presentation slides - The Myeloma Beacon

Carfilzomib, Lenalidomide, and
Dexamethasone vs Lenalidomide and
Dexamethasone in Patients with
Relapsed Multiple Myeloma:
Interim Results from ASPIRE, a
Randomized, Open-Label, Multicenter Phase
3 Study
A. Keith Stewart, S. Vincent Rajkumar, Meletios A. Dimopoulos, Tamás
Masszi, Ivan Spicka, Albert Oriol, Roman Hájek, Laura Rosiñol, David S.
Siegel, Georgi G. Mihaylov, Vesselina Goranova-Marinova, Péter Rajnics,
Aleksandr Suvorov, Ruben Niesvizky, Andrzej Jakubowiak, Jesus F. San
Miguel, Heinz Ludwig, Naseem Zojwalla, Margaret E. Tonda, Biao Xing,
Philippe Moreau and Antonio Palumbo
1
Background
 Phase 3 trials confirmed lenalidomide plus high-dose dexamethasone
(RD) as a reference treatment for relapsed multiple myeloma (MM)
 Lenalidomide plus weekly low-dose dexamethasone (Rd) is less toxic
than RD, while yielding similar response rates
 Carfilzomib is an irreversible epoxyketone proteasome inhibitor
approved in the United States as a single agent in relapsed and
refractory MM
 Carfilzomib, lenalidomide, and weekly dexamethasone (KRd) was well
tolerated in phase 1/2 trials with encouraging clinical activity in newly
diagnosed and relapsed MM
2
ASPIRE: Carfilzomib, Lenalidomide, and Dexamethasone
(KRd) vs Lenalidomide and Dexamethasone (Rd)
 Primary endpoint: PFS
 Secondary endpoints: OS, ORR, DOR, health-related QOL, safety
Key inclusion criteria:
Key exclusion criteria:
• Symptomatic MM
• Creatinine clearance <50 mL/min
• Measurable disease
• PD while on bortezomib
• 1–3 prior treatments
• If previously treated with Rd:
• Relapsed or progressive disease
• ≥PR to at least 1 prior regimen
− PD during the first 3 months
of any treatment
− PD at any time if Rd was the
most recent treatment
• Lenalidomide or dexamethasone
intolerance
3
ASPIRE Study Design
28-day cycles
KRd
Carfilzomib 27 mg/m2 IV (10 min)
Randomization
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)
N=792
Lenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
Stratification:
• β2-microglobulin
After cycle 12, carfilzomib given on days 1, 2, 15, 16
After cycle 18, carfilzomib discontinued
• Prior bortezomib
• Prior lenalidomide
Rd
Lenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
4
Patient and Disease Characteristics at Baseline
Intent-to-Treat (ITT) Population (N=792)
KRd
Rd
(n=396)
(n=396)
64 (38–87)
65 (31–91)
46.7
52.5
0–1
89.9
91.2
2
10.1
8.8
High
12.1
13.1
Standard
37.1
42.9
Unknown
50.8
43.9
85.0 (28.9)
85.9 (30.2)
93.4
90.4
80.6
80.6
Characteristic
Median age, years (range)
≥65 years, %
ECOG performance status, %
Cytogenetic risk category by FISH, %
Mean creatinine clearance, mL/min (SD)
≥50 mL/min, %
Serum β2-microglobulin
≥2.5 mg/L, %
5
ECOG, Eastern Cooperative Oncology Group; FISH, fluorescence in situ hybridization; SD, standard deviation.
Patient and Disease Characteristics at Baseline (continued)
ITT Population (N=792)
Characteristic
Presence of neuropathy at baseline, %
KRd
Rd
(n=396) (n=396)
36.4
34.6
2 (1–3)
2 (1–3)
Transplant
54.8
57.8
Bortezomib
65.9
65.7
15.2
14.6
Lenalidomide
19.9
19.7
Any IMiD
58.8
57.8
21.5
22.2
36.9
35.1
6.1
6.8
Number of prior regimens, median (range)
Prior therapies, %
Non-responsive to prior bortezomib*
Refractory to prior IMiD in any prior regimen
Bortezomib and IMiD
Non-responsive to prior bortezomib* and refractory to prior IMiD
*Non-responsive is defined as less-than-minimal response to any bortezomib-containing regimen, disease progression during any bortezomibcontaining regimen, or disease progression within 60 days after the completion of any bortezomib-containing regimen.
