1. IFM Phase II Study: KRd Induction and Consolidation Before Len Maintenance Highly Effective in Newly Diagnosed MM
New Findings in Hematology: Independent Conference Coverage of ASH 2016*; December 3-6, 2016; San Diego, California
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
KRd, carfilzomib/lenalidomide/dexamethasone; Len, lenalidomide; MM, multiple myeloma.
This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

2. KRd in Newly Diagnosed MM: Background
For pts with newly diagnosed MM, current standard of care includes:
Induction and consolidation with IMiDs, proteasome inhibitors, and corticosteroids
High-dose melphalan and ASCT followed by lenalidomide maintenance
Unclear whether further additional cycles of chemotherapy may improve survival
Risk of bortezomib AEs may hamper benefit of additional therapy
Carfilzomib: nonneurotoxic proteasome inhibitor that has demonstrated good results in both frontline and refractory/relapse settings[1-3]
Current trial evaluated prolonged use of carfilzomib as a replacement for bortezomib in initial therapy and consolidation regimens[4]
AE, adverse event; ASCT, autologous stem cell transplantation; IMiD, immunomodulatory drug; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma.
1. Chen R, et al. Discov Med. 2016;22:121: Jakubowiak AJ, et al. Blood Korde N, et al. JAMA Oncol. 2015;1: Roussel M, et al. ASH Abstract 1142
Slide credit: clinicaloptions.com

3. KRd in Newly Diagnosed MM: Phase II Study Design
Open-label, single-arm, multicenter study
Primary endpoint: sCR at completion of consolidation
Secondary endpoints: ORR at various points, MRD for pts with ≥ VGPR , safety/tolerability, PFS
Induction*
Carfilzomib 20/36 mg/m² IV Days 1, 2, 8, 9, 15, 16
Lenalidomide 25 mg Days 1-21
Dexamethasone 20 mg Days 1-2, 8-9, 15-16, (Cycles 1-4)
PBSC harvest (high-dose cyclophosphamide) followed by high-dose melphalan 200 mg/m2 and ASCT
Pts < 65 yrs of age
with symptomatic ND MM
(N = 46)
Consolidation*
Carfilzomib 36 mg/m² IV Days 1, 2, 8, 9, 15, 16
Lenalidomide 25 mg Days 1-21
Dexamethasone 20 mg Days 1-2, 8-9, 15-16, (Cycles 5-8)
Maintenance lenalidomide 10 mg Days 1-21 for 13 cycles*
ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; MRD, minimal residual disease; ND, newly diagnosed; PBSC, peripheral blood stem cell; sCR, stringent CR; VGPR, very good PR.
*Mandatory antithrombotic prophylaxis with low molecular weight heparin.
Slide credit: clinicaloptions.com
Roussel M, et al. ASH Abstract 1142.

4. KRd in Newly Diagnosed MM: Baseline Characteristics
Pt Characteristic
KRd Induction and Consolidation
(N = 46)
Median age, yrs (age)
56 (40-65)
Male, n (%)
32 (70)
ISS II + III, %
25 (54)
Median β2-macroglobulin level, mg/L (range)
2.8 ( )
Cytogenetics assessed, n 43
Standard risk, n (%)
High risk, n (%)
34 (79)
9 (21)
t(4;14), n (%)
del(17p), n (%)
5 (12)
4 (9)
ISS, International Staging System; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma.
Slide credit: clinicaloptions.com
Roussel M, et al. ASH Abstract 1142

5. KRd in Newly Diagnosed MM: Responses at End of Consolidation
Endpoint, n (%)
End of Consolidation
(N = 46)
sCR
26 (57)
MRD using flow cytometry
32 (70)
MRD using next-generation sequencing
23 of 34 (68)
≥ CR
28 (61)
≥ VGPR
39 (85)
ORR
41 (89) PD
1 (2)
KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; MRD, minimal residual disease; PD progressive disease; sCR, stringent CR; VGPR, very good PR.
Slide credit: clinicaloptions.com
Roussel M, et al. ASH Abstract 1142

