A 62-year-old man with transplant-eligible NDMM
Noopur Raje, MD: Welcome to this CancerNetwork® around the practice program, “Recent Advances in Multiple Myeloma: Expert Insights from the Dana-Farber Cancer Institute and Massachusetts General Hospital.” I’m your host, Dr. Noopur Raje, professor of medicine at Harvard Medical School, Massachusetts, and director of the multiple myeloma program at 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, MP: I am Jacob Laubach. I am a member of the Jerome Lipper Myeloma Program at Dana-Farber and Assistant Professor of Medicine at Harvard Medical School.
Noopur Raje, MD: Welcome, Jacob. Omar?
Omar Nadeem, MD: Hello, I am Omar Nadeem. I am a faculty member of the Dana-Farber Cancer Institute 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 the Mass General Cancer Center, and I’m an assistant professor of medicine at Harvard Medical School.
Noopur Raje, MD: Thank you all for joining me. Today we will discuss several key multiple myeloma data updates from recent meetings. We will review this data in the context of the myeloma treatment landscape and discuss how we are applying this evidence to our clinical practice and improving patient outcomes. We will begin with the case of a patient eligible for a transplant; Jacob kindly agreed to present one. Jacob, do you want to continue your business?
Jacob Laubach, MD, MP: The case is a 62-year-old man who presented with right shoulder discomfort and rib cage pain in the fall of 2020. The presentation with musculoskeletal symptoms raised concerns of myeloma multiple, and serum protein electrophoresis identified an IgA of 4.6 g/dL [immunoglobulin A] monoclonal protein kappa with total proteins of 12.1 g/dL. Total IgA was 7420, and there was reciprocal depression of IgG and IgM. The serum concentration of free kappa light chain was 870 mg/L with a kappa/lambda ratio of 87. The BUN [blood urea nitrogen] was 15, creatinine about 1, and calcium was slightly elevated at 11 g/dL. There was mild anemia with a hemoglobin of approximately 11, a hematocrit of 31%. White blood cell count was normal at approximately 7,000 per μL, and platelet count was approximately 260,000. Beta 2 microglobulin was substantially elevated at 5.7 mg/L, and albumin was 2.9 g /dL.
CT imaging was taken of the thorax and right shoulder, and this demonstrated diffuse lytic bone lesions, as well as a pathological fracture of the right seventh rib. A PET [positron emission tomography]/ A CT scan was done later and again showed extensive lytic bone lesions including the thoracic and lumbar spine, pelvis, bilateral rib cage and right scapula. The patient also underwent bone marrow evaluation, which demonstrated substantial bone marrow infiltration of approximately 80% clonal plasma cells. FISH [fluorescence in situ hybridization] translocation identified 4;14 and deletion 13q.
The patient initiated a 4-day pulse of dexamethasone as plans were made to initiate definitive induction therapy. At this point, he switched 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 a month. After 2 cycles, as the patient developed mild to moderate peripheral neuropathy, he switched from a 21 to 28 day cycle, with a weekly dose of bortezomib. The patient continued 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 which were found to be polytypic. He then underwent stem cell mobilization and harvesting with filgrastim and plerixafor per standard of care, and received high-dose treatment with melphalan 200 mg/m2 and autologous transplant.
Noopur Raje, MD: This is a great case, Jacob, thanks for sharing. Just to set the scene, I think we all use triple drug combinations. We are now moving on to quadruplets, as your patient received in this case. You presented the data well with daratumumab, RVd [lenalidomide, bortezomib, dexamethasone]. You presented the GRIFFIN trial at this year’s ASH [American Society of Hematology] Meet. Can you give us some background on the GRIFFIN trial and the update you presented at ASH last year?
Jacob Laubach, MD, MP: I would be delighted to. I like your choice of words about how this field is changing. The evolution has been fascinating over the past decade as we have moved from induction regimens to 2-drug, then 3-drug, and now 4-drug. The GRIFFIN trial was a randomized phase 2 study involving approximately 210 patients. Patients were randomized to receive standard RVd versus daratumumab plus induction of RVd, followed in all patients by high-dose treatment and autologous transplant, then maintenance with either daratumumab and lenalidomide or lenalidomide alone in patients who had received RVd. This was the basic design of the study. With initial data analysis and initial presentation in 2020, it was clear that the addition of daratumumab resulted in a significant improvement in depth of response. This included traditional measures, such as strict complete response rates, but also MRDs [minimal residual disease] negativity, which is a critical endpoint in clinical trials in this era of myeloma treatment where depth of response is of interest and is becoming clinically more important in terms of treating patients.
The 3-year update showed us several important things. First, the depth of response that was seen with the addition of daratumumab persisted. There was an improvement in the level of MRD negativity with the clonoSEQ assay between years 2 and 3 of maintenance, showing that ongoing multi-agent maintenance therapy with lenalidomide and daratumumab led to this improvement in depth of the answer. 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. . Finally, there were no true additional cumulative toxicities associated with the use of daratumumab. Unsurprisingly, the daratumumab/lenalidomide combination is very well tolerated.
Noopur Raje, MD: I think you’ve summed up the GRIFFIN data pretty well. For me, the big takeaway is that the depth of the answers just gets deeper over time. The combination of 2 maintenance drugs, even beyond the 2-year period, had an impact.
Transcript edited for clarity.