6
Primary Endpoint: Progression-Free Survival
ITT Population (N=792)
KRd
(n=396)
Proportion Surviving
Without Progression
1.0
Median PFS, mo
HR (KRd/Rd) (95% CI)
P value (one-sided)
0.8
Rd
(n=396)
26.3
17.6
0.69 (0.57–0.83)
<0.0001
0.6
0.4
0.2
KRd
Rd
0.0
No. at Risk:
KRd
Rd
7
0
6
396
396
332
287
12
18
24
30
36
Months Since Randomization
279
206
222
151
179
117
112
72
24
18
42
1
1
48
Primary Endpoint: Progression-Free Survival by Subgroup
KRd
(n)
396
Rd
(n)
396
HR (95% CI)
Intent-to-treat group
Overall
Subgroup
Age, years
18–64
211
188
≥65
185
208
Risk group by FISH
High-risk
48
52
Standard-risk
147
170
ß2-microglobulin, mg/L
<2.5
68
71
≥2.5
324
319
Prior treatment with bortezomib
No
135
136
Yes
261
260
Prior treatment with lenalidomide
No
317
318
Yes
79
78
Non-responsive to bortezomib in any prior regimen
No
336
338
Yes
60
58
Refractory to IMiD in any prior regimen
No
311
308
Yes
85
88
0.25
8
0.50
0.75
Favors KRd
1.00
HR
1.25
1.50
Favors Rd
1.75
PFS by Risk Group
KRd
(n=396)
9
Rd
(n=396)
Risk
Group by
FISH
N
Median,
months
N
Median,
months
HR
P-value
(one-sided)
High
48
23.1
52
13.9
0.70
0.083
Standard
147
29.6
170
19.5
0.66
0.004
Secondary Endpoints: Response
P<.0001
100
Percentage of Patients
90
80
70
P<.0001
sCR
14.1% vs 4.3%
69.9
87.1
66.7
60
50
P<.0001
40.4
40
30
KRd
Rd
31.8
20
10
9.3
0
≥CR
≥VGPR
ORR (≥PR)
 Median duration of response was 28.6 months in the KRd group and 21.2 months in
the Rd group
10
PFS by Response Category in the KRd Group
+ Censored
Survival Probability
1.0
sCR
CR
VGPR
PR
MR
SD
PD
0.8
0.6
0.4
0.2
0.0
0
10
20
30
Time From Randomization
(Months)
11
40
50
Secondary Endpoints: Interim Overall Survival Analysis
Median Follow-Up 32 Months
KRd
(n=396)
Proportion Surviving
1.0
Median OS, mo
HR (KRd/Rd) (95% CI)
P value (one-sided)
0.8
NE
NE
0.79 (0.63–0.99)
0.018
0.6
0.4
0.2
KRd
Rd
0.0
0
No. at Risk:
KRd
Rd
6
12
18
24
30
36
42
48
Months Since Randomization
396
396
369
356
343
313
315
281
280
237
191
144
52
39
2
3
 Median OS was not reached; results did not cross the prespecified stopping
boundary (P=0.005) at the interim analysis
12
Rd
(n=396)
Kaplan-Meier 24-Month Overall Survival Rates
80
Percentage of Patients
70
60
50
40
30
73.3%
65.0%
KRd
Rd
20
10
0
•
13
Unadjusted P value from the stratified log-rank test comparing the overall
survival curves up to 24 months was 0.0046
Adverse Events (AEs), Treatment Discontinuations, and Deaths
Safety Population (n=781)
KRd
Rd
(n=392)
(n=389)
Median treatment duration, weeks (range)
88.0
57.0
Any AE, %
96.9
97.2
83.7
80.7
69.9
77.9
Discontinuation due to disease progression
39.8
50.1
Discontinuation due to AE
15.3
17.7
Serious AE, %
59.7
53.7
Deaths within 30 days of last dose, %
7.7
8.5
Deaths due to disease progression