6. KRd in Newly Diagnosed MM: Responses Throughout Treatment
Endpoint (N = 46), n
After Induction, n
After
ASCT, n
After of Consolidation, n
Best Response, n (%)
sCR 9 15 26
32 (70)
sCR + CR 11 19 28
35 (76)
VGPR 25 18
7 (15)
≥ VGPR 36 37 39
42 (91) PR 6 3 2 --
ORR 42 40 41
46 (100) PD 1
ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; PD progressive disease; sCR, stringent CR; VGPR, very good PR.
Slide credit: clinicaloptions.com
Roussel M, et al. ASH Abstract 1142

7. KRd in Newly Diagnosed MM: Progression and Survival
PD (n = 3): 1 before ASCT, 2 during maintenance
Death (n = 2): 1 during ASCT, 1 during follow-up
Median PFS: not reached (95% CI: 27.4-not reached)
Estimated 2-yr PFS: 91%
ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; PD progressive disease.
Slide credit: clinicaloptions.com
Roussel M, et al. ASH Abstract 1142

8. KRd in Newly Diagnosed MM: Grade 3/4 Adverse Events
Nonhematologic AE, n
KRd
Induction
Consolidation
Infections 7 1
Musculoskeletal disorders 5 2
Cardiovascular disorders --
GI disorders
Injury, poisoning, procedural complications
Hepatobiliary disorders
Skin/subcutaneous disorders
General disorders or administration site conditions
Grade 3/4 Hematologic AE, n
KRd Induction
KRd Consolidation
Neutropenia 6 12
Lymphopenia 5 17
Thrombocytopenia 1 7
Anemia --
No incidence of peripheral neuropathy reported
AE, adverse event; GI, gastrointestinal; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma.
Slide credit: clinicaloptions.com
Roussel M, et al. ASH Abstract 1142

9. KRd Induction and Consolidation KRd Induction and Consolidation
KRd in Newly Diagnosed MM: Serious AEs and Cardiovascular/Pulmonary Toxicity
Serious AE, n
KRd Induction and Consolidation
(n = 45)
Any 30
Infections/infestations 12
Musculoskeletal/connective tissue 9
Cardiac and vascular 8
Blood and lymphatic 3
Injury, poisoning, procedural complications
Gastrointestinal disorders 2
General disorders
Psychiatric disorders 1
Cardiovascular Toxicity,
All Grades, n
KRd Induction and Consolidation
(n = 45)
Cardiac failure 2
Pulmonary embolism
Venous thrombosis
Intracardiac thrombosis
Superficial thrombosis 1 8
Bradycardia
Arrhythmia
Atrial fibrillation
Tachycardia
Hypertension 4
Cough
Dyspnea 9 5
AE, adverse event; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma.
Slide credit: clinicaloptions.com
Roussel M, et al. ASH Abstract 1142

10. KRd in Newly Diagnosed MM: Conclusions
8 cycles of induction and consolidation with KRd in pts with ND MM was highly effective
61% CR/sCR at end of consolidation (primary endpoint)
70% of pts with negative MRD at end of consolidation
Time to response quicker than standard intensive VRd
At time of transplant, 78% achieved ≥ VGPR with KRd vs ~ 50% in historical VRD studies
No peripheral neuropathy but cardiovascular toxicity a concern
Mechanism of cardio-vascular events needs further investigation
KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; ND, newly diagnosed;; sCR, stringent CR; VGPR, very good PR; VRD, bortezomib/lenalidomide/dexamethasone.
Slide credit: clinicaloptions.com
Roussel M, et al. ASH Abstract 1142

11. Go Online for More CCO Coverage of ASH 2016!
Short slideset summaries of all the key data
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Leukemias
Lymphomas/CLL
Myeloma/plasma cell disorders
MDS and myeloproliferative neoplasms
clinicaloptions.com/oncology