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Relapsed/ Refractory Myeloma - update
Sep 2015
Natural History of MM
MGUS or smoldering myeloma
Asymptomatic Symptomatic
ACTIVE MYELOMA
M P
rote
in (g
/L)
20
50
100
1. RELAPSE
2. RELAPSE
REFRACTORY RELAPSE
First-line therapy
Plateau remission
Second-line Third-line
Relapsed/ Refractory Myeloma
• Definitions changing • Double refractory Myeloma • Challenges in management • Treatment approach • Treatment options
Definitions
• Primary refractory Myeloma - never achieved a minimal response or better with induction therapy
• Relapsed Myeloma - Relapsing disease after a period of remission to induction therapy
• Relapsed & Refractory Myeloma - disease that is not responsive to salvage therapy or progresses within 60
days of last therapy in patients who achieve MR
• Double refractory Myeloma - Disease refractory to lenalidomide and bortezomib therapy
RajKumar et al Blood 2011;117(18):4691-4695
Double refractory Myeloma
• Refractory to IMiD and Bortezomib • Double-refractory disease, prognosis is poor, with
a median overall survival (OS) and progression-free survival (PFS) of 9 months and 5 months1
• Relatively frailer phenotype ( low counts, renal impairment, poor PS) and complex genotype ( clonal tides, enrichment of high risk genetic features) adds to the complexity
• Carfilzomib (FDA) and pomalidomide are approved agents in this setting
S Kumar Leukemia. 2012;26(1):149–57
Case No 1
• 50 year old male presented with back pain and hip pain. No sig PMH
• IgA lambda paraprotein, Renal impairment creatinine 350 umol/L and anaemia, ISS 3 – IgA kappa MM. No high risk genetic features
• Started on Velcade and dexamethasone, radiotherapy to hip and vertebroplasty to L2 compression fracture
• LC continue to rise, give VCD x 2 – SD • Ongoing pain and renal impairment started on
BTD x 4 – Minimal response
Case No 1 • DTPACE with carboplatin x 2 – PR and VTD x 2 • Stem cells mobilised with plerixafor • Pre transplant marrow 80% PC • ASCT – Reduced dose melphalan conditioning • Achieved PR • Started on cyclo/ Len/ Dex 2 months post
transplant • Now on Len maintenance almost 2 years out • ECOG -1 back to work • Primary refractory myeloma
Case No 2
• 58 year old lady diagnosed with MM 2006 • IgA MM - ISS1. No significant PMH • Treated with CTD followed by ASCT – 2007 • Biochemical relapse 2010 – Treated on
Myeloma X trial • Received 4 x PAD chemo followed by Second
ASCT • Well until 2012
Case no 2
• Relapse with rising paraprotein and bone pain March 2012
• Started on Bisphosphonates and Cyclo/ Len ? Dex • Achieved Partial response • Switched to Len monotherapy maintenance Dec
2012 • Current in good partial response with ECOG 1 • Biochemical relapse and eligible for second
transplant
Case No 3
• 66 year old lady presented with anemia and bone pain, Jan 2013
• IgA Kappa MM , ISS 1, Genetics failed • CTD x 6 – VGPR, tolerated therapy well apart
form mild SOB • Stem cells collected • ASCT with HDM conditioning July 2013
Case No 3
• Well apart form back pain • Attends routine monitoring March 2014 , MRI
done – Unremarkable in CR confirmed by marrow
• Admitted July 2014 with back pain anuria , creatinine 530 umol/l. Started on dialysis
• BM – 60% PC, t(4:14) and del p53 on MM FISH • Treated with VTD x 3 – progressive disease
Case No 3
• BTD x 2 – Partial response • Thalidomide related tremors, Thal held.
Progressive disease. • Switched to Lenalidomide / Dex - SD, poor QoL • Palliated and RIP Nov 2014 • Early relapse with high risk features
Assessment of relapsed MM
• Patient related factors * Age & Performance status * Frailty & Comorbidity * Marrow reserve, renal function, pre existing toxicity
• Disease/ Treatment related factors * Initial & subsequent therapy – duration, response, tolerance * Remission period * Genetic features * Number of relapses
Questions at relapse 1. To treat or not to treat asymptomatic relapses. When treatment can be safely delayed? 2. When retreatment should be considered. What should be the response duration cutoff? 3. Can drugs be chosen based on disease biology? 4. How to use available drugs- Sequential approach? Multidrug combination approach? 5. For how long should a relapse treatment be continued?Limited number of cycles? Indefinite? 6. When to consider a rescue second ASCT? What should be the minimal response duration from the first ASCT? 7. Is there a role for allogeneic transplantation? When should it be considered?
Current Treatment options
• Lenalidomide based therapy • Bortezomib based therapy • Bortezomib re treatment • DRMM – Pomalidomide based therapy,
Bendamustine based therapy
Lenalidomide + dexamethasone: International multicentre clinical trials
Lenalidomide Phase III study design1,2
RANDOMISE
Endpoints
► Primary endpoint: time to progression (TTP)
► Secondary endpoints – Response rate, overall survival, safety
* Study MM-009: 48 centres; U.S. and Canada (N=353) ** Study MM-010: 50 centres; Europe, Australia and Israel (N=351)
1.Weber DM, et al. N Engl J Med. 2007;357:2133-42. 2.Dimopoulos MA, et al. N Engl J Med. 2007;357:2123-32.
Lenalidomide + dex delivers a significantly superior response compared with dex alone in relapsed/refractory multiple myeloma
Pooled analysis from MM-009 and MM-010 shows statistically significant higher response rates for lenalidomide + dex compared with dex alone1
Len= lenalidomide Len + dex = lenalidomide + dexamethasone CR = complete response VGPR = very good partial response PR = partial response
References: 1.Dimopoulos MA, et al.
