Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients: Initial Results of a Multicenter, Open Label Phase II Study

Bringhen S et al.Proc EHA 2013;Abstract S578.

Background

VMP and MPT, which are standard therapies for elderly patients with newly diagnosed multiple myeloma (NDMM), induce about a 30% near-complete response/complete response rate, with a 35% discontinuation rate due to adverse events.

Carfilzomib, an irreversible proteasome inhibitor, has shown significant activity and favorable toxicity in MM.

Preliminary results with a combination of carfilzomib with cyclophosphamide and dexamethasone (CCd) showed encouraging activity in elderly patients with NDMM (Proc ASH 2012;Abstract 730).

Study objective: To present updated efficacy and safety results with the CCd regimen after 8 months of follow-up for patients with symptomatic NDMM who are ≥65 years old or ineligible for autologous stem cell transplantation.

Bringhen S et al. Proc EHA 2013;Abstract S578.

Phase II Study Design

Bringhen S et al. Proc EHA 2013;Abstract S578.

CCd InductionCycles 1-9

C MaintenanceUntil progression

Response Assessments

CarfilzomibDose (mg/m2)

Dosing CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE

Cyclophosphamide300 mg/m2 orally

Dexamethasone40 mg orally

Primary objectives:Safety: Grade 4 neutropenia (>3 d), Grade 4 thrombocytopenia (>7 d), Grade ≥3 nonhematologic toxicityEfficacy: Partial response (PR)

Cycle day

N = 58

Response Rate by Treatment Duration

With permission from Bringhen S et al. Proc EHA 2013;Abstract S578.

65

55

45

35

25

15

5

-5

% o

f p

ati

en

ts

100908070605040302010

0

% o

f p

ati

en

ts

Cycle 2 Cycle 4 Cycle 6 Cycle 9 Cycle 2 Cycle 4 Cycle 6 Cycle 9

CR = complete response; sCR = stringent complete response; nCR = near complete response; VGPR = very good partial response; PR = partial response

13

41

14

41

15

46

24

64

63

89

67

92

72

94

76

96

sCR sCR/CR/nCR ≥VGPR ≥PR

Subgroup Analysis of Best Response Rates

With permission from Bringhen S et al. Proc EHA 2013;Abstract S578.

% o

f p

ati

en

ts

ISS 1

* Defined as presence of t(4;14) or t(14;16) or del17p

sCR/CR/nCR ≥PR≥VGPR

ISS 2 ISS 3 Standard High*

100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

ISS stage FISH risk

37

56

87

50

72

89

29

57

86

45

64

87

29

65

88

Time to Response

With permission from Bringhen S et al. Proc EHA 2013;Abstract S578.

Median treatment duration, cycles (range): 8 (1-9)%

of

pati

en

ts

Months

1.00

0.75

0.50

0.25

0.00

PR

VGPR

CR/nCR

sCR

0.0 2.5 5.0 7.5 10.0 12.5 15.0

CR = complete response; sCR = stringent complete response; nCR = near complete response;VGPR = very good partial response; PR = partial response

Progression-Free and Overall Survival

PFS = progression-free survival; OS = overall survival

With permission from Bringhen S et al. Proc EHA 2013;Abstract S578.

PFS OS

Pati

en

ts (

%)

Time (months)

1.00

0.75

0.50

0.25

0.000.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Time (months)

1.00

0.75

0.50

0.25

0.000.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

1-year PFS

86%

1-year OS

87%

Adverse Events of All Grades

With permission from Bringhen S et al. Proc EHA 2013;Abstract S578.

Grade 3-5 adverse events — Cardiac: Acute myocardial infarction, atrial fibrillation, heart failure, hypertension; gastrointestinal: Ileum perforation; infections: Pneumonia, bronchitis

Hematologic Nonhematologic

Anemia

Neutropenia

Thrombocytopenia

Cardiac

Gastrointestinal

Fatigue

Infection

PNP

Respiratory

VTE

Carfilzomib dose reduction

Drug discontinuation

Percent of patients

0 10 20 30 40 60

70 8050 0 5 10 15

20 25 30 35 40

45 50

Percent of patients

Grade 1-2 Grade 3 Grade 4

Author Conclusions

CCd showed encouraging activity in elderly patients with NDMM in comparison to results with MPT and VMP from other studies.1-3 – ≥VGPR: 76% vs 36% (MPT) or 41% (VMP)– nCR/CR/sCR: 64% vs 27% (MPT) or 30%* (VMP)– sCR: 24% (not reported for MPT or VMP)

The CCd combination was well tolerated. Grade 3 or 4 adverse events included– Thrombocytopenia: 4% vs 3% (MPT) or 37% (VMP)– Peripheral neuropathy: 0% vs 6% (MPT) or 14% (VMP)– Venous thromboembolic events: 0% vs 9% (MPT) or 1% (VMP)– Treatment discontinuation: 11% vs 35% (MPT) or 33% (VMP)

Bringhen S et al. Proc EHA 2013;Abstract S578.

* CR only, nCR not reported1 Blood 2011;118:1239; 2 New Engl J Med 2008;359:906; 3 Lancet 2006;367:825

Investigator Commentary: Initial Results of the Phase II Study of CCd for Patients with NDMM

From this and several other studies, it is increasingly obvious that melphalan is much more toxic than dexamethasone and cyclophosphamide. Melphalan probably adds some benefit over cyclophosphamide and dexamethasone, but in continuous or maintenance therapy the advantages are limited and do not counterbalance the disadvantages of its toxicity. Cyclophosphamide is better tolerated than melphalan, including by patients older than 75 years.

More importantly, this study showed that it is possible to double the rate of CR or nCR with CCd (64%) in comparison to the VMP regimen (30%). Patients achieved a stringent CR of 24% with CCd. As other studies have demonstrated, carfilzomib is well tolerated. When it was used in doses up to 36 mg/m2 in patients older than 75, no major side effects were observed.

Interview with Antonio Palumbo, MD, August 12, 2013