0.5
1.3
Deaths due to AEs
6.9
6.9
Category
Grade ≥3 treatment-emergent AE
Treatment discontinuations, %
14
AEs Occurring in ≥25% of Patients in Either Arm
KRd (n=392)
Rd (n=389)
AE, %
All Grade
Grade ≥3
All Grade
Grade ≥3
Anemia
42.6
17.9
39.8
17.2
Neutropenia
37.8
29.6
33.7
26.5
Thrombocytopenia
29.1
16.6
22.6
12.3
Hematologic AEs
15
AEs Occurring in ≥25% of Patients in Either Arm
KRd (n=392)
Rd (n=389)
AE, %
All Grade
Grade ≥3
All Grade
Grade ≥3
Diarrhea
42.3
3.8
33.7
4.1
Fatigue
32.9
7.7
30.6
6.4
Cough
28.8
0.3
17.2
0
Pyrexia
28.6
1.8
20.8
0.5
Upper respiratory tract infection
28.6
1.8
19.3
1.0
Hypokalemia
27.6
9.4
13.4
4.9
Muscle spasms
26.5
1.0
21.1
0.8
Non-hematologic AEs
16
Other AEs of Interest
Safety Population (n=781)
KRd (n=392)
Rd (n=389)
AE, %
All Grade
Grade ≥3
All Grade
Grade ≥3
Dyspnea
19.4
2.8
14.9
1.8
Peripheral neuropathy*
17.1
2.6
17.0
3.1
Hypertension
14.3
4.3
6.9
1.8
Acute renal failure*
8.4
3.3
7.2
3.1
Cardiac failure*
6.4
3.8
4.1
1.8
Deep vein thrombosis
6.6
1.8
3.9
1.0
Ischemic heart disease*
5.9
3.3
4.6
2.1
Pulmonary embolism
3.6
3.1
2.3
2.3
Second primary malignancy*
2.8
2.3
3.3
2.8
17
*Grouped term.
EORTC QLQ-C30 Global Health Status/Quality-of-Life Score
Health-Related Quality-of-Life
18
70
Carfilzomib group
Control group
EORTC Global Health Status improved
in the KRd group vs the Rd group over
18 cycles of treatment (P=0.0001)
65
60
55
50
Cycle 1
(Baseline)
Cycle 3
Cycle 6
Cycle 12
Assessment Time Point (Day 1)
Cycle 18
Conclusions
 PFS was significantly improved by 8.7 months with KRd
(HR, 0.69; P<0.0001)
‒An unprecedented median PFS of 26.3 months with
KRd
 Interim OS analysis: trend in OS favoring the KRd group;
Kaplan-Meier 24-month OS rates 73.3% (KRd) versus
65.0% (Rd)
 ORR was higher with KRd (87.1% vs 66.7%); significantly
more patients achieved ≥CR (31.8% vs 9.3%)
19
Conclusions (continued)
 AEs led to fewer discontinuations in the KRd group, and
patients remained on study treatment longer
‒Cardiac and renal events were reported at rates
consistent with or lower than prior studies of
single-agent carfilzomib
 KRd consistently improved health-related quality of life
(Global Health Status) compared with Rd over 18 cycles
of treatment
 KRd represents a new standard of care in relapsed MM
20
Acknowledgements
 We thank the following additional investigators:
Austria: Hermine Agis, Hedwig Kasparu; Belgium: Michel Delforge, Hilde Demuynck, Nathalie Meuleman, Pascal
Pierre, Henri Schots, Jan Van Droogenbroeck, Marie-Christiane Vekemans, Ka Lung Wu; Bulgaria: Stefcho
Goranov, Liana Gercheva, Nikolay Tzvetkov, Julian Raynov, Janet Grudeva; Canada: Nizar Bahlis, Andrew Belch,