Leukemia. 2009;23:2147-2152
Lenalidomide + dex significantly improves TTP compared with dex alone1
References: 1.Dimopoulos MA, et al. Leukemia.
2009;23:2147-2152
Lenalidomide + dex increased overall survival compared with dex alone1
• At a median follow-up of 48 months for surviving patients, a significant benefit in overall survival (median of 38.0 vs 31.6 months, P=0.045) was retained in the lenalidomide + dex arm1. This was achieved despite nearly half the patients in the control group receiving lenalidomide at the time of disease progression or study unblinding, which may have contributed to a greater than expected overall survival in the dex only patient group.
References: 1.Dimopoulos MA, et al. Leukemia.
2009;23:2147-2152
Len= lenalidomide Len + dex = lenalidomide + dexamethasone dex - dexamethasone
Response rates with lenalidomide higher when patients are treated in earlier lines1
CR = complete response VGPR = very good partial response PR = partial response
References: 1.Stadtmauer EA, et al. Eur J
Haematol. 2009;82(6):426-32.
Lenalidomide at first relapse
References: 1.Stadtmauer EA, et al. Eur J Haematol.
2009;82(6):426-32.
Phase III APEX Trial: Bortezomib vs High-Dose Dexamethasone in Relapsed
MM
Richardson P, et al. N Engl J Med. 2005;352:2487-2498.
Pts with relapsed MM following 1-3
therapies, not refractory to
dexamethasone
(N = 669)
Dexamethasone 40 mg PO* Days 1-4, 9-12, and 17-20
for four 5-wk cycles (n = 336)
Bortezomib 1.3 mg/m2 IV Days 1, 4, 8, 11
for eight 3-wk cycles (n = 333)
Treatment for 280 days
*Pts who progressed on dexamethasone allowed to cross over to receive bortezomib in a companion study.
Dexamethasone 40 mg PO Days 1-4
for four 5-wk cycles
Bortezomib 1.3 mg/m2 IV Days 1, 8, 15, 22
for three 5-wk cycles
Treatment for 273 days
Induction Maintenance
Time to progression – APEX study
Richardson P, et al. Blood. 2007;110:3557-3560.
Phase III APEX Trial: OS (Extended Follow-up)
Median OS
– Bortezomib: 29.8 months
– Dexamethasone: 23.7 months
– P = .027
> 62% of dexamethasone-treated pts crossed over to receive bortezomib
– 1-yr survival rate 80% for bortezomib vs 67% for dexamethasone (P = .001)
Bortezomib retreatment - RETRIEVE study
British Journal of Haematology, 2013, 160, 649–659
RETRIEVE study
British Journal of Haematology, 2013, 160, 649–659
ORR 40%. In patients who achieved PR, median DOR and TTP were 6. 5 and 8. 4 months
DRMM TREATMENT OPTIONS
Dat
e pr
epar
ed: J
une
2013
MM-003 Study Design: POM + LoDEX vs. HiDEX • Objective: To compare the efficacy and safety of POM+LoDex vs. HiDEX in RRMM
• Primary endpoint: PFS
• Key secondary endpoints: OS, ORR (≥ PR), TTP, DoR, QoL and safety
† PD was independently adjudicated in real time. BORT: bortezomib; D: day; DoR: duration of response; DVT: deep vain thrombosis HiDEX: high-dose dexamethasone; LEN: lenalidomide; LoDEX: low-dose dexamethasone; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; POM: pomalidomide; PR: partial response; Qol: quality of life; RRMM: relapsed/refractory multiple myeloma; SPM: second primary malignancy; TTP: time to progression; Tx: treatment; yrs: years.
(n = 302) POM: 4 mg/day D1-21 + LoDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1, 8, 15, 22
Follow-Up for OS and SPM until 5 years post-enrollment
(n = 153) HiDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1-4, 9-12, 17-20
28-day cycles
PD† or intolerable AE
PD† Companion trial MM-003C
POM 21/28 days RAN
DO
MIS
ATIO
N 2
:1
(n=4
55)
San Miguel J, et al. Lancet Oncology 2013; 14(11)1055-1066.
Thromboprophylaxis required for pts receiving POM or at high risk of DVT
San Miguel et al: ASH 2013; Oral Presentation & Abstract 686.
Dat
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1300
17a
Pomalidomide use in RRMM
• Retrospective audit – UCL, Oxford, Kings, Southampton
• Aim: To assess the clinical efficacy of pomalidomide in a real-world setting in multiple UK centres
• Analysis: Toxicity, ORR, PFS, OS
Rabin et al - Abstract IMW
Dat
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une
2013
MM-003: Baseline Characteristics and Prior Tx Characteristic POM + LoDEX
(n = 302) HiDEX
(n = 153)
Median age, yrs (range) 64 (35-84) 65 (35-87) Median time from initial Dx (y) 5.3 6.1 ECOG status 0/1/2/3 (%) 36/46/17 24/56/16 ISS I/II/III (%) 27/38/30 24/37/35 CrCL < 60 mL/min (%) 31 39 Median number Prior Tx, n (range) 5 (2-14) 5 (2-17)
Prior DEX (%) 98 99 Prior THAL (%) 57 61 Prior SCT (%) 71 69
Prior LEN & BORT (%) 100 100 Prior alkylator (%) 99 98 LEN-refractory (%) 95 92
BORT-refractory (%) 79 79
LEN- and BORT-refractory (%) 75 74
BORT: bortezomib; CrCl: creatinine clearance; DEX: dexamethasone; Dx: diagnosis; ECOG: Eastern Cooperative Oncology Group; HiDEX: high-dose dexamethasone; ISS: International Staging System; LEN: lenalidomide; LoDEX: low-dose dexamethasone; POM: pomalidomide; SCT: stem cell transplant; THAL: thalidomide; Tx: treatment.
