TIMER
NEW TREATMENT OPTIONS FOR PATIENTS WITH ADVANCED RELAPSE / REFRACTORY MULTIPLE
MYELOMA
Paula Rodríguez OteroClínica Universidad de Navarra
NEW TREATMENT OPTIONS FOR PATIENTS WITH ADVANCED RELAPSE /
REFRACTORY MULTIPLE MYELOMA
Paula Rodríguez Otero
University of Navarra
Natural History of Multiple Myeloma
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
MGUS=monoclonal gammopathy of undetermined significance.
Kumar, Blood 2008
Despite the benefit observed with novel agents in the last years,… other drugs are still needed for relapsed/refractory patients
Evolution of MM OS over the years
1971–76
1994–001989–94
1977–821983–88
Time
0 20 40 60 80 100 120 140
Surv
ival
0.0
0.2
0.4
0.6
0.8
1.0
2001–06
Surv
ival
100%
80%
60%
40%
20%
0
60483624120
Months from Time Zero
Events/N Median (m)
— Overall Survival 170/286 9 (7.11)— Event-Free Survival 217/286 5 (4.6)
Kumar, Leukemia 2012
Outcome of pts refr to Btz & IMIDs*
Historical evolution of MM patients
* 286 pts refractory to BTZ and relapsed or refractory or ineligible to receive an IMiD
2006–10
Kumar, Leukemia 2014
Novel Drugs in MM
- Derivatives from the already approved
- Novel Proteasome Inhibitors
- Novel IMIDs
- Novel Alkylators
- Novel Mechanisms of action
- MoAb: anti CS1 & anti-CD38
- Deacetylase Inhibitors
- KSP inhibitors
- Checkpoint inhibitors
- XPO-1 inhibitors
Proteasome inhibitors
TypeCatalytic inhibition
Reversibilitypo/iv
DosingChymotryp Casp Tryp
Bortezomib Boronate X X Reversible Iv 1, 4, 8, 11
IxazomibMLN-9708
Boronate X X Reversible po 1, 8, 15
Carfilzomib Epoxi-ketone X Irreversible iv 1-2, 8-9, 15-16
Oprozomib Epoxi-ketone x Irreversible po BID
Marizomib Salinospore X X X Irreversible iv 1, 4, 8, 11
CEP-18770 Boronate X X Reversible iv 1, 4, 8, 11
β-subunit ring of the proteasome: Catalytic sites Caspase-L
β7β1
β2
β6
β5 β4
β3
Trypsin-L
Chymotrypsin-LCarfilzomib
NPI-0052
Bortezomib
MLN-9708
The proteasome is an intracellular enzyme complex responsible for the degradation of regulatory & misfolded and potentially toxic proteins.
Biological effects of proteasome inhibition: - Inhibition of Proliferation- Cell Cycle Arrest- ER stress and unfolded protein response- Blockade of NFkB pathway
Carfilzomib single agent in R/R MM: Summary efficacy data
Bortezomib (APEX) ≥ PR 43%6
PX-171-003 A01/A12: Relapsed after Btz & Len/Thal + Refr to last regimen
PX-171-0043,4: Relapsed to 1-3 prev. Lines
1. Jagannath S, et al. Clin Lymphoma Myeloma Leuk 2012;12:310-82. Siegel D, et al. Blood 2012; 120: 2817-25
3. Vij R, et al. Blood 2012; 119: 5661-704. Vij R, et al. Br J Haematol 2012; 158: 739-48
5. Siegel D, et al. ASCO 2012. Abstract 8035.6. Richardson PG, et al. Blood 2007;110:3557-60
Population Study NDose of
CarfilzomibORR (%)
PFS (mo) / OS (%)
BTZ-naïve 004004
5970
20 mg/m2
20/27 mg/m242.452
8.3 (TTP)
NR (TTP)
BTZ-treated003A0003A1
004
4625735*
20 mg/m2
20/27 mg/m2**20 mg/m2
16.723.717.1
3.7 / 15.6
BTZ-refractory
003A15 194 20/27 mg/m2 16.5
BTZ-treated FOCUS trial 30320/27 mg/m2
vs Pred/Cycl-Prd30% 3.7 vs 3.3
*Subgroup of patients included in 004 study and bortezomib-exposed
**1st cycle 20 mg iv QD x2 for 3 weeks (28-day cycle). Subsequently 27 mg
VdBortezomib 1.3 mg/m2 (IV bolus or subcutaneous injection)
Days 1, 4, 8, 11
Dexamethasone 20 mg
Days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycles until PD or unacceptable toxicity
KdCarfilzomib 56 mg/m2 IV
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)Infusion duration: 30 minutes for all doses
Dexamethasone 20 mg Days 1, 2, 8, 9, 15, 16, 22, 23
28-day cycles until PD or unacceptable toxicity
N=929
Stratification:• Relapsed MM
• 1–3 prior treatments
• Prior treatment with V or K was allowed if:
• ≥PR to prior treatment
• ≥6 month PI treatment-free interval
• Was not removed owing to toxicity
• Creatinine clearance ≥15 mL/min
Carfilzomib-Dex vs Bortezomib-Dex in RMMPhase III ENDEAVOR trial : Study design
Dimopoulos MA et al, Lancet Oncol. 2016 Jan;17(1):27-38
Carfilzomib-Dex vs Bortezomib-Dex in RMMPhase III ENDEAVOR trial : PFS and OS data
1.0
0.8
0.6
0.4
0.2
0
Prop
orti
on S
urvi
ving
W
itho
ut P
rogr
essi
on
0
Months Since Randomization
KdVd
6 12 18 24 30
Kd Vd
Events, n 171 243
Median PFS, mo 18,7 9.4
HR (95% CI) 0.53 (0.44-0.65)p<0.0001
Primary endpoint: PFS
ORR (Kd vs Vd): 77% vs 63%. ≥CR: 13% vs 6%Median DOR (Kd vs Vd): 21.3 vs 10.4 months
KdVd
Prop
ortio
n Su
rviv
ing
0 6 12 18 24 30
1.0
0.8
0.6
0.4
0.2
