Upfront Therapy, Including the Role of Transplant for Relapsed Stage II Multiple Myeloma

C. Ola Landgren, MD, PhD:This patient is a 61-year-old male who was diagnosed with multiple myeloma. He has undergone standard workup that leads to the diagnosis. He has evidence of a monoclonal protein in his blood and skewed light chain ratio. Bone marrow biopsy has been conducted showing 40% light chain-restricted plasma cell infiltration with normal risk by cytogenetics and FISH. Also, he has undergone additional blood testing showing decreased hemoglobin and preserved kidney function. And he has been considered to be a candidate to start therapy.

There is no contraindication for any of the commonly used drugs. He started on a 3-drug combination including bortezomib, lenalidomide, and dexamethasone. He received 4 cycles of that therapy and then he was evaluated for his response. He only had a partial response after completion of his combination therapy, which is not that very good. He has then gone forward with collection of stem cells treated with high-dose melphalan and received an autologous stem cell transplantation. After follow-up for 100 days, the response evaluation shows that he now has obtained a complete response. He’s MRD-negative, so the transplant did a good job for this patient. He was then put on lenalidomide maintenance after about 100 days’ post transplant, and he was started on 10 mg on days 1 through 21, on a 4-week schedule. He has been followed in the interim while on maintenance. But after 1 year of follow-up, he comes back with back pain, he’s fatigued, and his performance status is decreased. Additional workup is initiated, and the bloodwork shows that his hemoglobin is dropping again. He now also has an M-spike that’s detectable in the blood again after being first in complete response and MRD-negative to begin with. The patient has evidence of progressive disease. The question now is, what’s going to happen? How is this patient going to be treated?

The initial therapy this patient was given was a combination of bortezomib, lenalidomide, and dexamethasone. All the data we currently have available strongly support the use of a 3-drug combination independent of the cytogenetics, the signature of the disease. In the United States, the combination of bortezomib, lenalidomide, and dexamethasone is the most commonly used treatment for patients.

Transplant was developed in the late 1980s for the use in multiple myeloma, and in the mid-1990s, it became very popular to use that. It was given because after combination therapy—that used to be the old so-called VAD therapy, with vincristine, Adriamycin, and dexamethasone—the responses were very poor. So, the addition of melphalan really made sense to try to bring down the disease. With all the new drugs that have been approved after the turn of the century, the question has come up on the table: is the transplant really mandatory? You need to give every patient transplant. There are ongoing studies that are investigating the role of transplant in the era of modern therapy. And the study that is the largest so far with the most mature results is the study that was initially started in France by the French Intergroup, and later there was another group that joined, the North American Group, led by the Dana-Farber Cancer Institute. At our institution, at Memorial Sloan Kettering, we are the second largest enroller in North America.

There are many patients that have been treated on that study, and the preliminary results were presented at ASH in 2015. At that presentation, it was found that patients that were treated with the combination of bortezomib with lenalidomide and dexamethasone for 3 cycles collected stem cells and continued with an additional 5 cycles. And then, lenalidomide maintenance—compared to patients that got 3 cycles of the same combination with bortezomib/lenalidomide/dexamethasone—collected a stem cell, got the transplant, and then got 2 more cycles of that combination followed by maintenance. There was no difference in overall survival at 3 years of follow-up.

When looking at the primary endpoints of the study, which was progression-free survival, patients that were treated with a combination followed by transplant had a longer, on average, progression-free survival. The French group also did subanalysis that was not part of the primary analysis, but was part of the pre-planned secondary analysis showing that patients that obtain a minimal residual disease on either of the 2 arms had the same progression-free survival.

So, we are at the point where we don’t really know what the right thing to do is. Transplant is still a therapy that works. It’s a therapy that counts with a lot of toxicity. I do think for clinics that don’t have access to monitoring for MRD, to use combination therapy followed by transplant is probably the best we can offer for patients. But, looking at the French study and other ongoing studies, my prediction is that probably the use of transplant could be based on the depth of the response. But the data will have to mature a little bit more, and then we will have to see what the right thing is.

Case Scenario 1:

January 2015

• The patient is a 61-year-old male who was diagnosed with ISS stage II MM.
• Performance status 0.
• At diagnosis bone marrow shows 40% light chain restricted plasma cells, FISH cytogenetics show hyperdiploid phenotype.
• M-spike of 3.2 g/dL IgG kappa, serum free light chains kappa 60 mg/dL, lambda 1.5 mg/dL, ratio=40
• Bloodwork show beta-2 microglobulin=4.2 mg/dL, Hg=8.2 g/dL, creatinine=0.9 mg/dL.
• PET/CT shows multiple focal bone lesions in upper and lower extremities and in L2 and L3.Bone lesions have increased SUVs.
• Based on these data and diagnosis of standard risk he was started on lenalidomide, bortezomib, and dexamethasone (RVD) induction.
• He achieved a partial response with RVD.
• He then had an autologous stem cell transplantation and achieved MRD negativity.
• He was started on lenalidomide maintenance of 10 mg.

April 2016

• Patient was experiencing back pain, loss of appetite and weight loss.
• Blood work show beta-2 microglobulin=4.0 mg/dL, Hg=9 g/dL, creatinine=1.5 mg/dL.
• M-spike is 0.5 g/dL, serum free light chains kappa 60 mg/dL, lambda 0.6 mg/dL, ratio=10.
• Performance status 1.
• Based on these criteria he was diagnosed with standard-risk multiple myeloma.
• He was started on daratumumab, bortezomib, and dexamethasone.