San Miguel J, et al. Lancet Oncology 2013; 14(11)1055-1066. San Miguel et al: ASH 2013; Oral Presentation & Abstract 686.
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Median number of cycles was 4 (range 1-32), and median daily dose was 4 mg. Fifteen patients (19%) had dose reductions. In those with a GFR <45ml/min at baseline, 50% (7/14) started at a dose < 4mg
Dat
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une
2013
MM-003: Response (ITT)
a Pts (n = 11) who crossed over to receive POM were analysed per original randomised arm. b Kaplan-Meier estimate; patients with ≥ PR
Response POM + LoDEX (N = 302)
HiDEXa
(N = 153) P Value
ORR (≥ PR), n (%) 97 (32) 17 (11) < .001
≥ VGPR 21 (7) 1 (1) —
sCR/CR 4 (1) 0 (0) —
≥ MR, n (%) 122 (40) 23 (15) —
≥ SD, n (%) 247 (82) 94 (61) —
Median DOR,b mos (95% CI) 7.5 (6.0-9.5) 5.1 (1.7-8.5) .031
CI; confidence interval; CR, complete response; DOR, duration of response; HiDEX , high-dose dexamethasone; ITT, intent to treat; LoDEX, low-dose dexamethasone; MR, minimal response; ORR, overall response rate; POM, pomalidomide; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.
San Miguel J, et al. Lancet Oncology 2013; 14(11)1055-1066. San Miguel et al: ASH 2013; Oral Presentation & Abstract 686.
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Response & Toxicity
• Overall response (≥ PR) was 53%, VGPR 5%, and at least stable disease was achieved in 58/62 (94%).
• PFS was 4.3 months, and OS was 13.7 months. • Impaired renal function (GFR <45ml/min, 14 patients)
did not appear to influence PFS (4.0 months vs 4.5 months, p=0.44), or OS (10.8 vs 13.7 months, p=0.80).
• High risk FISH was present in 11/40 (28%) patients, who had comparable outcomes to standard risk patients: PFS 3.6 months vs 4.5 months, (p=0.70) and OS 11.3 vs not reached (p=0.19).
Rabin et al - Abstract IMW
Dat
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2013
MM-003 Grade 3/4 Adverse Events: Event (%) POM + LoDEX
(n = 300) HiDEX*
(n = 150) Grade 3/4 haematologic AEs
Neutropaenia 49 17 Febrile neutropaenia 9 0
Anaemia 33 39 Thrombocytopaenia 22 26
Grade 3/4 non-haematologic AEs (> 5%) Infections 33 25
Pneumonia 14 8 Bone Pain 7 5 Fatigue 5 6 Asthenia 4 7 Glucose intolerance 4 7
Grade 3/4 AEs of interest Rash 1 0 DVT/PE 1 0 Peripheral neuropathya 1 1
Discontinuation due to AEs 9 10 a Peripheral neuropathy includes the preferred terms hyperaesthesia, neuropathy peripheral, peripheral sensory neuoropathy, paraesthesia, hypoaesthesia, and polyneuropathy. AE: adverse event; DVT: deep vein thrombosis; HiDEX: high-dose dexamethasone; LoDEX: low-dose dexamethasone; PE: pulmonary embolism; POM: pomalidomide.
* Pts may have received POM + LoDEX following crossover.
San Miguel J, et al. Lancet Oncology 2013; 14(11)1055-1066. San Miguel et al: ASH 2013; Oral Presentation & Abstract 686.
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Response & Toxicity • Inclusion of a third agent at start of therapy (14
patients) did not appear to confer benefit (PFS 4.3 vs 4.0 months, p=0.40)
• In eight patients with biochemical or clinical progression on pomalidomide/dexamethasone, a third agent was added, and 7 achieved SD/PR
• Grade 3/4 non-haematological toxicities occurred in 27/79 (34%) patients: pneumonia 15 patients (19%) and neutropaenic sepsis 9 patients (11.4%) being the commonest.