0
Secondary endpoint: OSKd
(n=464)Vd
(n=465)Events, n 75 88
Median OS, mo NE 24.3
HR (95% CI) 0.79 (0.58-1.08)p=0.066
Months Since Randomization
Carfilzomib-Dex vs Bortezomib-Dex in RMMPhase III ENDEAVOR trial: Safety profile
TreatmentKd
(n=464)Vd
(n=465)
Discontinuation due to AE, % 14.0 15.7
Death due to AE, % 3.9 3.4
Grade 3 AEs, %
Hypertension, % 8.9 2.6
Dyspnea, % 5.6 2.2
Cardiac failure, % 4.8 1.8
Acute renal failure, % 4.1 2.6
Grade ≥ 2 PN, % 6.3 32
Dimopoulos MA et al, Lancet Oncol. 2016 Jan;17(1):27-38
Berenson J, ASH 2015 Abst 373
Carfilzomib Days 1, 8, and 15 (30 minutes infusion)
Dexamethasone IV or PO Days 1, 8, 15, and 22 (day 22 omitted for cycles 9+)
Treatment Schedule (Phase 1 and 2)
28 day cycles - Both drugs given until PD or unacceptable toxicity
Champion-1: Carfilzomib-Dexamethasone weekly Study design
DOR (≥PR), median months (95% CI) 16.3 (12.7–NA)
TTR (≥PR), median months (range) 1.6 (0.7–7.2)
Median PFS (95% CI): 14.3 months (9.9–21.0) 1.00
0.75
0.50
0.25
0.00
Prop
orti
on P
rogr
essi
on-F
ree
0 6 12 18 24
Time (months)
30
ORR 77%; CBR 84%; sCR 5%, VGPR 30%.ORR and CBR in Btz refr: 63% & 76% respect.
MTD: 20/70 mg/m2
Phase III trial (ARROW) ongoing
Study population (N = 700)• Measurable disease
• Relapsed progressive MM after 1-3 prior therapies
• ECOG PS 0-2
Stratification:• Prior bortezomib
• Prior lenalidomide
• β2-microglobulin levels
1:1
KRdCarfilzomid 27mg/m2 IV
Day 1, 2, 8, 9, 15, 16 (20 mg/m2 on days 1 and 2 of cycle 1 only)
Lenalidomide 25 mgDays 1-21
Dexamethasone 40 mgOnce weekly days 1, 8, 15, and 22
RdLenalidomide 25 mg
Days 1-21
Dexamethasone 40 mgOnce weekly days 1, 8, 15, and 22
After cycle 12, CFZ given on days 1, 2, 15, 16After cycle 18, CFZ to be discontinued
Both arms to receive 28 day cycles until progression
Primary endpoint: PFS
National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/NCT01080391. Accessed: October 28, 2014.
Carfilzomib-Len-Dex (KRd) in Relapsed MMPhase III ASPIRE trial
Phase III ASPIRE trial
Stewart et al. ASH 2014 (Abstract 79), oral presentationStewart et al. N Engl J Med 2014 Dec 6
No. at Risk:KRd
Rd396 332 272 222 179 112 24 1396 287 206 151 117 72 18 1
1.0
Months Since Randomization
0.8
0.6
0.4
0.2
0.0
Prop
ortio
n Su
rviv
ing
With
out P
rogr
essi
on
KRdRd
0 6 12 18 24 30 36 42 48
The progression-free survival benefit in the carfilzomib group was observed across all predefined subgroups
Stewart et al. ASH 2014 (Abstract 79), oral presentation. Stewart et al. N Engl J Med 2014 Dec 6 [Epub ahead of print].
ORR (KRd vs Rd): 87.1 vs 66.7%. ≥CR: 31.8 vs 9.3%KRd Rd
(n=396) (n=396)
Median PFS, mo 26.3 17.6HR (KRd/Rd) (95% CI) 0.69 (0.57–0.83)P value <0.0001
KRd Rd(n=396) (n=396)
Median OS, mo NE NEHR (KRd/Rd) (95% CI) 0.79 (0.63–0.99)P value (one-sided) 0.018
1.0
0.8
0.6
0.4
0.2
0.0Pr
opor
tion
Surv
ivin
g
KRdRd
0 6 12 18 24 30 36 42 48Months Since Randomization
KRdRd
396 369 343 315 280 191 52 2396 356 313 281 237 144 39 3
Carfilzomib-Len-Dex (KRd) in Relapsed MMPhase III ASPIRE trial: PFS* and OS results (N=792)
KRd Rd
Treatment discontinuation due to AE, % 15.3 17.7
Grade ≥3Anemia, %Neutropenia, %Thrombocytopenia, %PN, %Cardiac failure, %Ischemic heart disease, %
17.929.616.62.63.83.3
17.226.512.33.11.82.1
Stewart et al. ASH 2014 (Abstract 79), oral presentationStewart et al. N Engl J Med 2014 Dec 6 [Epub ahead of print]
Cardiovascular impact of CFZ in MM:Baseline elevated cardiac peptides and abnormal cardiac strain (60% at baseline)Arise in the NT-proBNP occurs immediately after Cfz based chemotherapy.5% of severe cardiac events attributable to cfz Rosental et al.ASH2014
Carfilzomib-Len-Dex (KRd) in Relapsed MMPhase III ASPIRE trial: Safety profile data
Tourmaline-MM1: Phase 3 study of weekly oral ixazomibplus lenalidomide-dexamethasone
Rand
omiz
atio
n
Ixazomib + Lenalidomide + DexamethasoneIxazomib: 4 mg on days 1, 8, and 15Lenalidomide: 25 mg* on days 1-21
Dexamethasone: 40 mg on days 1, 8, 15, 22
N=722
1:1
Placebo + Lenalidomide + DexamethasonePlacebo: on days 1, 8, and 15
Lenalidomide: 25 mg* on days 1-21Dexamethasone: 40 mg on days 1, 8, 15, 22
Repeat every 28 days until progression, or unacceptable toxicity
Stratification:• Prior therapy: 1 vs 2 or 3• ISS: I or II vs III• PI exposure: yes vs no
Global, double-blind, randomized, placebo-controlled study design
*10 mg for patients with creatinine clearance ≤60 or ≤50 mL/min, depending on local label/practice
