Multiple Myeloma - Episode 4

Case 1: Treatment-Associated Toxicities in Myeloma

December 23, 2019


Ola Landgren, MD, PhD:Let’s talk about some other aspects of it. What about the toxicities, in adding the antibody, just to touch on toxicity? Does it add any new toxicities in the up-front setting?

Nina Shah, MD:Mainly cytopenias. That’s what we’ve really seen, and I think that’s…

Ajai Chari, MD:Neutropenia.

Nina Shah, MD:Yeah, and neutropenia and lymphopenia too. That’s manageable. I think this is manageable.

Ola Landgren, MD, PhD:Do you see any increased rates of infections?

Nina Shah, MD:You can. I think practically, it’s, again, manageable depending on how you use it and what kind of prophylaxis...

Ola Landgren, MD, PhD:Has it prompted your programs to add antibiotics prophylactically?

Alfred Garfall, MD:We’re studying the question. We are doing a comprehensive review of patients, looking back over the last several years at those who have had early death to try to understand what the causes are and whether there appears to be early risk of serious infection that should warrant a prophylactic approach. But I think the recent study that was published showing a potential overall survival benefit in a UK population with prophylactic antibiotics is very provocative. I think that could potentially mitigate whatever increased risk of infection comes with these more intensive regimens.

Ola Landgren, MD, PhD:This is from the British presentation?

Alfred Garfall, MD:Yes.

Ola Landgren, MD, PhD:We have, at our institution, not implemented any prophylactic antibiotic use, but we are looking carefully. So far, there is no change.

Ajai Chari, MD:I think an important issue with that is that myeloma causes infections, right? In that British study, these are not potent. There are a lot of melphalan-based regimens that are slow to respond. And so clearly, if you’re not controlling the disease quickly, that can also contribute to infection. But I do think daratumumab does add to the risk for respiratory infections. We need to be paying attention, particularly in the older, perhaps fragile patient population. I think the other toxicity that’s worth mentioning is the stem cell collection issue. We know that CD38 is expressed on myeloid precursor cells, and that’s probably the mechanism of the increased neutropenia with the addition of daratumumab. But in the GRIFFIN study, there’s a slight decrease in the stem cell collection. And in CASSIOPEIA, there was more need for support.

Alfred Garfall, MD:That’s important because CASSIOPEIA was a transplant study, so it does show the…

Nina Shah, MD:Right. But people were still able to be collected in GRIFFIN pretty well. The difference between 8 or 9 million cells, or 7 or 9 million cells, I don’t think is big enough to… That wouldn’t drive me as much.

Ajai Chari, MD:Well, the medians may not tell the whole story, though. Right? Because there’s the typical patient. But then you have the extremes of failures, having to recollect, having to go back to Cy [cyclophosphamide] mobilization. Another important distinction between GRIFFIN and CASSIOPEIA is that Europeans routinely use cyclophosphamide mobilization, right?

Nina Shah, MD:Right, which we don’t.

Ajai Chari, MD:And we don’t.

Nina Shah, MD:Well, Al does.

Ajai Chari, MD:Part of the lack of difference in CASSIOPEIA in Europe might have been the Cy mobilization.

Ola Landgren, MD, PhD:Adding 1 extra detail from my experience, I think if you do 4 cycles and collect, which has been the standard since the older regimens, if you do 5 or 6 or more cycles and you collect—we have tried with VRd [bortezomib, lenalidomide, dexamethasone] and KRd [carfilzomib, lenalidomide, dexamethasone] after 6 cycles versus 4 cycles—in our hands there is no difference in the yield for collection. But if you start adding daratumumab, we have seen that if you do 4 versus 6 cycles that the yield seems to, on average, go down. There are patients for whom we can still collect more than 10 million at 6 cycles, but there is a slightly lower yield if we go beyond 4 cycles.

Ajai Chari, MD:I think the other thing to keep in mind is with the CAR [chimeric antigen receptor] T-cell era, where more and more patients are going to potentially get pancytopenia, I’ve needed to use stem cells as a booster rescue from CAR T-cell here. Just eking out 8 million may not be enough.

Nina Shah, MD:It depends on how many bags.

Ajai Chari, MD:Yeah. This may be an issue for young, fit patients. We all have these patients who are below age 40, and we want options for these patients going forward.

Nina Shah, MD:We’ve actually changed it. We are going to definitively collect more for the patients who are a little younger, understanding that they may get a transplant or maybe 2 transplants, or have several boosts in order to make eligibility for CAR T-cell therapy, and then maybe potentially to recover from CAR T, although we don’t exactly know.

Ola Landgren, MD, PhD:Before we go to the next case, I have a second case I would like to present here. I have 1 last question, just to discuss very briefly around the table. Do you use MRD [minimal residual disease] testing? We could talk about high rates of MRD negativity. Do you use that in your standard of care setting, Nina?

Nina Shah, MD:I use it to give me information, but not to make decisions.

Ola Landgren, MD, PhD:How about you, Ajai?

Ajai Chari, MD:The only time I ever act on it is if it’s a standard-risk patient who’s having some toxicity with therapy and there’s a discontinuation. Other than that, I’m not acting on it.

Ola Landgren, MD, PhD:How about you, Alfred?

Alfred Garfall, MD:Same. I’m not even getting it routinely, because I don’t think there are a lot of data to support actionability right now. And you?

Ola Landgren, MD, PhD:In my clinic, I have given talks about it many times. We do check for MRD status. If patients are MRD negative in a newly diagnosed setting, we give them the option to collect and store the stem cells and go right to maintenance versus going to a transplant with maintenance. If we are positive, we would counsel them to the standard road to transplant. And 5 years later, I can tell you I don’t have any gut feeling that there is any difference in outcome. That’s obviously a controversial question. For all patients who come to us, we say there is no randomized data to fully know that. We don’t think there’s an overall survival difference. There may be a slightly shorter progression-free survival, but we think it’s fair to involve the patient in the decision making.

Alfred Garfall, MD:When patients progress, I assume there is consideration of transplant at that point?

Ola Landgren, MD, PhD:At that point, patients are offered transplantation. Absolutely. But they’re also offered other drugs as well, so that’s another question.

Transcript edited for clarity.