• Grade 3/4 neutropenia occurred in 28 patients (35%) and thrombocytopenia in 17 patients (22%)
Rabin et al - abstract IMW
Progression free survival
Rabin et al - abstract for IMW
Overall Survival
Rabin et al - abstract IMW
Conclusions
• ORR of 53% is higher than observed in Phase III trial
• Renal impairment and patients with high risk cytogenetics fare comparably to standard risk and normal renal fn patients
• Addition of third agent should be explored prospectively to enhance effectiveness of this combination
• Is well tolerated in heavily pre treated and refractory MM patients
BTD in DRMM
Ann Hematol (2015) 94:643–649
BTD in DRMM
FOCUS Study Design
43
Control Arm • Corticosteroid (prednisone 30 mg PO, dexamethasone 6
mg PO, or equivalent) every other day) • Optional cyclophosphamide (50 mg PO every day)
Carfilzomib Arm • IV [10-min infusion]
• Days 1, 2, 8, 9, 15, and 16 of 28-day cycles for cycles 1–9 • 20 mg/m2 on days 1 and 2 of cycle 1 • 27 mg/m2 thereafter
• Days 1, 2, 15, and 16 of 28-day cycles for cycles ≥10
• 1:1 randomization
• Stratified by:
• Number of prior therapies
• Geographic region
• Multicenter (81 sites): Europe, Asia-Pacific
Inclusion Criteria
• Measurable disease
• Relapsed and refractory multiple myeloma
• ≥3 prior regimens
• Mandatory prior treatment
– Bortezomib
– IMiDs
– Alkylating agent
– Corticosteroid
• Refractory to the most recent regimen
• Platelets ≥30 × 106
• Creatinine clearance ≥15 mL/min
Patient and Disease Characteristics at Baseline
Characteristic Carfilzomib
(n=157) Control (n=158)
Median age, years (range) ≥65 years, %
63 (32–85) 47.8
66 (43–81) 56.3
ECOG performance status, % 0–1 2 3
80.9 18.5 0.6
78.5 20.9 0.6
Cytogenetic risk category by FISH, % High Standard Unknown
14.0 43.3 42.7
18.4 48.1 33.5
ISS stage at baseline, % I–II III
49.7 48.4
46.2 51.9
Measurable disease category, % Light chain proteinuria/ UPEP-positive
53.5
41.1
44 ECOG, Eastern Cooperative Oncology Group; FISH, fluorescence in situ hybridization; ISS, International Staging System; UPEP, urine protein electrophoresis
Patient and Disease Characteristics at Baseline (continued)
Characteristic Carfilzomib
(n=157) Control (n=158)
Number of prior regimens, median (range) >6 prior regimens, %
5 (3–15) 28.7
5 (3–17) 27.8
Time from initial diagnosis to start of FOCUS, median years (range) 6 (1.6–20.4) 5.4 (1.5–23.5)
Prior therapies, % Bortezomib/IMiD/alkylator/corticosteroid Transplant Anthracycline
100 68.2 74.5
100 64.6 77.2
Refractory, % Bortezomib (any prior regimen)
Bortezomib (last prior regimen) IMiD (any prior regimen) Bortezomib and IMiD (any prior regimen)
65.6 22.9 93.0 61.8
68.4 25.9 91.8 63.3
Creatinine clearance, % <30 mL/min 30–<50 mL/min
10.8 17.8
8.9
22.8 45 IMiD, immunomodulatory agent
Treatment Received
46
Treatment Carfilzomib (n=157)
Control (n=153)
Median number of cycles (range) 5 (1–35) 3 (1–35)
Median K relative dose intensity†, % 99.87 -
Median corticosteroid relative dose intensity, % - 99.86
Received optional cyclophosphamide, % - 94.8
Median cyclophosphamide dose received, mg/cycle** - 1083.3
†Relative dose intensity = actual dose intensity / planned dose intensity
*Maximal dexamethasone dose per cycle: 84 mg
**Maximal cyclophosphamide dose per cycle: 1400 mg
Primary Endpoint: Overall Survival
47
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 0.0
0.2
0.4
0.6
0.8
1.0
Time from randomization (months)
Prop
ortio
n su
rviv
ing
157 129 101 89 75 61 53 42 21 13 8 7 5 3 1 158 121 100 79 62 55 45 41 26 19 15 9 5 4 3
Carfilzomib Control
No. at Risk 0 0
Carfilzomib Control Censored
Carfilzomib Control Deaths, n 129 125 Median OS, mo 10.2 10.0 HR (95% CI) 0.975 (0.760–1.249) One-sided P value 0.42
Secondary Endpoints: Response
Response, n (%) Carfilzomib (n=157)
Control (n=158)
One-sided P-value*
Best overall response
≥VGPR 6 (3.8) 5 (3.2) -
PR 24 (15.3) 13 (8.2) -
MR 19 (12.1) 15 (9.5) -
ORR 30 (19.1) 18 (11.4) 0.03
CBR 49 (31.2) 33 (20.9) 0.02
DCR 119 (75.8) 107 (67.7) 0.05
Median DOR, months (95% CI) 7.2 (4.6–12.0) 9.5 (3.7–NE) -
48 CI, confidence interval; DCR, disease control rate; DOR, duration of response; MR, minimal response; NE, not estimable; ORR, overall response rate; PR, partial response; VGPR, very good partial response
*Multiplicity unadjusted p-value
Secondary Endpoint: Progression-Free Survival
49
0 3 6 9 12 15 18 21 24 27 30 33
Time from randomization (months)
Prop
ortio
n pr
ogre
ssio
n-fr
ee
Carfilzomib Control Events, n 132 109 Median PFS, mo 3.7 3.3 HR (95% CI) 1.091 (0.843–1.410) One-sided P value* 0.25
Carfilzomib Control Censored
76 41 23 18 12 9 7 6 3 1 0 57 38 26 18 14 11 10 7 4 3 0
Carfilzomib Control
No. at Risk 157 158
0.0
0.2
0.4
0.6
0.8
1.0
More censoring due to non-protocol therapy in the control arm (32; 20.3%) compared with the K arm (12; 7.6%) in the PFS analysis
*Multiplicity unadjusted p-value
NOVEL THERAPEUTIC STRATEGIES
Relapsed MM Patient
Drugs tested in relapsed myeloma
Monoclonal antibodies in Myeloma
56
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
NEJM, Jan 8th, 2015
ASPIRE Study Design
57