1. Rajkumar S, et al. Blood 2011;117:4691–5.
Response and progression (IMWG 2011 criteria1) assessed by an independent review committee (IRC) blinded to both treatment and investigator assessment
Primary endpoint: • PFSKey secondary endpoints:
• OS
• OS in patients with del(17p)
Moreau P, ASH 2015 Abst 727
Moreau P, ASH 2015 Abst 727
A significant, 35% improvement in PFS with IRd vs placebo-Rd
Number of patients at risk:
IRd
Placebo-Rd
360 345 332 315 298 283 270 248 233 224 206 182 145 119 111 95 72 58 44 34 26 14 9 1 0
362 340 325 308 288 274 254 237 218 208 188 157 130 101 85 71 58 46 31 22 15 5 3 0 0
1.0
0.8
0.6
0.4
0.2
0.0
0 1 2 3 4 5 6 7 8 9 10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Prob
abili
ty o
f pro
gres
sion
-fre
e su
rviv
al
Time from randomization (months)
Log-rank test p=0.012
Hazard ratio (95% CI): 0.742 (0.587, 0.939)
Number of events: IRd 129; placebo-Rd 157
Median PFS:
IRd: 20.6 months
Placebo-Rd: 14.7 months
Median follow-up: ~15 months
Interim OS analysis @ 23 months of FU: 81 and 90 deaths in ixazomib and placebo, respectively
Tourmaline-MM1: Ixazomib +/- Rd: Final PFS analysis
ORR (IRd vs Rd): 78.3% vs 71.5% CR (IRd vs Rd): 11.7% vs 6.6%
Moreau P, ASH 2015 Abst 727
IRd (N=361), % Placebo-Rd (N=359), %
Preferred terms All-grade Grade 3-4 All-grade Grade 3AEs overlapping with lenalidomideDiarrhea 45 6 39 3Nausea 29 2 22 0Rash* 36 5 23 2Upper respiratory tract infection
23 <1 19 0
Thrombocytopenia 31 19 16 9AEs with proteasome inhibitorsPeripheral neuropathy* 27 2 22 2
Peripheral edema 28 1 20 1
AEs with lenalidomideThromboembolism* 8 2 11 3
Neutropenia* 33 23 31 24
*Represents multiple MedDRA preferred terms.
Tourmaline-MM1: Ixazomib +/- RD: SafetyIncreased rates with IRd driven by low-grade events
Activity of other Proteasome Inhibitors in RRMM
- MARIZOMIB + DEX (n = 21) (90% Btz exposed ):
- Twice weekly (≥0.4 mg/m2 ) x 4doses, 21 day cycles,
- ≥PR: 19% - Diarrhea (38/35%), nausea (10/30%)anemia (22%)
Richardson PG, et al. Blood. 2011;118: Abstract 302;.
- OPROZOMIB + DEX (n = 69) (38% Btz exposed ): Median number of prior lines: 4
≥PR: 31% (2/7 sched) & 23% (5/14 sched)
Diarrhea (38/35%), nausea (10/30%) anemia (22%)
Vij R, et al. Blood. 2014; 124(21): Abstract 34
- OPROZOMIB + POMA + DEX (n = ?). Median number of prior lines: 8. 2
different schedules: 150mg 5/14 or 210 mg 2/7: 210mg 2/7 chose for dose expansion.
ORR (2/7): 85.7% Shah J, ASH 2015 Abstract 378
Novel Drugs in MM
- Derivatives from the already approved
- Novel Proteasome Inhibitors
- Novel IMIDs- Novel Alkylators
- Novel Mechanisms of action
- MoAb: anti CS1 & anti-CD38
- Deacetylase Inhibitors
- XPO-1 inhibitors
- Checkpoint inhibitors
Activity of Poma + Dex in relapse and RRMM
Dex 40 mg weeklySchey (JCO 2004): 24 pts (2mg): 54%PR
Lenalidomide + Dex5 ≥ PR: 60% (15% CR) TTP: 13.4 m
Lacy1,2 34 Len refr 3.5 2 mg (1-28) 32 % PFS 5.0 m
Lacy1,2 60 Len refr 2 4 mg (1-28) 37% PFS 7.9 m
Leleu3 84 Prev. Len & Btz5
5
4 mg (1-21) 35 % PFS 5.5 m
4 mg (1-28) 34 % PFS 4.4 m
Lacy1,2 70 Len & Btz refr6 2 mg (1-28) 26 % PFS 6.5 m
6 4 mg (1-28) 29 % PFS 3.3 m
Richardson4 113 Prev Len & Btz. Refr to last line 5 4 mg (1-21) 34 % PFS 4.6 m
n Population No prior tx Dose ≥ PR PFS
Lacy1,2 60 60% prev IMIDs 2 2 mg (1-28) 65 % PFS 13 m
1. Lacy. ASH 2011. Abst 3963. 2. Lacy. ASH 2012. Abst 201.3. Leleu X, et al. Blood. 2013; 121:1968-75. 4. Richardson. IMW 2013. Abst O-15.
