Selecting Induction Therapy for Newly Diagnosed MM

Melissa Alsina, MD:This is a 75-year-old patient with newly diagnosed myeloma who clearly needs therapy. She’s fit because she has no comorbidities, has a good performance status, and has an active life. The first choice for a patient like this would be a triplet with Revlimid [lenalidomide], Velcade [bortezomib], and dexamethasone. At this point this is the most common induction regimen that is used.

However, the field is rapidly changing because new data have emerged from Europe and here, showing that when you combine these 4 drugs, you add daratumumab to VRd [bortezomib-lenalidomide-dexamethasone], you get actually better responses. That is the regimen that is still not Food and Drug Administration approved, so it is not really available or feasible to give it to a patient but definitely would be an option. I think at this point probably the first option would be Revlimid, Velcade, and dexamethasone. If you are able to add the daratumumab, that would be good.

Another option in this patient, given that she’s an older patient, would be if you give her Revlimid, daratumumab, and dexamethasone. That regimen currently is approved for patients who are nontransplant candidates, but in reality, it’s a very effective regimen, inducing 48% complete remissions. I think that would also be a suitable option for this patient if for any reason she’s not already on Velcade.

We have learned over the years that maintenance is very important. There are phase IIb randomized trials showing that lenalidomide prolonged progression-free survival and overall survival when you use it as maintenance therapy post transplant. There are other studies ongoing looking at other combinations, including with lenalidomide with daratumumab or lenalidomide with Velcade. Right now, the biggest challenge treating myeloma patients is the high-risk patient population. These patients, fortunately, are only 15% of newly diagnosed myeloma patients. It seems that no matter what treatment we give them, they still have a poorer survival. We frequently consider other treatments for maintenance that are not just lenalidomide. In practice, we usually use a combination like a doublet for patients who have high-risk myeloma.

The GRIFFIN study is a study that recently completed accrual. It’s a study that included patients who were younger than 70 years old and had newly diagnosed untreated myeloma. They were considered transplant eligible. The study first had a run-in for safety of 16 patients. The treatment schema was that the patients were to receive lenalidomide, bortezomib, and dexamethasone with daratumumab for 4 cycles, followed by consolidation with transplant. This was followed by 2 more cycles of the same induction regimen and then followed by maintenance with daratumumab and lenalidomide.

This safety cohort includes 16 patients. The response rate was 100%, and actually after consolidation, about 63% of the patients were in complete remission. Based on these really good data, a randomized study was designed looking at this quadruplet combination compared with lenalidomide, bortezomib, and dexamethasone without daratumumab. A little over 200 patients were randomized in this study.

Accrual has been completed, and initial data were consistent with the data from those initial 16 patients, showing that you get a higher number of patients achieving stringent complete remission with the quadruplet, 42% versus 32%. The overall response rate is also higher. However, the important point is that we get deeper responses when we add the daratumumab. About 50% of these patients were minimal residual disease negative.

The CASSIOPEIA study was a study that was conducted in Europe, and it was for newly diagnosed myeloma patients who were considered transplant eligible. These patients had to be younger or equal to 65 years old. They had to have a newly diagnosed myeloma that was untreated. About 1000 patients were enrolled in this study. Patients were randomized to receive bortezomib, thalidomide, dexamethasone, and daratumumab versus bortezomib, thalidomide, and dexamethasone. Patients were to receive 4 cycles of induction therapy, followed by consolidation of transplant, followed by 2 more cycles of the induction therapy. Then patients were randomized to receive either daratumumab or observation as maintenance therapy.

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