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Case Study 1: Treating MM After RVd and Transplant

Insights From: Rafael Fonseca, MD, Mayo Clinic; Gareth Morgan, MD, PhD, UAMS Myeloma Institute; Thomas G. Martin, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Thursday, Mar 01, 2018



Transcript: 

Gareth Morgan, MD, PhD: The patient was followed up routinely. At a routine follow-up following a complaint of lumbar back pain, the patient was noted as having become anemic and hypercalcemic, with a collapse of his L4 and L5 vertebrae and what was clearly evidence of progressive disease. It was clearly not an indolent progression, as when he had last been seen he had none of these symptoms, so they’d come on quite quickly. So, it’s important to consider how you would treat him.

He had a 2-year remission. He went into a complete response, so it’s likely that he would respond to an IMiD/proteasome inhibitor combination. We had discussed switching modes of action. For this patient, I’d use carfilzomib, which is arguably the best-in-class proteasome inhibitor. It doesn’t have peripheral neurotoxicity. It is a good drug, because he hadn’t seen it before. He’d seen Revlimid [lenalidomide], so pomalidomide may be a better drug in combination. So, the combination of carfilzomib, pomalidomide, and dexamethasone would be a combination that you’d expect to work in this setting, and you’d expect him to do well.

I think the question becomes, would you do another transplant in this setting? I think that’s more difficult to answer. People normally take a disease-free period of about a year-and-a-half as being a threshold for when you may or may not use transplant again. And so, I think it would depend upon the physical state of the patient. One thing you would consider, as this patient has a lesion in his lumbar spine that had collapsed, is whether you might want to give radiotherapy to that site to consolidate your response there so that he doesn’t come back and get a spinal cord compression in the future.

The other thing to consider would be the use of daratumumab as an adjunct. That, I think, would depend on the level of response. If the patient responded well and went into a complete response, I think it would be very reasonable to continue carfilzomib and pomalidomide long-term. Experience would say patients will tolerate that. I guess there’s a question about the dosage of carfilzomib that you would use, and I think for long-term exposure you have to go to once-weekly. And for me, I would use 3 weeks out of 4 rather than 4 out of 4. That is usually tolerable for patients, and they can stay on that long-term without significant side effects.

There are a number of options that you can choose from for somebody who had what looks like a very well-used regimen upfront, which is RVd followed by a single transplant. I think all options are open. If you’ve had a good long-term remission, you could use RVd and a second transplant. You could switch to a different regimen. You could go from RVd to KPd [carfilzomib, pomalidomide, and dexamethasone] or KRd, depending if the patient had been on maintenance Revlimid or not. But those would probably be the standard options you would choose from. More recently, the combination of Revlimid plus daratumumab has been developed, which is functional, but traditionally I think you would go to something like KPd or KRd.

Rafael Fonseca, MD: For any patient that we would see in the clinic who has symptomatic progression after RVd and transplant, one needs to also consider the interval of time that has elapsed since the transplant itself. Now in this case, it’s not a very long period, but if you were to see a patient who is relapsing 5 years later and who had an excellent response to induction therapy, you know that some of the cells that remain behind may still be sensitive to the original agents. So, with that person in particular, I wouldn’t think of someone like that being “refractory” to proteasome inhibitors. If someone were to see this on a worldwide basis, they often will rechallenge with bortezomib.

Here in the United States, we think more of a second-in-class agent, so we would usually go for a carfilzomib-containing combination. But I think it’s important to consider that. Now, if the patient would relapse shortly after transplant, even if it was a biochemical relapse, I think there would be a greater concern with the current agents. You did not achieve the level of response you wanted, and you may want to consider a switch in class.

Thomas G. Martin, MD: When I’m selecting therapy—whether it’s maintenance therapy or it’s therapy at relapse—one of the main things I look at and ask the patient directly is, “In your past therapy, what was the drug that you tolerated the best? What was the drug that you tolerated the worst?” In fact, patients are a great source for this. Many patients will tell me, “I won’t take this drug again,” or, “I won’t take that drug,” or, “This one gave me so much diarrhea or made me feel too tired,” etc. It’s very important to ask the patient how they tolerated these drugs. It’s very important because we have so many others that we can select. For somebody who has more neuropathy, I won’t use bortezomib. I’ll use carfilzomib, daratumumab or pomalidomide. There are many choices. Patients can often have some GI side effects from lenalidomide, and then I’ll choose something else. I do think with lenalidomide toxicity, you can still try pomalidomide. That’s OK. I will often see less GI side effects from carfilzomib or the monoclonal antibody-based therapies.

