. There’s a lot of stratification of patient types. We heard earlier [about whether a patient is] transplant eligible. Is that an antiquated response? We talk about smoldering, very extreme high risk, high-risk genetics. I appreciate you giving us a background because these are relevant topics in myeloma.

I want to go back to you, Dr Thertulien. I want to talk to you about adequate treatment response. What do you think is an adequate treatment response for patients with transplant-ineligible myeloma? For instance, once they achieve an adequate response, would you put them on maintenance therapy? What treatments would you utilize? Maybe you want to touch on translocation 11;14 while you’re talking about these maintenance options.

Raymond Thertulien, MD, PhD: One thing you asked that I did not answer is how I treat high-risk patients. We all have our way of approaching high-risk patients, except in the first line. Dr [Omar] Nadeem already mentioned that we’re moving toward quadruplet [therapy], and high-risk patients are 1 area I’m using a quadruplet. When you look at the GRIFFIN trial, which used daratumumab with limited Velcade [bortezomib] and dexamethasone, patients with good-risk disease benefited the most. But when you look at the updated analysis, patients with high-risk disease also benefited from this trial. In my practice, I’m not completely sure that we absolutely need a quadruplet [regimen] for good-risk disease. My colleagues in myeloma perhaps agree with me because not all of them are using quadruplets for good-risk disease. We can always rescue those patients in the second or third lines by adding daratumumab to whatever regimen we use in subsequent lines.

For high-risk disease, in this day and age, we need a quadruplet [regimen]. That’s where we know we’re not doing these patients a service if we use a doublet or triplet [regimen], because they don’t do well. These are the patients whom I would use GRIFFIN data on. Some of my colleagues might use the MASTERor MANHATTAN data. I haven’t made that move because I’d like to have carfilzomibin my back pocket. When I use it up front, I’m concerned that I won’t have something to rescue those patients when they progress to the second or third line. I use the GRIFFIN data, the daratumumab, Velcade [bortezomib], dexamethasone in the front line for my high-risk patients.

Ryan Haumschild, PharmD, MS, MBA: Excellent. Thank you.

Transcript edited for clarity.

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