Impact of MRD Status on MM Treatment and Final Thoughts

Melissa Alsina, MD:For the quadruplet therapy, the main increased toxicity is based on increased cytopenias, increased risk for infections—mainly pneumonias—and obviously the infusion reactions that we see associated with daratumumab. The infusion reactions we see in about 40% of the patients, though they’re usually mild, grade 1 or 2, so that is not a big concern. The most important concern is the cytopenias, including neutropenia, given that these patients have a higher risk of infection.

These patients must be followed very closely, and they should receive herpes zoster prophylaxis with acyclovir or similar drugs because they have a higher incidence of herpes zoster infections.

The typical follow-up for the patient we discussed would be that if the patient went to transplant, 3 months after transplant we would do an assessment of response, including MRD [minimal residual disease]. We do this by next-generation sequencing. At this point, we’re not making treatment decisions outside a clinical trial regarding MRD positivity or negativity. We can follow these, and it would be important to determine how that could impact treatment in the future. In general, we know that MRD negativity is a surrogate for better survival. We are trying to define how to better use that in practice.

Currently, we are doing a clinical trial in which we are looking at MRD negativity or MRD assessment 3 months after transplant. Patients who are MRD negative would get lenalidomide, and patients who are MRD positive would get a combination, a doublet, and then we would look at the rate of MRD conversion. There are other trials looking at that same question. Evaluation of MRD now is readily available, because there’s a commercially available kit to look at MRD status by next-generation sequencing.

If the patient achieves MRD negativity with initial therapy, you would think that you are already where you need to be in terms of response. However, we don’t know that. That really hasn’t been studied. We’re not using MRD to make treatment decisions. For a patient who achieves MRD negativity with induction, if the patient is a transplant candidate, I would proceed with transplant until proven otherwise. Those studies are ongoing, and I think multiple randomized studies are looking at this, and hopefully in the future we’ll learn more how to use this as a tool to direct the treatment.

We are very excited about the availability of these quadruplets for induction therapy in myeloma to induce deeper responses and better hopefully progression-free survival. As I mentioned before, the main challenge remains the high-risk population. It’s very exciting now to see that a novel therapy such as CAR [chimeric antigen receptor] T-cell therapy are being studied in patients that are even newly diagnosed with high risk to see if we have another way of impacting the survival of these patients.

In general, patients with standard-risk myeloma respond well to therapy, achieve good responses, and have excellent survival. Those patients should receive all the treatments that are available. We shouldn’t hold back treatment for those patients. Again, for high-risk patients, we should keep exploring novel therapies and ways to actually improve the survival of these patients.

Transcript edited for clarity.

Case: 75-Year-Old Woman with Newly Diagnosed Multiple Myeloma

History and Presentation:

• 75-year-old woman; diabetic on metformin, no history of coronary artery disease or other comorbidities
• κ light chain multiple myeloma diagnosed November 2019
  • Durie-Salmon Stage IIIA, ISS Stage 2
  • Laboratory findings
    • Total proteinuria 5.82 g/day
    • Bence Jones protein (BJP) 3.6 g/day
    • Hypogammaglobulinemia
    • Albumin 3.9 g/dL
    • β2-microglobulin 4.7 mg/L
    • Creatinine 1.7 mg/dl
    • No paraprotein peak but kappa light chain 2000 with lambda light chain at 1
    • Kappa/lambda ratio=2000
• Bone marrow biopsy
  • Cellularity 25% with 80% plasma cells
• Cytogenetics 46, XX
• FISH no abnormalities
• Imaging
  • Skeletal survey: extensive lytic bone disease with healing fractures of left 7^thand the 8^thribs
  • MRI of the spine: multiple compression fractures
  • MRI of the pelvis: diffuse marrow infiltrative changes due to myeloma
• Cytogenetics/FISH: no adverse cytogenetics
• ECOG PS: 1
• Patient was started on D-VRd