Rd Lenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
KRd Carfilzomib 27 mg/m2 IV (10 min)
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only) Lenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
Randomization N=792
Stratification: • β2-microglobulin • Prior bortezomib • Prior lenalidomide
After cycle 12, carfilzomib given on days 1, 2, 15, 16 After cycle 18, carfilzomib discontinued
28-day cycles
Secondary Endpoints: Response
31.8
69.9
87.1
9.3
40.4
66.7
0
10
20
30
40
50
60
70
80
90
100
≥CR ≥VGPR ORR (≥PR)
KRdRd
Per
cent
age
of P
atie
nts
58
P<.0001
P<.0001
sCR 14.1% vs 4.3%
P<.0001
Median duration of response was 28.6 months in the KRd group and 21.2 months in the Rd group
Primary Endpoint: Progression-Free Survival ITT Population (N=792)
59
1.0
0.8
0.6
0.4
0.2
0.0
Pro
porti
on S
urvi
ving
W
ithou
t Pro
gres
sion
KRd Rd
0 6 12 18 24 30 36 42 48 Months Since Randomization
KRd Rd (n=396) (n=396) Median PFS, mo 26.3 17.6 HR (KRd/Rd) (95% CI) 0.69 (0.57–0.83) P value (one-sided) <0.0001
No. at Risk: KRd
Rd 396 332 279 222 179 112 24 1 396 287 206 151 117 72 18 1
Primary Endpoint: Progression-Free Survival ITT Population (N=792)
60
1.0
0.8
0.6
0.4
0.2
0.0
Pro
porti
on S
urvi
ving
W
ithou
t Pro
gres
sion
KRd Rd
0 6 12 18 24 30 36 42 48 Months Since Randomization
KRd Rd (n=396) (n=396) Median PFS, mo 26.3 17.6 HR (KRd/Rd) (95% CI) 0.69 (0.57–0.83) P value (one-sided) <0.0001
No. at Risk: KRd
Rd 396 332 279 222 179 112 24 1 396 287 206 151 117 72 18 1
PFS by Risk Group
61
KRd
(n=396)
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
PFS by Risk Group
62
KRd
(n=396)
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: Interim Overall Survival Analysis Median Follow-Up 32 Months
63
Median OS was not reached; results did not cross the prespecified stopping boundary (P=0.005) at the interim analysis
1.0
0.8
0.6
0.4
0.2
0.0
Pro
porti
on S
urvi
ving
KRd Rd
0 6 12 18 24 30 36 42 48 Months Since Randomization
KRd Rd (n=396) (n=396) Median OS, mo NE NE HR (KRd/Rd) (95% CI) 0.79 (0.63–0.99) P value (one-sided) 0.018
No. at Risk: KRd
Rd 396 369 343 315 280 191 52 2 396 356 313 281 237 144 39 3
Conclusions
64
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%)
QoL Global Health Status improved
UK-REV130008 Feb 2013
A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma
J.J. Shah, M.D.1, E.A. Stadtmauer, MD2, R. Abonour, MD3, A.D. Cohen, MD4, W.I. Bensinger, MD5, C. Gasparetto, MD6, J.L. Kaufman, MD7, S. Lentzsch, MD8, D.T. Vogl, MD, MSCE2, R.Z. Orlowski, M.D., Ph.D1, E.L. Kim, MPH9, M.B. McKinley, BSN, MBA9 and B.G.M. Durie, MD10
1M. D. Anderson Cancer Center, Houston, TX; 2Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; 3Indiana University Simon Cancer Center, Indianapolis, IN; 4Fox Chase Cancer Center, Philadelphia, PA; 5Fred Hutchinson Cancer Research Center, Seattle, WA; 6Duke University Medical Center, Durham, NC; 7Winship Cancer Institute of Emory University, Atlanta, GA; 8Columbia University Herbert Irving Comprehensive Cancer Center, NY; 9Academic Myeloma Consortium (AMyC), CORE Science Solutions, A Criterium Company, Culver City, CA; 10Cedars-Sinai Samuel Oschin Cancer Center, Los Angeles, CA.
Wang et al. ICML. 2011; Oral Presentation & Abstract 109
Shah et al: ASH 2012; Oral & Abstract 74.
UK-REV130008 Feb 2013 UK-REV130008 Feb 2013
Study objectives and design • Primary objectives: MTD and tolerability of Car-Pom-dex in RRMM • Secondary objectives: ORR, TTP, PFS, OS and TNT
• Phase I (n=12) 3+3 dose-escalation with dose expansion (n=20) at MTD:
CAR POM DEX
Cohort-1 27 mg/m2 * 3 mg 40 mg **
Cohort 1 (initial dose level)
27 mg/m2 * 4 mg 40 mg **
Cohort 2 36 mg/m2 * 4 mg 40 mg **
Cohort 3 45 mg/m2 * 4 mg 40 mg **
Cohort 4 56 mg/m2 * 4 mg 40 mg **
* CAR doses on days 1 and 2 of cycle 1 for all cohorts was 20 mg/m2; subsequent dosing shown in table ** DEX reduced to 20 mg after cycle 1 *** Patients treated until progression / unacceptable toxicity MTD: maximum tolerated dose; ORR: overall response rate; TTP: time to progression; TNT: time to next therapy; PFS: progression free survival; OS: overall survival; Car: carfilzomib; POM: pomalidomide; DEX: dexamethasone
Cycle 1–6 (28d cycle) CAR D1,2,8,9,15,16 POM D1–21 DEX Weekly
Cycles: 7+ (28d cycle)*** CAR D1,2,15,16 POM D1–21 DEX Weekly
Shah et al: ASH 2012; Oral & Abstract 74.
• MTD was determined as CAR 20/27 mg/m2, POM 4 mg, DEX 40mg
UK-REV130008 Feb 2013 UK-REV130008 Feb 2013
Patient demographics
• Eligibility criteria: R/R MM; prior Tx with and refractory to LEN
Characteristic N = 32
Gender Male: 20 (62.5%) Female: 12 (37.5%)
Age, median (range) 63.5 years (44–78)
N prior regimens, median (range) 6 (1–15)
ECOG PS 0: 16 (50%) 1: 14 (44%)
2: 2 (6%) Years since initial DEX, median (range) 5.0 years (1.2–9.1)
Prior stem cell transplant 21 (65.6%)
Prior BORT 31 (97%)*
Prior LEN 32 (100%)
* All but two patients refractory R/R: relapsed and/or refractory; Tx: treatment; LEN: lenalidomide; N: number; DEX: dexamethasone; BORT: bortezomib ; MM: multiple myeloma; ECOG: Eastern Cooperative Oncology Group . Shah et al: ASH 2012; Oral & Abstract 74.