5. Dimopoulos MA, et al. Leukemia. 2009;23:2147-52.
Comparison of Pom-Dex trials (& combinations)
1. San Miguel, Lancet Oncology 2013; 2. Dimopoulos MA, et al. ASH 2014. Abstract 80; 3. Baz et al. ASH 2014. Abstract 303; 4. Richardson et al. ASH 2015. Abstract 3036
*EFS at 12 months
MM-0031 STRATUS(MM-010)2
Pom-Dex vsPom-Cyclo-Dex3 Pom-Btz-Dex4
Treatment PD PD PD PCD PVDn 302 604 36 34 34
Population Failed Bort & Len & refr to last lineAt least 2 prior lines & Len-
refractory1-4 prior lines & Len-refractory
ORR, % 31 35 39 65 65
≥ VGPR, % 14 12 45
PFS, months 4.0 4.2 4.4 9.5 -
OS, months 13.1 11.9 16.8 NR -
a Pts may have received POM + LoDEX following crossover.
POM + LoDEX(N = 300)
HiDEXa
(N = 150)
Grade 3/4 hematologic AEs (%)
Neutropenia 49 17
Febrile neutropenia 9 0
Anemia 33 39
Thrombocytopenia 22 26
Grade 3/4 non-hematologic AEs (%)
Infections 33 25
Pneumonia 14 8
Bone Pain 7 5
Fatigue 5 6
Asthenia 4 7
Glucose intolerance 4 7
Discontinuation due to AEs (%) 9 10
San Miguel J, et al. Patient Outcomes by Prior Therapies and Depth of Response: Analysis of MM-003, a Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) vs High-Dose Dexamethasone (HiDEX) in Relapsed/Refractory Multiple Myeloma (RRMM). Oral presentation at: American Society of Hematology. 2013; December 7-10; New Orleans, LA.
Pom-Dex vs HiDEX in RRMMPhase III MM-003 trial: Safety profile
Novel Drugs in MM
- Derivatives from the already approved
- Novel Proteasome Inhibitors
- Novel IMIDs
- Novel Alkylators
- Novel Mechanisms of action
- MoAb: anti CS1 & anti-CD38
- Deacetylase Inhibitors
- XPO-1 inhibitors
- Checkpoint inhibitors
Melflufen
Chauhan Clin Cancer Res 2013 & Wickström Invest New Drugs 2008
N=29. 4 (2-11) prior lines.
All prior IMiDs and PIs and 18 (62%) prior melphalan
4 /6 pts @ 55 mg had DLTs (haem.)MTD 40 mg
G 3/4 rel. TEAEs: Thromboc. (41%) & Neutropenia (31%)
Phase I/II
• Melflufen is a highly lipophilic alkylator, consisting of
melphalan + 4-fluoro-L-phenylalanine.
• Intracellular peptidases that are overexpressed in most
malignant cells, will rapidly cleave melflufen releasing the
hydrophilic, active metabolite melphalan.
• In vitro, equimolar treatment of tumor cells with melphalan
and melflufen, results in a 10-20 fold higher intracellular
concentration of melphalan.
Paba-Praba ASH 2014
ORR @ MTD 60%
1 VGPR & 2 PR
Median time on txfor responding pts 13
w.
Novel Drugs in MM
- Derivatives from the already approved
- Novel Proteasome Inhibitors
- Novel IMIDs
- Novel Alkylators
- Novel Mechanisms of action
- MoAb: anti CS1 & anti-CD38- Deacetylase Inhibitors
- XPO-1 inhibitors
- Checkpoint inhibitors
Elotuzumab (SLAMF7:Signaling Lymphocytic Activation Molecule F7: Anti-CS1)
- ELOTUZUMAB Single agent1 26% SD- ELOTUZUMAB + LEN-DEX (Phase II) ORR: 76-92%; PFS 18 - 33 m
Elotuzumab + Len + Dex in RRMM patients Phase III – Eloquent trial (646 patients): Study design
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: days 1, 8, 15, 22; Cycles 3+: days 1, 15
Len (25 mg PO): days 1–21Dex: 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 wks until progressive disease,
• Survival: every 12 wks after disease progression
Repeat every 28 days
• Endpoints:
– Co-primary: PFS and ORR
– Other endpoints: OS (data not yet mature); DOR, quality of life, safety
• All patients received premedication to mitigate infusion reactions prior to Elo administration
Lonial S et al, NEJM 2015 Aug 13;373(7):621-31
Eloquent-2: Extended Progression-Free Survival
Dimopoulos M, ASH 2015 Abst 28
ORR (ELd vs Ld): 79% vs 66%. ≥VGPR: 32.7% vs 27.9%
27% reduction in the risk of disease progression or death
0.0
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
480 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Prob
abili
ty p
rogr
essi
on fr
ee
E-LdLd
0.
