Experts discuss a patient with transplant-eligible, newly diagnosed multiple myeloma managed with induction daratumumab-RVd and maintenance therapy.
Noopur Raje, MD: Welcome to this CancerNetwork® Around the Practice program, “Recent Advances in Multiple Myeloma: Insights From Experts at Dana-Farber Cancer Institute and Massachusetts General Hospital.” I am your host, Dr Noopur Raje, a professor of medicine at Harvard Medical School, Massachusetts, and the director of the multiple myeloma program at the Massachusetts General Hospital. I have a great panel of experts joining me today, and I would like to invite my esteemed fellow panelists to introduce themselves. We’ll start with you, Jacob.
Jacob Laubach, MD, MPP: I’m Jacob Laubach. I’m a member of the Jerome Lipper Myeloma Program at Dana-Farber and an assistant professor of medicine at Harvard Medical School.
Noopur Raje, MD: Welcome, Jacob. Omar?
Omar Nadeem, MD: Hi, I’m Omar Nadeem. I’m one of the faculty members at the Dana-Farber Cancer Institute’s myeloma program and an instructor of medicine at Harvard Medical School.
Noopur Raje, MD: Welcome. Andrew?
Andrew J. Yee, MD: Hi. Andrew Yee, I’m one of Noopur’s colleagues at Mass General Cancer Center, and I am an assistant professor of medicine at Harvard Medical School.
Noopur Raje, MD: Thank you all for joining me. Today, we’ll discuss several key data updates in multiple myeloma from recent meetings. We will review these data in the context of the myeloma treatment landscape and discuss how we apply this evidence to our clinical practice and improve patient outcomes. We’ll start with a case of a transplant-eligible patient; Jacob has kindly agreed to present one of those. Jacob, do you want to go ahead with your case?
Jacob Laubach, MD, MPP: This is a 62-year-old gentleman who had presented with right shoulder discomfort and rib cage pain in autumn of 2020. The presentation with musculoskeletal symptoms led to concern for multiple myeloma, and serum protein electrophoresis identified a 4.6 g/dL IgA [immunoglobulin A] kappa monoclonal protein with total protein of 12.1 g/dL. The total IgA was 7420, and there was reciprocal depression of IgG and IgM. The serum free kappa light chain concentration was 870 mg/L with a kappa to lambda ratio of 87. The BUN [blood urea nitrogen] was 15, creatinine approximately 1, and the calcium was mildly elevated at 11 g/dL. There was mild anemia with a hemoglobin of approximately 11, hematocrit 31%. The white blood cell count was normal at about 7000 per μL, and the platelet count was around 260,000. The beta 2 microglobulin was substantially elevated at 5.7 mg/L, and the albumin was 2.9 g/dL.
CT imaging was taken of the chest and the right shoulder, and this demonstrated diffuse lytic bone lesions, as well as pathologic fracture of the right seventh rib. A PET [positron emission tomography]/CT scan was later performed, and again, showed widespread lytic bone lesions, including the thoracic and lumbar spine, pelvis, bilateral rib cage, and the right scapula. The patient also underwent bone marrow evaluation, which demonstrated substantial bone marrow infiltration of about 80% clonal plasma cells. FISH [fluorescence in situ hybridization] identified translocation 4;14 and deletion 13q.
The patient initiated a 4-day pulse of dexamethasone as plans were made to initiate definitive induction therapy. At that point, he transitioned to the combination of subcutaneous daratumumab, lenalidomide, subcutaneous bortezomib, and dexamethasone on a standard schedule for each of these agents. Denosumab was also initiated once monthly. After 2 cycles, as the patient developed mild to moderate peripheral neuropathy, he transitioned from a 21- to a 28-day cycle, with weekly dosing of bortezomib. The patient went on to complete 4 cycles of induction therapy, and a repeat bone marrow biopsy at this time showed normal cellularity with intact hematopoiesis and only scattered plasma cells that were found to be polytypic. He then underwent stem cell mobilization and stem cell harvest with filgrastim and plerixafor according to standard of care, and had high-dose therapy with melphalan 200 mg/m2 and an autologous transplant.
Noopur Raje, MD: This is a great case, Jacob, thank you for sharing that. Just to set the stage, I think all of us are using triplet drug combinations. We are now moving toward quadruplets, as your patient received in this case. You’ve nicely presented data with daratumumab, RVd [lenalidomide, bortezomib, dexamethasone]. You presented the GRIFFIN trial at this year’s ASH [American Society of Hematology] meeting. Can you give us a little background on the GRIFFIN trial and the update you presented at ASH this past year?
Jacob Laubach, MD, MPP: I’d be glad to. I love your choice of words of the way this field is evolving. The evolution has been fascinating over the course of the past decade as we’ve evolved from 2-drug induction regimens, then to 3-drug, and now to 4-drug therapy. The GRIFFIN trial was a randomized phase 2 study involving approximately 210 patients. Patients were randomized to receive standard RVd vs daratumumab plus RVd induction, followed in all patients by a high-dose therapy and autologous transplant, and thereafter maintenance with either daratumumab and lenalidomide, or lenalidomide alone in those patients who had received RVd. That was the basic design of the study. With initial analysis of the data and initial presentation in 2020, it was clear that the addition of daratumumab led to significant improvement in depth of response. That included traditional measures, such as stringent complete response rates, but also MRD [minimal residual disease] negativity, which is a critical endpoint in clinical trials in this era of myeloma therapy where depth of response is interesting, and clinically becoming more important in terms of how we treat patients.
The 3-year update showed us several important things. First, the depth of response that had been seen with the addition of daratumumab persisted. There was improvement in the level of MRD negativity with the clonoSEQ assay between years 2 and 3 of maintenance, showing that ongoing multiagent maintenance therapy with lenalidomide and daratumumab led to this improvement in depth of response. Significantly, the progression-free survival difference widened during this time, and after 3 years of follow-up, the progression-free survival rate for the 4-drug regimen was 89%, which is unprecedented in our field. Then finally, there were no real, additional cumulative toxicities associated with the use of daratumumab. Not surprisingly, the daratumumab, lenalidomide combination is very well tolerated.
Noopur Raje, MD: I think you’ve summarized the GRIFFIN data quite nicely. For me, the big takeaway is that the depth of responses keeps deepening over time. The 2-drug combination as maintenance, even beyond the 2-year timeframe, had an impact.
Transcript edited for clarity.