UK-REV130008 Feb 2013 UK-REV130008 Feb 2013
Results: Efficacy
* High / Int Risk defined as 17p-positive, t(4:14), t(14:16), hypodiploid by mSmart risk classification ORR: overall response rate; VGPR: very good partial response; PR: partial response; MR: minimal response; SD: stable disease; PFS: progression free survival; OS: overall survival; Int: intermediate.
13
37 54
17 18
23 18
0102030405060708090
100
ALL (n=30) High / Int Risk (n=11)
SDMRPRVGPR
Perc
enta
ge re
spon
se
Shah et al: ASH 2012; Oral & Abstract 74.
• Clinical benefit rate (≥MR) = 67% • Responses observed in high-risk cytogenetic patients • Responses & OS were sustain & durable independent of risk status
All Patients N = 30
Median PFS 7.4 months 1 year OS 90%
UK-REV130008 Feb 2013 UK-REV130008 Feb 2013
Results: Tolerability
AEs: adverse events.
Grade 3 / 4 Haematological AEs ≥ 20% patients
All Grades n(%)
Grade 3/4 n(%)
Anaemia 20 (62) 12 (37) Neutropenia 18 (56) 9 (28)
Thrombocytopenia 27 (84) 18 (56)
Febrile neutropenia 2 (6) 2 (6)
Grade 3 / 4 Non Haematological AEs ≥ 20% patients
All Grades n(%)
Grade 3/4 n(%)
Diarrhoea 10 (31) 0 (0) Fatigue 18 (56) 1 (3)
Dyspnoea 9 (28) 0 (0) Hypocalcaemia 11 (34) 0 (0)
• No grade 3 / 4 Peripheral neuropathy
Shah et al: ASH 2012; Oral & Abstract 74.
UK-REV130008 Feb 2013
UK-REV130008 Feb 2013 UK-REV130008 Feb 2013
Authors’ conclusions
• MTD was CAR 20/27 mg/m2, POM 4 mg, DEX 40mg in RRMM
• Limited grade 3/4 non haematological toxicities, the regimen was well tolerated and highly active in heavily pre-treated, refractory patients
• Enrolment on-going for an 82-patient phase II trial in the Mayo Clinic
MTD: maximum tolerated dose; CAR: carfilzomib; POM: pomalidomide; DEX: dexamethasone Shah et al: ASH 2012; Oral & Abstract 74.
72
ELOQUENT-2: a phase 3, randomized, open-label
study of lenalidomide/dexamethasone with/without elotuzumab in patients with
relapsed/refractory multiple myeloma
Meletios Dimopoulos*†1, Sagar Lonial†2, Antonio Palumbo3, Darrell White4, Sebastian Grosicki5, Ivan Spicka6, Adam Walter-Croneck7, Philippe Moreau8, Maria-Victoria Mateos9, Hila Magen10,
Andrew Belch11, Donna Reece12, Meral Beksac13, Andrew Spencer14, Heather Oakervee15, Masafumi Taniwaki16, Christoph Röllig17, Ka Lung Wu18, Anil Singhal19, Jesus San Miguel20, Morio
Matsumoto21, Jessica Katz22, Eric Bleickardt23, Valerie Poulart24 and Paul Richardson25 on behalf of the ELOQUENT-2 Investigators
1National and Kapodistrian University of Athens, Athens, Greece; 2Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA; 3A.O.U. San Giovanni Battista di Torino - Ospedale Molinette, Torino, Italy; 4QEII Health Science Center and Dalhousie University, Halifax, Canada; 5Silesian Medical University, Katowice, Poland; 6Charles University Hospital, Prague, Czech Republic; 7Medical University of Lublin, Lublin, Poland;
8University Hospital, Nantes, France; 9University Hospital of Salamanca-IBSAL, Salamanca, Spain; 10Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, and Tel Aviv University, Ramat Aviv, Israel; 11Cross Cancer Institute and University of Alberta, Edmonton, Canada; 12Princess Margaret
Hospital, Toronto, Canada; 13Ankara University, Ankara, Turkey; 14Alfred Health-Monash University, Melbourne, Australia; 15Barts and the London NHS Trust, London, UK; 16Kyoto Prefectural University of Medicine, Kyoto, Japan; 17Universitatsklinikum der TU, Dresden, Germany; 18ZNA
Stuivenberg, Antwerp, Belgium; 19AbbVie Biotherapeutics Inc. (ABR), Redwood City, USA; 20Clinical Universidad de Navarra, Pamplona, Spain; 21Nishigunma National Hospital, Shibukawa, Japan; 22Bristol-Myers Squibb, Princeton, USA; 23Bristol-Myers Squibb, Wallingford, USA; 24Bristol-
Myers Squibb, Braine-l'Alleud, Belgium; 25Dana-Farber Cancer Institute, Boston, USA
Presented at the European Hematology Association (EHA) 20th Congress; Vienna, Austria; June 11–14, 2015
S471
From N Engl J Med, Lonial S et al, Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. Copyright © (2015) Massachusetts Medical Society. Reprinted with permission
ELOQUENT-2 Study Design Open-label, international, randomized, multicenter, phase 3 trial
(168 global sites)
Key inclusion criteria
RRMM
1–3 prior lines of therapy
Prior Len exposure permitted in 10% of study population (patients not refractory to Len)
Elo plus Len/Dex (E-Ld) schedule
(n=321) Elo (10 mg/kg IV): Cycle 1 and 2:
weekly; Cycles 3+: every other week Len (25 mg PO): Days 1–21
Dex: weekly equivalent, 40 mg
Len/Dex (Ld) schedule (n=325) Len (25 mg PO): Days 1–21;
Dex: 40 mg PO Days 1, 8, 15, 22
Repeat every 28 days
Assessment
