Insights from Experts at Mayo Clinic on Translating Evidence to Clinical Practice - Episode 3

NDMM Management: Assessing Response and Determining Duration of Therapy

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Comprehensive insight on optimizing newly diagnosed multiple myeloma management, ranging from response assessment to use of consolidation and maintenance therapy.

Transcript:

Shaji Kumar, MD: It’s challenging in terms of whether we should be using a triplet or quadruplet regimen for patients with newly diagnosed myeloma. We have had extensive debates within our group about the right approach. As Morie pointed out initially, we don’t have the long-term outcome data from the GRIFFIN trial, and there are still some unanswered questions in terms of the maintenance part post transplant. There is a divide in the practice across different groups as well as within groups. Generally, my approach has been to use the VRd [bortezomib, lenalidomide, and dexamethasone] combination for patients with standard-risk multiple myeloma going to stem cell transplant and use the DARA [daratumumab]-VRd combination for patients with high-risk multiple myeloma, primarily extrapolating from the data suggesting a deeper response may be a critical factor for improved outcomes in the patients with high-risk disease. However, I am sure there are differences among us in terms of how we do that.

Prashant Kapoor, MD: To your point, Shaji, the Spanish group has shown, in the PETHEMA/GEM2012 trial, the value of achieving MRD [minimal residual disease] negativity, particularly for patients with high-risk disease. Depth of response can affect the overall prognosis in patients with high-risk disease, suggesting that risk stratification is a dynamic process. Patients with high-risk features who obtain positive results can achieve outcomes that are at least initially similar to the outcomes of patients with standard-risk features.

Shaji Kumar, MD: It also brings up the question: What is your goal for depth of response? Does it matter for the risk status? At what time will you say this patient does not have adequate depth of response prior to a transplant, and you may need to think about a different therapy?

Prashant Kapoor, MD: That is quite interesting in that with the PETHEMA/GEM2012 trial, the sensitivity of MRD detection was much higher as opposed to some studies, including the one that I discussed. Depth of response depends on a number of factors. But to your question about whether we should necessarily beat the transplant-eligible patients until they have achieved MRD-negative state: I think that’s a question that still needs to be answered, although there are studies to suggest we don’t need deep response to take them to transplant. As long as you achieve MRD negativity at some state and sustain it, you would have good outcomes. The timing of MRD negativity achievement isn’t as important as actually achieving MRD negativity and, more importantly, sustaining that MRD-negative state.

Shaji Kumar, MD: Morie,talking about therapy for these patients, what is your practice in terms of how long you continue treatment, or are there certain things that would make you say, “This is enough therapy”?

Morie Gertz, MD: When we are outside of a clinical trial and talking about how long we are treating patients—and this, of course, is an era of maintenance therapy—progression-free survival and response depth aren’t the only considerations. Quality of life of the patient is a big driver. We are now expecting patients with standard risk to live for 10 years. If we give indefinite therapy, these patients will spend 10 years on therapy. It depends; if the maintenance therapy is lenalidomide, does that mean they are on apixaban or rivaroxaban for 10 years? Are they having cramps? Are they having intractable diarrhea? What is the level of fatigue associated with the lenalidomide? It’s not a straightforward question. For patients who are tolerating the lenalidomide and don’t have noticeable adverse effects, it’s legitimate to continue therapy indefinitely in a non-trial setting. If you look at the scientific community and what the thought leaders are doing, most of the trials at clinicaltrials.gov are indefinite lenalidomide therapy. The trials address whether you are MRD negative, and if 36 months of therapy are completed, then you can be randomly assigned, half continuing but half stopping therapy. It reminds me of TKIs [tyrosine kinase inhibitors] in CML [chronic myeloid leukemia], and it raises the question: How long do you stay on TKI, and will it be indefinite? That’s an appropriate setting, but no trial where patients don’t achieve MRD-negative status recommends time-limited therapy. Depending on the degree of toxicity in the patient, which would include financial toxicity, I would be continuing treatment in these patients. However, for some patients, the GI [gastrointestinal] toxicity, cramps, and expense of the novel anticoagulants make it hard for them to justify treatment when they are feeling well, and after being on treatment for 3, 4, or 5 years, they keep asking: How much longer?

Shaji Kumar, MD: Do you factor in MRD status when making that decision?

Morie Gertz, MD: It has to be in a clinical trial. I am more comfortable discontinuing, but in that circumstance, it has to be partly driven by the patient. You always run the risk that, MRD positive or negative, they do better when MRD negative. I am not seeing a cure in the line and I am not seeing the plateau, so they are going to relapse. I am not going to feel good if they are MRD negative and I stopped the lenalidomide without their consent, and then they progress 6 or 8 months later.

Shaji Kumar, MD: Talking about maintenance therapy and potential consolidation therapy, what’s your practice? Do you tend to use consolidation consistently or only in a select group of patients? If so, what makes you determine that?

David Dingli, MD: I don’t use consolidation in all patients. The aim of transplant is to maximize the chance that the patient achieves an MRD-negative state. If the transplant achieves an MRD-negative state for the patient, then I would go immediately to maintenance therapy. If the patient does not achieve an MRD-negative state, then I offer them either a second transplant or, if they have high-risk disease or consolidation, maintenance therapy. When it comes to the choice of consolidation, I generally use the same regimen that I used during induction, assuming they tolerated it well. Sometimes, the patient develops neuropathy. As we all know, sometimes this neuropathy is fine before transplant, but it may flare up after transplant. In that situation, I would generally switch the bortezomib to carfilzomib and then give 2 or 4 cycles of consolidation, reassess, or MRD negativity state was achieved. For MRD-negative and standard-risk patients, I would go with lenalidomide maintenance alone. More difficult are the high-risk patients, even if they achieve MRD-negative state. In the past, we’ve gone with bortezomib maintenance because we have studies for 17p deletion and t(4;14). In this scenario, bortezomib maintenance is important, but we have learned many of these patients have multiple mutations. In general, I prefer to use a doublet in this scenario, which is either bortezomib and lenalidomide, and less likely carfilzomib and lenalidomide. One can quote the FORTE trial in this scenario.

Transcript edited for clarity.