Chaim Shustik, Sarit Assouline, Matthew Cheung, Kevin Song, Kuljit Grewal, Vi Dao, Vishal Kukreti; Czech
Republic: Vladimir Maisnar, Roman Hajek, Vlastimil Scudla, Evzen Gregora; France: François Boue, Jean-Claude
Eisenmann, Thierry Facon, Cyrille Hulin, Eric Voog, Michel Attal, Laurent Garderet; Germany: Patrick Brück, Ralph
Naumann, Stefan Knop, Hartmut Goldschmidt, Frank Griesinger, Martin Kropff, Helmut Ostermann, Eckhart
Weidmann, Roland Fenk, Michael Pfreundschuh, Georgia Schilling; Greece: Argirios Symeonidis; Hungary: Janos
Jakucs, Miklos Egyed, Tamas Masszi, Zoltan Gasztonyi, Agnes Nagy, Zita Borbenyi, Arpad Illes, Miklos Udvardy;
Israel: Dina Ben-Yehuda, Andrei Braester, Riva Fineman, Itai Levi, Arnon Nagler, Hila Magen-Nativ, Lev Shvidel;
Italy: Anna Cafro, Paolo De Fabritiis, Gianluca Gaidano, Mario Petrini; Netherlands: Pieter Sonneveld, Sonja
Zweegman; Poland: Tadeusz Robak, Andrzej Hellmann, Paweł Wiszniewski, Sławomir Górnik, Jan Walewski,
Mieczyslaw Komarnicki, Malgorzata Calbecka, Slawomira Kyrcz-Krzemien, Andrzej Moskwa, Alina Urbanowicz;
Romania: Anca Lupu, Horia Bumbea, Andreea Moicean, Catalin Danaila, Galafteon Oltean; Russia: Kudrat
Abdulkadyrov, Boris Afanasyev, Yulia Alexeeva, Dzhelil Osmanov, Galina Salogub, Nuriet Khuazheva, Larisa
Mendeleeva, Irina Sokolova; Serbia: Dragomir Marisavljevic, Aleksandar Savic, Jelena Bila, Lana MacukanovicGolubovic, Ljiljana Tukic; Spain: Maria Echeveste Gutierrez, Jose Maria Grasa Ullrich, Felipe Prósper, Maria
Victoria Mateos, Javier De la Rubia, Laura Rosiñol; Sweden: Cecilie Blimark, Hareth Nahi; United Kingdom: Simon
Bolam, Faith Davies, Heather Oakervee, Mary Drake, Ashutosh Wechalekar, Cathy Williams, Fenella Willis,
Supratik Basu; United States: Moshe Talpaz, Luhua Wang, Francis Buadi, William Bensinger, Peter Lee,
Parameswaran Venugopal, Guangzhi Qu, Jeffrey Matous, Stewart Sharp, Parameswaran Hari, Sundar Jagannath,
Ian Anderson, George Carrum, Vaishali Sanchorawala, Veena Charu, Gustavo Fonseca, Cristina Gasparetto, Kelly
Pendergrass, Jitendra Gandhi, Delva Deauna-Limayo, Kanwaldeep Kaur Rasila, Steven Coutre, Todd Zimmerman,
Kathleen Halka, Larry Anderson, Madhu Midathada, Edward Agura, Rafat Abonour, Kenneth Meehan, Amitabha
Mazumder, Peter Rosen
21
Acknowledgements (continued)
 We are grateful to the patients for their participation in the ASPIRE
study
 We also thank the members of the data monitoring and independent
review committees
 The ASPIRE study was supported by Onyx Pharmaceuticals, Inc., an
Amgen subsidiary
 Editorial assistance was provided by BlueMomentum, a division of
KnowledgePoint360, an Ashfield Company, and supported by Onyx
Pharmaceuticals, Inc., an Amgen subsidiary
22

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