1
1-year PFS 2-year PFS 3-year PFS
No. of patients at risk:E-LdLd
321325
293266
259215
227181
171130
144106
12580
10767
9460
8551
5936
3415
197
83
PFS (months)30
195157
00
68%
41%
26%
57%
27%
18%
PFS: 19.4 vs 14.9 HR 0.73 (95% CI 0.60, 0.89)
p=0.0014
PFS (19.4 vs 14.9 m)
460 2 4 6 1416 2022 2628 3234 36 40 448 1012
E-Ld
Ld
0.0
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time to next treatment (months)
Prob
abili
ty o
f pat
ient
s w
itho
ut n
ext
trea
tmen
t
18 24 30 38 4842
0.1
No. of patients at risk:E-LdLd 321
325315305
282251
259232
208174
198166
174135
165120
153105
13889
12685
9446
6530
4620
145
225193
31
294276
239206
182148
14496
11876
3213
63
00
TNT: 33 vs 21 mHR 0.62 (95% CI 0.50, 0.77)
TNT (33 vs 21 m)
Eloquent-2: Interim Overall Survival
Dimopoulos M, ASH 2015 Abst 28
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
510 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
No. of patients at risk:E-LdLd
321325
314305
303287
291269
283255
266241
250228
239218
224208
217200
196184
190171
152134
9588
4841
1517
1-year OS 2-year OS
OS (months)
Prob
abili
ty a
live
53
00
E-Ld
Ld
No. of patients at risk:
3-year OS E-Ld Ld
HR 0.77 (95% CI 0.61, 0.97; 98.6% CI 0.58, 1.03); p=0.0257
Median OS (95% CI)
43.7 m(40.3,NE)
39.6 m(33.3, NE)
Prespecified interim analysis for overall survival indicates a strong trend (p=0.0257) with early separation sustained over time for E-Ld vs Ld
TreatmentELd
(n=464)Ld
(n=465)
Grade 3 AEs, %
Fatigue, % 9 8
Neutropenia, % 35 44
Thrombocytopenia, % 21 20
Anemia, % 20 21
Infusion reactions, %11% gr 1/2
1% gr 3NA
Lonial S, ASCO 2015. Abstract 8508. Dimopoulos MA, ASH 2015 oral presentation 28.
- Addition of elotuzumab did not increase the incidence of AE compared to Len/Dex alone. - 70% of infusion reactions occur with the first dose.- Only 2 patients discontinue the study due to an infusion reaction.
Elotuzumab + Len + Dex in RRMMPhase III – Eloquent trial: Results
Anti CD38 in MM: single agent activity in RRMM
Daratumumab Isatuximab
Study details 3 studies: GEN5011, SIRIUS2 & combined analysis4
First in-human, phase 1 dose escalation3
Patients Pts with rel/ref MMn=148 (SIRIUS n=42 and GEN501 n=106)
Pts with rel/ref MMn=40
Dose 16 mg/kg Dose is not yet defined
Results
• ORR 31% (36% GEN501 & 29%SIRIUS)
• Median DOR: 7.6 m• 1 year OS: 77% / 69%• Median PFS: 5.6m , 3.7 m,
Infusion-related reactions gr 1-2
• At ≥ 10 mg/kg: 29%• At 20 mg/kg: 24%5
• Infusion-reactions mainlygrade 1/2, only with first dose
1Lokhorst HM et al, NEJM 2015, 363:8; 1Lokhorst et al. ASCO 2014; Abstract 8513; Lonial S JCO 2015, 3Martin et al. ASCO 2014; Abstract 8532; 4Usmani S, et al ASH 2015 oral presentation 29, 5Martin T, ASH 2015 oral presentation 509
Dara/SAAR are CD38 MoAB showing activity as single agents in RRMM patients
• For the combined analysis, median OS = 19.9 (95% CI, 15.1-NE) months
• 1-year overall survival rate = 69% (95% CI, 60.4-75.6)
Daratumumab in monotherapy: Two studies: GEN501 & SIRIUS – PFS and OS analysis
PD/NE: 3.7 (1.7-7.6) months
Responders: NE (7.4, NE)
MR/SD: 3.2 (2.8-3.7) months
PD/NE: 0.9 (0.9-1.0) months
0
Pati
ents
pro
gres
sion
-fre
e an
d al
ive,
%
2 6 8 12 14 18 20Time from first dose, months
Patients at riskResponders
MR/SDPD/NE
0
25
50
75
100
4 10 16
RespondersMR/SDPD/NE
467725
46450
35130
2730
1310
500
300
000
41210
1420
300
0
Pati
ents
aliv
e, %
2 6 8 12 14 18 22Time from first dose, months
Patients at riskResponders
MR/SDPD/NE
0
25
50
75
100
4 10 16
MR/SD
467725
467416
456311
44577
42475
29374
310
000
466712
43537
15101
20
1351
Responders: NE (19.9, NE)
MR/SD: 17.5 (15.1-NE) months
PD/NE: 3.7 (1.7-7.6) months
Responders
PD/NE
Progression-free survival Overall Survival
Usmani S, ASH 2015 Abst 29
Anti-CD38 MoAb plus Len/dex in RRMM
Daratumumab + Len/Dex SAR650984 + Len/Dex
Target CD38 CD38
Single-agent activity Yes Yes
Study details
Phase 1/2 dose escalation & expansion
Prior IMiDs: 80%Pts ref or intolerant to Len
