A Curative Strategy for High-Risk Smoldering Multiple Myeloma?

In a phase II trial of patients with previously untreated smoldering multiple myeloma (SMM), the combination of carfilzomib, lenalidomide, and dexamethasone, followed by autologous hematopoietic cell transplantation (AHCT) and consolidation therapy, led to an overall response rate of 98 percent, with nearly half of patients experiencing a complete response (CR).

“This curative approach for high-risk SMM seems to be encouraging,” said María-Victoria Mateos, MD, PhD, from the University Hospital of Salamanca in Spain, during her presentation of results from the multicenter, open-label, phase II GEM-CESAR trial at the 2017 ASH Annual Meeting.

The study enrolled 90 patients with SMM at high risk of progression (defined as bone marrow [BM] plasma cells [PCs] ≥10% and serum M-protein ≥3d/dL, or 95% of aberrant PCs within the total PCs BM compartment). Patients with one or more biomarkers predicting “imminent risk of progression to MM” were included in GEM-CESAR, but they were regularly screened with computed tomography or positron-emission tomography scans. If bone disease was detected, they were excluded from the trial.

Patients were all older than 70 years (median age = 59 years; range not provided) and were candidates for AHCT. Twenty-eight patients (31%) had at least one of the MM biomarkers.

Per study protocol, patients were treated with:

  • induction: six, 4-week cycles of carfilzomib 36 mg/m2 twice-weekly, lenalidomide 25 mg on days 1-21, and dexamethasone 40 mg weekly
  • intensification: melphalan 200 mg/m2 followed by AHCT
  • consolidation: two cycles of carfilzomib, lenalidomide, and dexamethasone
  • maintenance: lenalidomide 10 mg on days 1-21 plus dexamethasone 20 mg weekly for up to two years

Minimal residual disease (MRD) was evaluated by next-generation flow cytometry after each treatment phase, and then once yearly.

Most patients (n=71) completed the six induction cycles, 42 had received intensification, 35 had received consolidation, and 29 were in the maintenance phase.

After a median follow-up of 10 months (range not provided), 69 patients (98%) responded to treatment after the completion of induction therapy, about half of whom had a CR or stringent CR (sCR). Two patients achieved CR but relapsed before the end of induction, the authors noted. The high response rates and rates of MRD-negativity after induction appeared to be maintained throughout each phase of treatment (see TABLE).

“The depth of response improved with the duration of treatment, achieving up to 85 percent CR or better in patients who completed induction, AHCT, and consolidation,” Dr. Mateos said. She also noted that, at 28-month follow-up, rates of progression-free survival and overall survival were 94 percent and 98 percent, respectively.

During each phase, no patients discontinued treatment because of adverse events (AEs), though four patients developed grade 3/4 neutropenia (2 during consolidation and 2 during maintenance). Treatment-related AEs included pneumonia (n=1), respiratory infection (n=1), infections (n=2), enterocolitis (n=1), cutaneous exanthema (n=1), meningitis (n=1), and massive ischemic stroke (n=1). The safety profile was acceptable, the authors wrote, adding that, “although infections are the most frequent treatment-related AEs, most were mild and manageable.”

The lack of a comparator arm limits the study’s findings. The trial defined cure as MRD negativity sustained for at least five years, so longer-term follow-up is needed to confirm whether this approach is actually curative.

The authors report relationships with Amgen and Celgene, manufacturers of carfilzomib and lenalidomide.


Mateos MV, Lopez JM, Rodrigues-Otero P, et al. Curative strategy for high-risk smoldering myeloma (GEM-CESAR): carfilzomib, lenalidomide and dexamethasone (KRd) as induction followed by HGT-ASCT, consolidation with KRd and maintenance with Rd. Abstract #402. Presented at the 2017 American Society of Hematology Annual Meeting, December 10, 2017; Atlanta, GA.