Tumor response: every 4 weeks until progressive disease
Survival: every 12 weeks after disease progression
Endpoints: – Co-primary: PFS and ORR – Other: overall survival (data not yet mature), duration of response,
quality of life, safety All patients received premedication to mitigate infusion reactions prior to
elotuzumab administration Elotuzumab IV infusion administered ~ 2–3 hours
Characteristic E-Ld (n=321) Ld (n=325) Age (years), median (range) 67 (37–88) 66(38–91) ≥65 years 187 (58) 183 (56) Region, %
Europe 61 60 North America 21 21 Rest of the world 18 19
International Staging System disease stage, n (%) I 44 43 II 32 32 III 21 21 Not reported 4 14
Cytogenetics (FISH) del(17p)
Yes 32 32 No 66 67 Not reported 2 1
t(4;14) Yes 9 10 No 89 89 Not reported 2 1
1q21 Yes 46 50 No 53 49 Not reported 2 1
Baseline Demographics and Disease Characteristics
FISH = fluorescence in situ hybridization
Baseline Demographics and Disease Characteristics
Characteristic E-Ld (n=321) Ld (n=325) Prior regimens, median (range) 2 (1–4) 2 (1–4) Prior therapies, %
Bortezomib 68 71 Melphalan* 69 61 Thalidomide 48 48 Lenalidomide† 5 7
Response to most recent line of therapy, %‡
Refractory 35 35 Bortezomib refractory 22 21 Thalidomide refractory 9 11 Relapsed 65 65
Prior stem cell transplantation, % 52 57 *Oral or intravenous. †Prior lenalidomide was permitted if best response was ≥partial response and patients were not refractory to prior lenalidomide treatment; patients could not receive more than 9 cycles of lenalidomide and had at least 9 months between the last dose of lenalidomide and progression. ‡One patient in the elotuzumab group had an unknown response to the most recent line of therapy
Treatment Summary
E-Ld (n=321) Ld (n=325)
Number of treatment cycles, median (range) 19 (1–42) 14 (1–40)
Patients on treatment, n (%)* 113 (35) 66 (21)
Duration of treatment, median (wk) 73 52
Full dose intensity (i.e. ≥90%), n (%)
Elotuzumab 264 (83) –
Lenalidomide 163 (51) 161 (51)
Dexamethasone 146 (46) 148 (47)
*At the time of the cut-off date for the interim analysis
Co-primary Endpoint: Progression-Free Survival
PFS analysis used the primary definition of PFS
E-Ld−treated patients had a 30% reduction in the risk of disease progression or death; treatment difference at 1 and 2 years was 11% and 14%, respectively
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
38 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
No. of patients at risk: E-Ld Ld
321 325
303 295
279 249
259 216
232 192
215 173
195 158
178 141
157 123
143 106
128 89
117 72
85 48
59 36
42 21
32 13
12 7
7 2
57%
68%
27%
41%
1-year PFS 2-year PFS
PFS (months)
Prob
abili
ty p
rogr
essi
on fr
ee
From N Engl J Med, Lonial S et al, Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. Copyright © (2015) Massachusetts Medical Society. Reprinted with permission
E-Ld Ld HR 0.70 (95% CI 0.57, 0.85);
p=0.0004
Median PFS (95% CI)
19.4 mo (16.6, 22.2)
14.9 mo (12.1, 17.2)
E-Ld
Ld
1 0
0 0
Co-primary Endpoint: Overall Response Rate
*Defined as partial response or better. †Complete response rates in the E-Ld group may be underestimated due to interference from therapeutic antibody in immunofixation and serum protein electrophoresis assay
0
20
40
60
80
100
Res
pons
e ra
te (%
)
E-Ld Ld
p=0.0002
79
66
Overall response
rate*
Complete response
(sCR + CR)†
Very good partial
response
Combined response
(sCR + CR + VGPR)
Partial response
4 7
21 28
33 28
38 46
Phase I Trial: Daratumumab in Combination With Len/Dex in Rel/Ref MM
• Phase I/II dose-escalation trial of daratumumab in combination with len/dex in rel/ref MM (safety cohort: n =45; efficacy cohort: n = 43) – Daratumumab is a human mAb targeting CD38-expressing cells – Dose escalation: daratumumab 2-16 mg/kg/wk for 8 wks, twice monthly
for 16 wks, then once monthly for 24 mos in total or until PD, unmanageable AE
– Lenalidomide 25 mg on Days 1-21 of each 28-day cycle – Dexamethasone 40 mg/wk for of each 28-day cycle
• Median prior lines of therapy: 2 (range: 1-4); most with prior exposure to IMiDs and/or a proteasome inhibitor; 3 pts refractory to len
• MTD: daratumumab 16 mg/kg + len 25 mg and dex 40 mg/wk
Plesner T, et al. ASH 2014. Abstract 84.
Daratumumab in Combination With Len/Dex: Overall Best Response
• Mean follow-up: 12.9 mos (Part 1); 5.6 mos (Part 2) • Median time to response: 1 mo for 16 mg/kg in Part 2; median time to CR: 4.9 mos in Part 2
CR 31% CR 6.7%
VGPR 46%
PR 23%
VGPR 43%
PR 37%
CR 6.7%
CR 8.0% CR
11.8%
VGPR 43.3%
VGPR 52%
VGPR 52.9%
Plesner T, et al. ASH 2014. Abstract 84. Reproduced with permission.
