Aggressive Approach to High-Risk Smoldering Myeloma Gains Consensus

December 2020, Vol 11, No 6

Although smoldering myeloma is acknowledged as a clinical entity, debate continues about whether to treat, when to treat, and how to treat this condition, said Natalie S. Callander, MD, Leader, Myeloma/Lymphoma Disease-Oriented Team, University of Wisconsin Carbone Cancer Center, Madison, at the 2020 NCCN hematologic malignancies conference.

“The definitions [of smoldering myeloma] vary in different countries, and the epidemiology is uncertain. In the US there is no diagnostic code for this entity, so estimates of the number of patients with smoldering myeloma are based on patients in the database with a code for multiple myeloma who have not been treated for the past 6 months. Based on that, about 10% to 15% of patients with the code for multiple myeloma have smoldering myeloma, and they tend to be women, older, and more often African American,” Dr Callander explained.

The SLiM CRAB criteria are used to determine which patients with smoldering myeloma are likely to have disease progression. These criteria include a high M-protein level, >60% bone marrow plasma cells (BMPC), and a serum free light chain (FLC) ratio of ≥100.

Advanced imaging that are needed to differentiate between smoldering myeloma and multiple myeloma include positron emission tomography (PET), magnetic resonance imaging (MRI), computed tomography (CT), and 18F-fluorodeoxyglucose (FDG)-PET.

“If you are going to categorize smoldering myeloma, you need to show that a patient does not have multiple myeloma by advanced imaging, including PET, whole-body MRI, low-dose whole-body CT, and FDG-PET,” Dr Callander said. “Advanced imaging will upstage 15% to 25% of patients previously classified as having smoldering myeloma.”

The 20/2/20 model is now replacing the SLiM CRAB criteria to stratify patients. The 20/2/20 criteria include the presence of >20% BMPC, an M-protein spike of >2 g/dL, and an FLC ratio of >20.

“This is a simpler model [than SLiM CRAB] and easy to use in clinical practice to stratify smoldering myeloma patients for progression,” Dr Callander said. “It has been validated in a larger study and will be used for clinical trials.”

The Goals of Treatment

The goals of treatment of smoldering myeloma are currently a matter of debate. Some hematologists/oncologists believe that the goal of treatment should be slowing the progression of disease, whereas others believe that aggressive treatment is important and may represent a cure, Dr Callander stated.

The QuiRedex study, a multicenter, randomized clinical trial, showed that in 119 patients with high-risk smoldering myeloma, treatment with lenalidomide (Revlimid) plus dexamethasone for 2 years slowed the disease progression by 66% versus observation. Quality of life was similar in the 2 study arms, and no increase in secondary malignancies was observed. The intervention had no effect on low-risk patients with smoldering myeloma.

“The results were quite striking, but there was some toxicity,” she noted.

In a small clinical trial of 18 patients with high-risk smoldering myeloma, all patients received aggressive treatment with carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd) for 8 cycles, followed by lenalidomide maintenance treatment. The rate of very good partial response was 100%. The minimal residual disease (MRD) rate was 63%, although the importance of that finding is not clear.

The phase 2 GEM-CESAR study included patients with high-risk smoldering myeloma. Approximately 32% of the patients met the SLiM CRAB criteria for smoldering myeloma. The study evaluated the use of 6 cycles of KRd as induction therapy, followed by autologous stem-cell transplant, then KRd as consolidation therapy, then lenalidomide plus dexamethasone for 2 years. The median age of the patients was 59 years. Approximately 32% of the patients met the SLiM CRAB criteria for smoldering myeloma. At 28 months, the overall survival rate was 98% and the progression-free survival (PFS) rate was 93%.

The ASCENT study is designed to evaluate treatment with KRd plus daratumumab (Darzalex) for 6 cycles, followed by 6 additional cycles as consolidation therapy, then maintenance therapy with lenalidomide and daratumumab for 12 cycles. To date, 50 patients with smoldering myeloma have been enrolled in the study. MRD status and best response will be evaluated at each phase of the study.

CENTAURUS was a phase 2 clinical trial that evaluated the use of single-agent daratumumab with intensive dosing in patients with smoldering myeloma. The 2-year PFS rate was 90%.

“There are lots of trials in the smoldering myeloma space, and many have been negative,” Dr Callander said. “At ECOG [Eastern Cooperative Oncology Group], we think we should treat people who would benefit the most.”

The phase 3 EA173 study will compare split-dose daratumumab plus lenalidomide and dexamethasone versus lenalidomide plus dexamethasone alone in patients with high-risk smoldering myeloma. Study entry criteria will incorporate the 20/2/20 model. Patients will undergo imaging with PET and MRI, and the MRD status will be evaluated. In addition, patients’ and physicians’ rating of side effects, as well as quality-of-life measures, will be assessed. Thus far, 48 of a planned 288 patients have been enrolled in the study.

The Takeaway

In conclusion, Dr Callander advised listeners, “The high-risk group of patients with smoldering myeloma should be treated, and a clinical trial is preferred. They have a 20% to 40% risk of progression over the next 2 years. Patients with low-risk smoldering myeloma should be followed by observation with repeat imaging every 1 to 2 years,” she emphasized.

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