excluded
Phase Ib dose escalation trialPts rel + ref to
IMiD:84%
Patients n=32 n=31
ResultsORR 81%
(35% CR, 28% VGPR, 19% PR)
ORR 58% (6% sCR, 23% VGPR,
29% PR)PFS 6.2 months
Plesner et al. ASH 2014 (Abstract 84); ASH 2015 (Abs 507); Martin et al. ASH 2014 (Abstract 83); oral presentation
Chari A, ASH 2015 Abst 508
• ORR = 71%
• ORR in double-refractory patients = 67%
• Clinical benefit rate (ORR + minimal response) = 73%
• Rates of grade ≥3 AEs were similar to those observed with POM-D alone
DARA + POM-D(N = 75)
n (%) 95% CI
Overall response rate (sCR+CR+VGPR+PR)
53 (71) 59.0-80.6
Best responsesCRCRVGPRPRMRSDPD
4 (5)3 (4)
25 (33)21 (28)
2 (3)17 (23)
3 (4)
1.5-13.10.8-11.2
22.9-45.218.2-39.6
0.3-9.313.8-33.80.8-11.2
VGPR or better (sCR+CR+VGPR)
32 (43) 31.3-54.6
CR or better (sCR+CR) 7 (9) 3.8-18.3
ORR = 71%
43%VGPR or better
9%CR or better
28%
33%
4%5%
0
10
20
30
40
50
60
70
80
16 mg/kg
OR
R, %
PR VGPR CR sCR
N = 75
MMY-1001: Daratumumab + Pomalidomide + DexOverall response rate
Novel Drugs in MM
- Derivatives from the already approved
- Novel Proteasome Inhibitors
- Novel IMIDs
- Novel Alkylators
- Novel Mechanisms of action
- MoAb: anti CS1 & anti-CD38
- Deacetylase Inhibitors- Checkpoint inhibitors
- XPO-1 inhibitors
Inhibition of the aggresome and proteasome pathways causes a buildup of intracellular misfolded cytotoxic proteins, leading to MM cell apoptosis1-4
Accumulation of
Unfolded/ misfoldedproteins
Ubiquitinatedprotein aggregates
DACiRocilinostat, Vori &
Panobinostat
Bortezomib
1. Hideshima T, et al. Proc Natl Acad Sci USA. 2005;102:8567-8572. 2. Ocio EM, et al. Haematologica. 2010;95:794-803. 3. Catley L, et al. Blood. 2006;108:3441-3449. 4. Hideshima T, et al. Mol Cancer Ther. 2011;10:2034-2042.
Proteindegradation
Ubiquitinatedprotein
Proteasomal degradation
Dynein
Microtubule
Aggresomeformation
Lysosomal degradation
ProteindegradationHDAC6
Rationale for combining DACi + Bortezomib
No benefit in OS
PANORAMA 1: Panobinostat + Bort + Dex vs Bort + Dex
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
387 288 241 202 171 143 113 89 69 52 44 35 26 18 13 10 5 3 0
381 296 235 185 143 114 89 64 42 32 24 18 12 5 5 3 2 0 0
MonthsNumber of patients at riskPAN-BTZ-DexPbo-BTZ-Dex
100
80
60
40
20
0
PFS
Prob
abili
ty, %
PAN-BTZ-DexPbo-BTZ-Dex
San Miguel JF, et al. Lancet Oncol. 2014;15(11):1195-1206
PAN-BTZ-Dex Pbo-BTZ-Dex
Median PFS(m) 12 (10.3-12.9) 8.1 (7.6-9.2)
HR (95% CI) 0.63 (0.52 – 0.76)
ORR PanoBD vs PcboBD: 60.7% vs 54.6% CR: 27.6% vs 15.7%
PFS
73 57 42 36 32 25 20 15 10 6 4 3 2 2 1
74 54 37 23 11 9 5 4 2 2 2 2 2 0 0
Number of Patients at RiskPAN-BTZ-DexPbo-BTZ-Dex
PFS
Prob
abili
ty, %
100
80
60
40
20
00 2 4 6 8 10 12 1
416 18 20 22 24 26 28
Months
Censoring timesPAN-BTZ-Dex (n/N = 44/73)Pbo-BTZ-Dex (n/N = 54/74)
Subgroup Analysis by Prior Treatment:
PFS Prior BTZ + IMiDs w/ ≥ 2 Prior Lines
PAN-BTZ-Dex Pbo-BTZ-Dex
Median PFS(m) 12.5 (7.3-14.0) 4.7 (3.7-6.1)
HR (95% CI) 0.47 (0.31 – 0.72)
Other HDACi: Ricolinostat (ACY-1215) (HDAC6 inhibitor)
2. Yee, ASH 2014. Abstract 47721. Vogl, ASH 2014. Abstract 4764
- BORT + DEX1 ...........ORR 19% 1 VGPR, 2 PR In Btz refr. only 1 MR
n=16. 11 Btz refractory
G3/4 related AEs: Hemat. Amylase & creat incr.
- LEN+ DEX2 ORR 69%1 CR, In 6 Len refr. 1 VGPR, 1 PR, 2 MR
n=15. 14 prior Len. 6 Len refr
G3/4 related AEs: Hematologic and fatigue
Novel Drugs in MM
- Derivatives from the already approved
- Novel Proteasome Inhibitors
- Novel IMIDs
- Novel Alkylators
- Novel Mechanisms of action
- MoAb: anti CS1 & anti-CD38
- Deacetylase Inhibitors
- XPO-1 inhibitors
- Checkpoint inhibitors
XPO1-Inhibitors: Selinexor
Main AEs: Anorexia Nausea/Vomiting; Fatigue; Thrombocytopenia. Improve with Dex.
• Cancer cells (and MM) overexpress XPO1, causingincreased export of tumor suppressors and growthregulatory proteins from the nucleus
• Selinexor inhibit XPO1 mediated nuclear-cytoplasmic transport by transiently binding toXPO1 cargo binding site.