Part 1 0
20
40
60
80
100
Pats
(%)
Overall Best Response
Part 2
PR VGPR CR
100 86.7
50.0
60 64.7
0
20
40
60
Pts (
%)
VGPR or Better Response by Cycles of Treatment (Part 2)
≥ 2 Cycles (n = 30)
≥ 4 Cycles (n = 25)
≥ 6 Cycles (n = 7)
Daratumumab in Combination With Len/Dex: Adverse Events
Most Common (Incidence in > 10% Pts) AEs, % Part 1 (n = 13)
Part 2 (n = 32)
Total (N = 45)
Total number of pts with AEs 100 100 100 Neutropenia 62 65 64 Muscle spasms 62 38 44 Diarrhea 54 18 31 Fatigue 62 16 29 Cough 31 28 29 Constipation 54 13 27 Nausea 38 19 24 Nasopharyngitis 62 3 20 Bone pain 31 13 18 Upper respiratory tract infection 46 3 16 Insomnia 31 6 16 Dyspnea 23 6 11 Anemia 31 19 11
Plesner T, et al. ASH 2014. Abstract 84.
Daratumumab in Combination With Len/Dex: Safety
• Daratumumab related serious AEs
– Pneumonia, neutropenia, diarrhea (1 pt each receiving 16 mg/kg, early infusion program)
– Laryngeal edema (1 pt receiving 16 mg/kg, accelerated infusion program)
• 19/45 pts reported infusion-related reactions; mostly grade 1-2
≤ 8 mg/kg Part 1
(n = 10)
16 mg/kg Part 1 (n = 3)
16 mg/kg Part 2
Current Infusion Program (n = 21)
16 mg/kg Part 2
Accelerated Infusion Program (n = 11)
Plesner T, et al. ASH 2014. Abstract 84. Reproduced with permission.
60
40
20
0
Pts
(%)
20.0 20.0 33.3
38.1
4.8
63.6 Infusion-Related Reactions First Infusion
Subsequent Infusion
Phase I Trial: SAR650984 in Combination With Len/Dex in Relapsed/Refractory MM
• Phase Ib trial of SAR650984 + len/dex in relapsed/refractory MM – SAR650984 is a humanized IgG1 mAb to the CD38 receptor widely
expressed in many heme malignancies – Dose escalation: SAR650984 3-10 mg/kg on Days 1 and 15 of each 28-
day cycle + lenalidomide 25 mg on Days 1-21 of each 28-day cycle and dexamethasone 40 mg/wk during each 28-day cycle
Martin TG, et al. ASH 2014. Abstract 83.
Previous MM Treatment SAR650984 Dose, mg/kg q2w Overall
(N = 31) 3 (n = 4) 5 (n = 3) 10 (n = 24)
Median prior regimens, n (range) 10 (3-14) 7 (6-7) 6 (2-12) 7 (2-14)
Median prior lines, n (range) 6 (2-11) 6 (4-6) 4 (1-9) 4 (1-11)
Median time on last Len, mos (range) 7 (3-17) 3 (3-10) 10 (1-54) 9 (1-54)
Relapsed/refractory to IMiD 3 (75) 2 (67) 21 (88) 26 (84)
SAR650984 + Len/Dex: Efficacy Analysis
• DoR: 9.13 mo (range: 1.2-15.2)
Martin TG, et al. ASH 2014. Abstract 83. Reproduced with permission.
Response, % Total (N = 31)
ORR 58 sCR 6 VGPR 23 PR 29
CBR 65 MR 6
SD 19 PD 13 Not evaluable 3
Pts
(%)
SAR650984 Dose Level, mg/kg q2w
ORR 25% CBR 50%
ORR 67% CBR 67%
ORR 63% CBR 67%
ORR 58% CBR 65%
100
80
60
40
20
0 3
(n = 4) 5
(n = 3) 10
(n = 24) Overall (n = 31)
25
25
67
8
29
6
29
6 25 23
4
PR sCR VGPR MR
SAR650984 + Len/Dex: PFS by Previous Lines of Therapy
Prob
abili
ty
0
10
20
30
40
50
60
70
80
90
100
Mos 5 0 1 2 3 4 6 7 8 9 10 11 12 13 14 15 16 17
≥ 3 prior lines (n = 24) Overall (N = 31)
Median PFS: NR (95% CI: 6.2-NR)
Median PFS: 6.2 mos (95% CI: 4.80-13.33)
Median PFS: 5.8 mos (95% CI: 2.10-10.30)
1-2 prior lines (n = 7)
Martin TG, et al. ASH 2014. Abstract 83. Reproduced with permission.
SAR650984 plus Len/Dex: Tx-Emergent AEs
• There were 15 incidences of infusion reaction, all occurring in the first 2 cycles – 2 pts discontinued treatment: 1 serious grade 3 anaphylactic reaction in cycle 1 and
1 nonserious grade 3 maculopapular rash in cycle 2 (AEs resolved in both pts) – Remaining incidents were grade 1/2 and did not lead to treatment discontinuation
Pts
(n =
31)
(%)
Martin TG, et al. ASH 2014. Abstract 83. Reproduced with permission.
100
80
60
40
20
0
Grade 1 Grade 2 Grade 3 Grade 4
Agents under Investigation
• Ixazomib combinaion • Panorama 1 – Bortezomib/ Panobinostat/
Dexamethasone • CD19 CAR -N Engl J Med 2015;373:1040-7
• NYESO ex vivo TCR engineered T cells ( Nature
pre pub July 2015) • ARRY-520 , Kinesin spindle protein inhibitor
Conclusion
• Relapse MM patients required detailed clinical assessment – Discussion at MDT recommended
• Consider clinical trials where appropriate • Second ASCT is treatment of choice for
selected cohort of 1st relapse MM patients • Combination of PI/Mab + IMiD + Dex • DRMM management remains challenging with
OS less than a year
