Role of 4-Drug Regimens in Treatment of Multiple Myeloma

Melissa Alsina, MD:Four-drug combinations are being studied, and they will form part of the treatment schema in myeloma. The studies that were done in Europe were positive studies with the quadruplet, for both patients who are transplant eligible and patients who are nontransplant eligible. However, those regimens are not regimens we use for induction here, so we don’t use thalidomide or melphalan. The GRIFFIN data that we just discussed showed deeper responses. More than likely, it’s going to result in approval of that regimen. Daratumumab more than likely would become part of the induction therapy.

In myeloma, over the years we’ve had triplets like lenalidomide, bortezomib, and dexamethasone that induces those very good responses. If you look at the published data for these regimens, the reported response rate is 100%. However, with daratumumab added, it’s an increased number of deep responses like complete remissions, stringent complete remission, and minimal residual disease negativity. Because we have learned that all those are surrogates for better progression-free survival and overall survival, this is likely to be approved again, and it’s likely to become part of our induction therapy.

If this patient had high-risk myeloma, you probably could have selected the same induction regimen. We don’t have data yet on how the bortezomib, lenalidomide, and dexamethasone impacts the high-risk population from the GRIFFIN study. Probably the data are going to be coming. However, if you look, for example, at the CASSIOPEIA study that compared again VTd [daratumumab, bortezomib, thalidomide] versus VTd [daratumumab, bortezomib, thalidomide]—DARA [daratumumab], the group of patients who got VTd [daratumumab, bortezomib, thalidomide]–DARA [daratumumab] had a better rate of response and also had better progression-free survival.

When you look at complete remission, which was the primary end point of the study, patients with high-risk myeloma did not seem to benefit as well as the patient with standard-risk myeloma. However, in terms of progression-free survival, when you do the subset analysis, there was benefit. These patients again remain a challenge, but regimens that can actually get them get a better rate of complete remission are even more important in this patient population.

For patients who are transplant ineligible, right now we know that the best regimen available would be lenalidomide, dexamethasone, daratumumab. There are data from the MAIA study that show better progression-free survival, better rate of complete remissions, and better MRD [minimal residual disease] negativity. Daratumumab is a treatment that is very well tolerated, so you could easily administer this drug for patients who are more frail or older. The main issues with daratumumab would be increased risk of infections, so you have to follow these patients very carefully. Even when you’re seeing a patient who is nontransplant eligible, you do have to consider a triplet as opposed to a doublet. My first choice of treatment, again, based on the MAIA study, would be the combination of Revlimid [lenalidomide], dexamethasone, and daratumumab.

Once D-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone] gets approved, it may or may not impact what we do with regard to transplant. It’s really an unanswered question because the data that are looking at this regimen as induction includes transplant as part of the regimen. We do know that as you keep treating the patients, they get induction, followed by consolidation by transplant, followed by more intensification and then maintenance. The responses keep getting better. It’s not just induction that matters but all the treatment that we give these patients.

The question would be what if you have a patient who you continue to give this treatment to—not just for 4 cycles but until you get the deepest response. We know that for these regimens, while the time to response is only 1 month, the best response—for example, for regimens like daratumumab, lenalidomide, dexamethasone—you don’t see until 1 year. You would have to keep treating these patients to see the impact of only the quadruplet in contrast with transplant. I think we would need a study comparing these 2 to define if we can stop doing the transplants and just continue these patients on the quadruplet therapy.

The goal of therapy in myeloma now should be to get that patient in complete remission and possibly in MRD negativity. The other question would be, what would you do with a patient to whom you give the triplet and that patient achieves that goal before transplant? And is that transplant really necessary in that setting? Or is getting there to stringent complete remission and MRD negativity by whatever method enough?

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