EHA 2019 | GEM-CESAR shows promise for smoldering MM: KRd + HDT-ASCT therapy

On Saturday 15 June at the 24^th Congress of the European Hematology Association (EHA), Maria Victoria Mateos from the University Hospital of Salamanca, Salamanca, ES, presented the results of the GEM-CESAR phase II clinical trial. This study assessed the curative potential of carfilzomib, lenalidomide, and dexamethasone combination in patients with high-risk smoldering multiple myeloma (SMM).¹

SMM is an asymptomatic intermediate between active myeloma and the precursor stage, monoclonal gammopathy of undetermined significance (MGUS). Both the Spanish Myeloma Group and that of the Mayo Clinic (US), have shown that the early addition of lenalidomide to treatment significantly prevents SMM progression to active MM.^2,3 This trial sought to further assess the potential benefit of lenalidomide plus carfilzomib and dexamethasone (KRd) in SMM.

The primary endpoint of this single-arm trial was to increase minimal residual disease (MRD) negativity from 34% to ≥50%, as assessed by next generation flow cytometry (NGF). MRD was measured at three and five years post high-dose therapy (HDT) and autologous stem cell transplantation (ASCT; HDT-ASCT). Secondary objectives included response rates, time-to-progression (TTP), progression-free survival (PFS), overall survival (OS), and safety.

Study design & baseline characteristics

• N=90 patients with SMM at high risk of progression, aged <70 years, eligible for transplantation
• Dosing schedule:
  1. First stage. Induction KRd therapy (six 4-week cycles; n=90):
     • Carfilzomib (K): 36 mg/m² twice weekly
     • Lenalidomide (R): 25 mg on Days 1–21
     • Dexamethasone (d): 40 mg weekly
  2. Second stage. HDT-ASCT therapy (n=83):
     • Melphalan: 200 mg/m² followed by ASCT
     • ASCT: granulocyte colony-stimulating factor (G-CSF) was used in 93% of patients, while plerixafor in the rest 7%
  3. Third stage. Consolidation KRd therapy (two 4-week cycles; n=83):
     • K: 36 mg/m² twice weekly
     • R: 10 mg on Days 1–21
     • d: 20 mg weekly
  4. Maintenance stage:
     • KRd dosing same as in third stage for up to 2 years

• Table 1. Baseline characteristics:

PCBMI, plasma cells bone marrow infiltration; sFLC, serum free light chain
Baseline characteristic	Patient cohort (N=90)
Median age (range)	59 (33–70)
PCBMI (range)	22% (10–80)
High-risk classification by: Mayo Clinic model Spanish model Both	21% 52% 27%
Ultra high-risk patients with one or more of following: sFLC>100 >1 focal lesion on MRI ≥60% PCBMI	20% 12% 8%
PET without lytic lesions	6%
Cytogenetic abnormalities: Standard risk High-risk Unknown	62% 23% 14%

Key findings

• Table 2. Key response outcomes after induction therapy (stage 1):

CR, complete response; MRD, minimum residual disease; ORR, overall response rate; PD, progressive disease; PR, partial response; SDS, stable disease; VGPR, very good partial response
Stage 1	After induction therapy (n=90)	High-risk patients (n=60)	Ultra high-risk patients (n=30)
ORR	94%	95%	93%
≥CR	41%	40%	43%
VGPR	39%	42%	33%
PR	14%	13%	17%
SD	1%	2%	-
PD	3%	2%	3%
MRD negativity rate	30%	28%	33%

• Table 3. Key response outcomes after HDT-ASCT therapy (stage 2):

CR, complete response; HDT-ASCT,  high-dose therapy  autologous stem cell transplantation; MRD, minimum residual disease; ORR, overall response rate; PD, progressive disease; PR, partial response; SDS, stable disease; VGPR, very good partial response
Stage 2	After HDT-ASCT (n=83)	High-risk patients (n=55)	Ultra high-risk patients (n=28)
ORR	99%	95%	100%
≥CR	64%	64%	64%
VGPR	22%	22%	21%
PR	13%	13%	14%
SD	1%	2%	-
PD	-	-	-
MRD negativity rate	56%	58%	54%

• Table 4. Key response outcomes after consolidation therapy (stage 3):

CR, complete response;  MRD, minimum residual disease; ORR, overall response rate; PD, progressive disease; PR, partial response; SDS, stable disease; VGPR, very good partial response
Stage 2	After consolidation therapy (n=83)	High-risk patients (n=55)	Ultra high-risk patients (n=28)
ORR	100%	100%	100%
≥CR	76%	78%	71%
VGPR	18%	18%	18%
PR	6%	4%	11%
SD	-	-	-
PD	-	-	-
MRD negativity rate	61%	65%	53%

• After 1 year of maintenance therapy and treatment completion (n=40):
  • ≥CR rate: 85%
  • VGPR: 10%
  • PR: 5%
  • MRD negativity rate: 68%
• At 28 months follow-up:
  • OS rate: 98%
  • Two patients died
• At 30 months follow-up:
  • PFS rate: 93%
  • Five patients progressed biochemically

Safety

Induction (stage 1)

• Most common Grade 3–4 adverse events (AEs) of any kind were:
  • Infections: 10%
  • Skin rash: 9%
  • Thrombocytopenia: 5%
  • Neutropenia: 3%
  • Cardiological events (heart failure): 1%

HDT-ASCT (stage 2)

• Five patients did not proceed to HDT-ASCT
• No transplantation-related mortality or other transplantation-related toxicities were reported
• Eleven patients required a second mobilization
• Two mobilizations failed
• No patient discontinued treatment during or in 100 days after HDT-ASCT

Consolidation & maintenance (stages 3 & 4)

• Most common Grade 3–4 AEs of any kind were:
  • Neutropenia: 8%
  • Thrombocytopenia: 8%
  • Infections: 5%

Conclusions

• The results of this trial are very promising for SMM patients as 85% of patients involved in the study remain in CR at the KRd maintenance stage
• The trial reached its primary objective, with an MRD negativity rate of 68% at maintenance
• Infections were the most common treatment-emergent AE during KRd induction, but the overall safety profile of KRd with or without HDT-ASCT was tolerable and manageable