• Accumulation of Tumor suppressors in the nucleusamplifies the natural apoptotic function in cancercells with damaged DNA.
• Preclinical antitumoral & antiresorptive act. in MM
Chen et al. ASH 2014
First-in-class, oral Selective Inhibitor of Nuclear Export (SINE) that inhibits XPO1and activates Tumor Suppressor Proteins & reduces Oncoproteins
Tai et al. Leukemia 2014
PHASE I OF SELINEXOR PLUS/MINUS DEX IN RRMM
- Single agent (oral:3-45 mg twice/ w)….. 17% MR
- Plus Dex (45 mg)…………………………60% ORR (50% PR)
Under normal physiological conditions, immune checkpoints are crucial for: Maintenance of self-tolerance (prevent autoimmunity)
Protect tissues from damage
Activation of T-cell is a two-step process:
1- Interaction of TCR with a specific antigenic peptide-containing complex onAPC/tumor cells.
2- Co-stimulatorysignal, that induces activation and expansion of T-cells. In the absence of thissignal, T-cells fail to respondand are inactivated.
Overcoming tumour immune suppression
Topalian SL et al. Curr Opinion Immunol, 2012
Pembrolizumab: Targeting PD-1 (Programmed Cell Death 1) Releasing The Brakes
• Pembrolizumab is a potent and highly selective humanized monoclonal antibody of the IgG4/kappa isotype against PD-1
• Directly blocks the interaction between PD-1 and PD-L1/PD-L2
• Checkpoint Blockade of PD-1/PD-L1 signaling induces anti-MM immune responses, enhanced by lenalidomide. Gorgun ASH 2014: Ab 27
• PD-1 is overexpressed in T cells (at relapse & MRD) & PD-L1 in PC and MSC
• PD-1 blockade delays tumor progression (mouse model). Paiva B Leukemia 2015
1. Keir ME et al. Annu Rev Immunol. 2008;26:677-704; 2. Hallett WH et al. Biol Blood Marrow Transplant. 2011;17:1133-1145; 3. Homet Moreno B, Ribas A. Br J Cancer. 2015;112:1421-1427. Phase I of Nivolumab (BMS-936558) 67% SD
Pembrolizumab treatment in RRMM
KEYNOTE-023 (PhI):PEMBRO-LEN-DEX1
Ph I/II: PEMBRO – POMA –DEX2
Study designPEMBRO 200mg/2QW LEN 25mg 1-21 DEX 40mg weekly
PEMBRO 200mg/2QW POMA 4mg 1-21DEX 40mg weekly
Patient population- > 2 prior lines- PI & IMID exposure
- >2 prior lines- RRMM- PI & IMID exposure
Refractory status 76% Len-refractory30% Bort-refractory
50% double/triple/cuadruple refractory
89% Len-refractory82% Bort-refractory
70% double-refractory
ORRTotal (n=17): 76%
Len-refr (n=9): 56%Total (n=27): ORR: 60% Double refractory: 55%
SafetyAEs consistent with individual drug safety
profiles for approved indicationsIRAEs: no pneumonitis. No colitis.
Good safety profilePneumonia/Infection
Few cases pneumonitis / hepatitis
1San Miguel JF, ASH 2015 oral presentation 505; 2Badros A, ASH oral presentation 585
Type of relapse
Further options
Efficacy of previous
treatments
Toxicity of previous
treatments
Strategies at relapse: How to make the RIGHT CHOICE?
Intermediate relapse (1-3 years post ASCT)“Prolong survival until curative treatments are developed”
Sequential novel agent combinationsStarting with a different drug to that used in maintenance.( if less < 55 years & suboptimal response RIC-Allo?)
Late relapse (> 3 years post ASCT)Aggresive relapse: Reinduction (KRD) + 2nd ASCTBiological relapse: proceed direct to ASCT
Early relapse (< 1 year post ASCT)“Overcome drug resistance”
Combination of non cross-resistant agentsVTD-PACE or VRD +/- Adria & Cyclo RIC-Allo
60 year old man relapsing after ASCT: How to make the RIGHT CHOICE?
Decisions based on the duration of the previous response
Decisions based on treatment used up-front and its efficacy
Modest efficacy or progression under treatment
Switch drug class
IMiDProteasome inhibitor
or Alkylators if not used upfront
Biological progression
Increase dose/add a new drug
CR & Durable TFI (> 9-12m)
Re-treatment(1st or 2nd option)
75 year old man relapsing after frontline treatment: Can treatment be individualized at first relapse?
Type of relapseNumber of prior lines of therapy
Cytogenetic abnormalities,....
60y man 1st or 2nd relapse NOT LEN-refractory …
After Bortezomib based induction without maintenance(Lenalidomide or Bortezomib) until progression:
Lenalidomide – Dexamethasone until progression (PFS 15 m)
1Stewart AK, et al. NEJM 2015 Jan 8;372(2):142-52; 2Moreau P, ASH 2015 abst 727; 3Lonial S et al, NEJM 2015 Aug 13;373(7):621-31; 4Dimopoulos MA et al, Lancet Oncol. 2016 Jan;17(1):27-38
DoubletsKD (PFS 18 m)4
Kd (18 m) + Rd (15m) = 33 m
Triplets (with RD as backbone) KRD (PFS 26.3 m)1
IRD (PFS 20.6 m)2
EloRD (PFS 19.4 m)3
but
Type of relapse
Cytogenetic abnormalities
Age
Number/Typesof prior lines of
therapy
What are the factors influencing our decisions?