Transcript Edited for Clarity 
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Transcript: 

Gareth Morgan, MD, PhD: The patient was followed up routinely. At a routine follow-up following a complaint of lumbar back pain, the patient was noted as having become anemic and hypercalcemic, with a collapse of his L4 and L5 vertebrae and what was clearly evidence of progressive disease. It was clearly not an indolent progression, as when he had last been seen he had none of these symptoms, so they’d come on quite quickly. So, it’s important to consider how you would treat him.

He had a 2-year remission. He went into a complete response, so it’s likely that he would respond to an IMiD/proteasome inhibitor combination. We had discussed switching modes of action. For this patient, I’d use carfilzomib, which is arguably the best-in-class proteasome inhibitor. It doesn’t have peripheral neurotoxicity. It is a good drug, because he hadn’t seen it before. He’d seen Revlimid [lenalidomide], so pomalidomide may be a better drug in combination. So, the combination of carfilzomib, pomalidomide, and dexamethasone would be a combination that you’d expect to work in this setting, and you’d expect him to do well.

I think the question becomes, would you do another transplant in this setting? I think that’s more difficult to answer. People normally take a disease-free period of about a year-and-a-half as being a threshold for when you may or may not use transplant again. And so, I think it would depend upon the physical state of the patient. One thing you would consider, as this patient has a lesion in his lumbar spine that had collapsed, is whether you might want to give radiotherapy to that site to consolidate your response there so that he doesn’t come back and get a spinal cord compression in the future.

The other thing to consider would be the use of daratumumab as an adjunct. That, I think, would depend on the level of response. If the patient responded well and went into a complete response, I think it would be very reasonable to continue carfilzomib and pomalidomide long-term. Experience would say patients will tolerate that. I guess there’s a question about the dosage of carfilzomib that you would use, and I think for long-term exposure you have to go to once-weekly. And for me, I would use 3 weeks out of 4 rather than 4 out of 4. That is usually tolerable for patients, and they can stay on that long-term without significant side effects.

There are a number of options that you can choose from for somebody who had what looks like a very well-used regimen upfront, which is RVd followed by a single transplant. I think all options are open. If you’ve had a good long-term remission, you could use RVd and a second transplant. You could switch to a different regimen. You could go from RVd to KPd [carfilzomib, pomalidomide, and dexamethasone] or KRd, depending if the patient had been on maintenance Revlimid or not. But those would probably be the standard options you would choose from. More recently, the combination of Revlimid plus daratumumab has been developed, which is functional, but traditionally I think you would go to something like KPd or KRd.

Rafael Fonseca, MD: For any patient that we would see in the clinic who has symptomatic progression after RVd and transplant, one needs to also consider the interval of time that has elapsed since the transplant itself. Now in this case, it’s not a very long period, but if you were to see a patient who is relapsing 5 years later and who had an excellent response to induction therapy, you know that some of the cells that remain behind may still be sensitive to the original agents. So, with that person in particular, I wouldn’t think of someone like that being “refractory” to proteasome inhibitors. If someone were to see this on a worldwide basis, they often will rechallenge with bortezomib.

Here in the United States, we think more of a second-in-class agent, so we would usually go for a carfilzomib-containing combination. But I think it’s important to consider that. Now, if the patient would relapse shortly after transplant, even if it was a biochemical relapse, I think there would be a greater concern with the current agents. You did not achieve the level of response you wanted, and you may want to consider a switch in class.

Thomas G. Martin, MD: When I’m selecting therapy—whether it’s maintenance therapy or it’s therapy at relapse—one of the main things I look at and ask the patient directly is, “In your past therapy, what was the drug that you tolerated the best? What was the drug that you tolerated the worst?” In fact, patients are a great source for this. Many patients will tell me, “I won’t take this drug again,” or, “I won’t take that drug,” or, “This one gave me so much diarrhea or made me feel too tired,” etc. It’s very important to ask the patient how they tolerated these drugs. It’s very important because we have so many others that we can select. For somebody who has more neuropathy, I won’t use bortezomib. I’ll use carfilzomib, daratumumab or pomalidomide. There are many choices. Patients can often have some GI side effects from lenalidomide, and then I’ll choose something else. I do think with lenalidomide toxicity, you can still try pomalidomide. That’s OK. I will often see less GI side effects from carfilzomib or the monoclonal antibody-based therapies.

Transcript Edited for Clarity 
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