Insights from Experts at Mayo Clinic on Translating Evidence to Clinical Practice - Episode 4

Case Presentation 1: Selecting Therapy in Transplant-Ineligible NDMM

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Centering discussion on a patient case of transplant-ineligible newly diagnosed multiple myeloma, experts consider how they would approach workup and management.

Transcript:
Shaji Kumar, MD:
Let’s move on to a patient case. Morie, I will pass this on to you.

Morie Gertz, MD: This is a patient I am currently seeing. I am seeing her in 10 days, and I am getting progressively uncomfortable with my management. She is 55 years old and had months of progressive nondescript fatigue and rib pain. When she goes to an emergency department, her hemoglobin level is 7.4 g/dL, and her creatinine is 3.84 mg/dL. She has an 8 kappa monoclonal protein in her serum and her kappa free light chain is 278 mg/dL, or 2780 per liter, and that was March 6. We are just 6 weeks into this. The bone marrow was 90% plasma cells with a very low proliferative rate, and she didn’t have bad genetics. There was a hyperdiploid clone based on ploidy MYC arrangement and monosomy 13 and 14.

She was hospitalized, and because she was hospitalized, it’s impossible to consider an EMID [evolutionary metabolic infectious disease] of any type, even in the presence of renal failure. She received bortezomib, cyclophosphamide, and dexamethasone and had 4 total plasma exchanges. I saw her on March 11, a few weeks into it, and her free light chain was 143 mg/dL, which was not a positive response. I added daratumumab. Four days later, her absolute neutrophil count was 300, so I held her cyclophosphamide temporarily but have since resumed it. However, instead of giving her 500 mg weekly, I give her 300 mg weekly. On March 25, the free light chain was above 100 mg and today it’s about 110 mg. And now her creatinine is up to 6.42 mg/dL, and I have repeated that a few times.

I have problems deciding how long to use one regimen before I say it’s not adequate and move forward. I haven’t yet done a renal biopsy. She went to empiric therapy based on the light chain and the creatinine level, but the pattern of urinary protein wasn’t amyloid. Do I put her back on plasma exchange? Do I give her a big dose of cyclophosphamide? Should I just go to carfilzomib? I don’t know what to do. I am concerned she is going to need dialysis at 55 years old.

Shaji Kumar, MD: That isa challenging situation, which again brings up the question: What are the different characteristics we take into consideration when we start therapy for patients with newly diagnosed myeloma whom we don’t consider transplant eligible? This particular patient is younger, 55 years old, so the question is: Would we consider this patient transplant eligible or not?

Morie Gertz, MD: I am recommending a transplant but I would like her kidney to function better before transplant. I am so uncomfortable about irreversible loss of renal function as I am, quote, waiting for the response to happen.

Shaji Kumar, MD: David, what would be your initial treatment of choice in a patient who presents with renal failure?

David Dingli, MD: My approach is similar to what Morie said. I would use a combination of cyclophosphamide, bortezomib, and lenalidomide, and I would be inclined to use daratumumab very early, because we know that if the patient presents with myeloma kidney, meaning light chain cast nephropathy, lowering the light chains rapidly is quite important to maximize the chance of salvaging kidney function. That would be my approach to try to control her disease, salvage kidney function, improve her performance status, and, as Morie said, take her to transplant.

Morie Gertz, MD: I should say that with this induction, the bortezomib was given twice a week, not once a week.

Shaji Kumar, MD: Is that what you typically do for patients with renal failure?

Morie Gertz, MD: Yes. For renal failure, what David said about speed to reduce the light chain is so critical that even though it is more neurotoxic, with careful monitoring it’s not as big an issue. It’s a time when twice weekly bortezomib has merit.

Shaji Kumar, MD: You mentioned that you didn’t do a kidney biopsy. Are there situations where you would do a kidney biopsy in somebody presenting with renal failure?

Morie Gertz, MD: Hindsight is very important in this disease. It was obvious initially that this had to be cast nephropathy with that high light chain and no albuminuria to suggest kappa light chain deposition disease or renal amyloidosis. But 6 weeks in, it is not getting better. Now I am a little insecure about whether it’s the right diagnosis, but the treatment is not as effective as I had hoped, or I need to look a little harder.

Shaji Kumar, MD: You are planning on a biopsy, I assume.

Morie Gertz, MD: I have consulted with nephrology.

Shaji Kumar, MD: Talking about the different drugs in this combination, Prashant, what do you think about using EMID in this setting?

Prashant Kapoor, MD: Even though we haven’t reached the desired outcome in this patient, I would have done exactly the same thing that Morie did. Speed is of vital importance in this case, when a patient presents with renal dysfunction, where we want to rapidly decrease the plasma cell burden; in other words, we want to rapidly decrease the free light chains that are potentially damaging to the kidney. Because it is difficult to obtain EMID in a hospital setting, because it takes several weeks to get the drugs started, and because the dose of EMID can vary depending on the kidney function or when a patient or patient’s kidney function is in a state of flux, you cannot rely completely on a fixed-dose EMID. Ultimately, the patient should be on an EMID; the fact that the patient has hyperdiploidy is also something that should be taken into account. These patients are likely to respond better to an immunomodulatory agent but should use bortezomib, at least twice a week for the first few cycles, and potentially consider high-dose steroids. That is the only scenario where I would use this kind of regimen. Also, we have data on daratumumab in combination with CyBorD [cyclophosphamide, bortezomib, and dexamethasone] in a different patient population: AL [amyloid light chain] amyloidosis. I am comfortable adding daratumumab now that we have more data with this regimen. But overall, I wouldn’t necessarily change the approach at this point, although eventually the patient needs an immunomodulatory agent, specifically lenalidomide.

Transcript edited for clarity.