What are the factors influencing our decisions?: Age
ENDEAVOR trial (Kd vs Vd)2: Similar benefit among different ages
PFS in 65-74y ……… HR 0.53 (0.38–0.73)PFS in >75 y ……… HR 0.38 (0.23–0.65)
ASPIRE trial (KRd vs Rd)1: Only borderline benefit in patients older than 70y
PFS in >70 y ………… 23.8 vs 16 (HR 0.73, p=0.0521)PFS in < 70y .……….. 28.6 vs 17.6 (HR 0.66, p=0.0002)
ELOQUENT-2 trial (EloRd vs Rd)3: Significant benefit in patients older than 75y
PFS in < 75y ………… HR for PFS 0.76 (0.62-0.94)PFS in ≥ 75y ………… HR for PFS 0.59 (0.38-0.91)
TOURMALINE-MM1 (IRd vs Rd)4: No survival benefit in patients older than 65y
PFS in ≤ 65 y ……….. 20.6 vs 14.1 m (HR 0.689)PFS in 65-75y ……… 17.5 vs 17.6 m PFS in >75y ………… 18.5 vs 13.1 m (HR 0.86, p=n.s)
1Stewart AK, et al. N Engl J Med 2015;372:142–52; 2Dimopoulos MA, et al. Lancet Oncology 2016; 17: 27-38; 3Lonial S et al, NEJM 2015 Aug 13;373(7):621-31; 4Moreau P, ASH 2015 abst 727;
What are the factors influencing our decisions?: Prior lines of therapy
ENDEAVOR trial (Kd vs Vd)2: Better used at first relapse.
1 prior line ……… PFS (Kd vs Vd): 22.2 vs 10.1 (HR 0.45)
≥ 2 prior lines ……… PFS 14.9 vs 8.4 (HR 0.60)
ASPIRE trial (KRd vs Rd)1: Similar results after 1 or 2 or more prior lines
1 prior line ……… PFS 29.6 vs 17.6 (HR 0.69) ≥ 2 prior lines ……… PFS 25.8 vs 16.7 (HR 0.69)
ELOQUENT-2 trial (EloRd vs Rd)3: Better results after 2 or more prior lines. 1 prior line ..……… HR 0.79 (0.60 - 1.05) Prior IMID .………. HR 0.55 (0.21 – 1-25)≥ 2 prior lines ……… HR 0.68 (0.52 – 0.88)
TOURMALINE-MM1 (IRd vs Rd)4: Better results after three lines of therapy1 prior line ……… PFS 20.6 vs 15.9 (HR 0.83, n.s) 2 prior lines ……… PFS 17.5 vs 14.1 (HR 0.75, n.s)3 prior lines ………. PFS NE vs 10.2 (HR 0.36)
1Stewart AK, et al. N Engl J Med 2015;372:142–52; 2Dimopoulos MA, et al. Lancet Oncology 2016; 17: 27-38; 3Lonial S et al, NEJM 2015 Aug 13;373(7):621-31; 4Moreau P, ASH 2015 abst 727;
What are the factors influencing our decisions?: Cytogenetic abnormalities
ENDEAVOR trial (Kd vs Vd)2: KD does NOT OVERCOME adverse prongnosis of HR cytogenetics
Standard risk ……… PFS NE vs 10.2 (HR 0.44) (0.33 – 0.57) High risk ……..……… PFS 8.8 vs 6.0 (HR 0.66) (0.45 – 0.92)
ASPIRE trial (KRd vs Rd)1: KRD improves but does NOT OVERCOME the -ve prongnosis
Standard risk ……… PFS 29.6 vs 19.5 (HR 0.66) (0.48 – 0.90) High risk ……..……… PFS 23.1 vs 13.9 (HR 0.70) (0.43 – 1.13)
ELOQUENT-2 trial (EloRd vs Rd)3: EloRd improves but does NOT OVERCOME the –ve prognosisDel(17p) ……..……… HR 0.70 (0.49 – 0.99) t(4;14) ………………… HR 0.52 (0.29 – 0.93)
TOURMALINE-MM1 (IRd vs Rd)4: IRD OVERCOMES the adverse prognosis of HR cyto.Standard risk ..……… PFS 20.6 vs 25.6 (HR 0.64)High risk ……………… PFS 21.4 vs 9.4 (HR 0.54)
1Stewart AK, et al. N Engl J Med 2015;372:142–52; 2Dimopoulos MA, et al. Lancet Oncology 2016; 17: 27-38; 3Lonial S et al, NEJM 2015 Aug 13;373(7):621-31; 4Moreau P, ASH 2015 abst 727;
65 year old woman first or second relapse…
Following continuous Lenalidomide – Dexamethasone(Lenalidomide refractory)
1Dimopoulos MA et al, Lancet Oncol. 2016 Jan;17(1):27-38; 2San Miguel JF et al, Lancet Oncol 2014;15(11):1195-1206; 3Palumbo A, AHS 2015 abst 510.
Carfilzomib-dex PFS (18 m)1Triplets with Pom-Dex(as backbone)
PVD (PFS ? MM-007 trial)
Triplets based on bortezomib:PanobinostatVd (PFS 12m)2
EloVD (9.7m) ?
Treatment at second/subsequent relapse
Pomalidomide - Dexa(as a backbone)
+ Cyclophosphamide+ Ixazomib+ Bortezomib+ Daratumumab+ Elotuzumab
Daratumumab(single agent orcombination)
Clinicaltrial
NEW TREATMENT OPTIONS FOR PATIENTS WITH ADVANCED RELAPSE /
REFRACTORY MULTIPLE MYELOMA
Paula Rodríguez Otero
University of Navarra