How to address real-world challenges in RR Multiple Myeloma · O conteúdo desta apresentação é...
Transcript of How to address real-world challenges in RR Multiple Myeloma · O conteúdo desta apresentação é...
How to address real-world challenges in RR Multiple Myeloma María-Victoria Mateos HUSalamanca
PT/IXZ/0619/0034 RR: Relapsed/Refractory; MM: Multiple Myeloma
Conflict of Interest
• Honoraria from lectures and participation in advisory boards: janssen, Celgene, amgen, takeda, GSK, EDO, Pharmamar, Adaptive
O conteúdo desta apresentação é da autoria do palestrante, refletindo a sua perspetiva clínica e/ou trabalhos seus não publicados The content of this presentation is author`s own, reflecting his clinical perspective and or his unpublished works.
Esta apresentação constitui um serviço prestado à Takeda, tendo sido sujeita a honorários. This presentation constitutes a service provided to Takeda and has been subject to honoraria.
MGUS, monoclonal gammopathy of unknown significance; MM, multiple myeloma. 1. Durie BGM. Concise review of the disease and treatment options. Multiple myeloma, cancer of the bone marrow. International Myeloma Foundation, 2016. Available at: www.myeloma.org/sites/default/files/images/publications/UnderstandingPDF/concisereview.pdf (accessed January 2018); 2. Manier S et al. Nat Rev Clin Oncol 2017;14:100–113.
Tumour cell diversity and clonal evolution drive MM relapse
Relapsed refractory
Relapse
Remission MGUS or smouldering
myeloma
Active myeloma
Relapse
Time
M p
rote
in
SYMPTOMATIC ASYMPTOMATIC
1
2
RCT, randomised clinical trials. Yong K et al. Br J Haematol 2016;175:252–264.
Treatment intentions derived from evidence from RCTs may not reflect what is possible in real-life practice
• Clinical trials suggest that patients benefit from treatment at later stages, however, in reality, few patients reach fourth and fifth lines of treatment
• Understanding the reasons for discontinuation of treatment can provide an insight into patient outcomes and treatment decisions
RRMM: relapsed/refractory multiple myeloma.
Main objectives for the treatment of RRMM patients
Induces deep, long-
lasting responses
Well-tolerated
Minimal impact on
patient lifestyle and healthcare resources
RRMM: relapsed/refractory multiple myeloma.
Factors influencing the decision in order to make the right choice for RRMM patients
Type of relapse
Further options
Efficacy and toxicity
of the previous therapies
Relapse/Refractory MM patients ESMO guidelines 2017
First relapse after Bortezomib-based induction
Triplets based on Rd DaraRd or KRd or IxaRd or
EloRd
Rd
Pomalidomide-Dex (as a backbone)
+ Cyclo or Ixa or Bort or Dara or Elo
Daratumumab (single agent or
combination)
Clinical trial
At second or subsequent relapse
First relapse after IMiD-based induction
Doublets Kd / Vd
Triplets based on Bortezomib DaraVD or PanoVD or
EloVD or VCD
Main challenges • The selection of the rescue therapy is mainly influenced by the first line of therapy • The first line of therapy is rapidly evolving towards new standards of care • Treatment recommendations vary internationally
Moreau P et al.Annals of Oncology 2017
IMiD: Immunomodulatory drug; Kd: Carfilzomib and dexamethasone; Vd: Bortezomib and dexamethasone; DaraVD: Daratumumab, bortezomib and dexamethasone; PanoVd:Panobinostat, bortezomib and dexamethasone; EloVD: Elotuzumab, bortezomib and dexamethasone; Rd: Lenalidomide and dexamethasone; DaraRd: Daratumumab, lenalidomide and dexamethasone; KRd: Carfilzomib, lenalidomide and dexamethasone; IxaRd: Ixazomib, lenalidomide and dexamethasone; EloRd: Elotuzumab, lenalidomide and dexamethasone
Moreau P, et al. Ann Oncol 2017;00:1–11, 2017.
First relapse after Bortezomib-based induction
Triplets based on Rd DaraRd or KRd or IxaRd or EloRd
Doublets Rd X
Efficacy POLLUX
DaraRd vs Rd1-3 ASPIRE
KRd vs Rd4,5 ELOQUENT-2 ERd vs Rd6
TOURMALINE-MM1 IRd vs Rd7
PFS HR (95% CI) 0.44 (0.35–0.55) 44.5 m vs 17.5 m
0.670 (0.558–0.803) 26.3 m vs 17.6 m
0.71 (0.59–0.86) 19.4 m vs 14.9 m
0.74 (0.59–0.94) 20.6 m vs. 14.7 m
ORR, % 93 87 79 78 ≥ CR, % 57 (MRDneg 30%) 32 5 14 DOR, months NE 28.6 21.2 20.5
OS HR (95% CI) 0.63 (0.42–0.95) 0.79 (0.63–0.99) 48 m vs. 40 m
0.78 (0.63–0.96) 43.7 m vs 39.6 m
NE
1st line • Bortezomib-based combinations • Exposed or not to lenalidomide but no progressing under lenalidomide
therapy
Which patients do they fit today in the ESMO guidelines 2017?
Rd: Lenalidomide and dexamethasone; DaraRd: Daratumumab, lenalidomide and dexamethasone; KRd: Carfilzomib, lenalidomide and dexamethasone; IxaRd: Ixazomib, lenalidomide and dexamethasone; EloRd: Elotuzumab, lenalidomide and dexamethasone PFS: Progression free survival; HR: Hazard ratio; ORR: Overall response rate; CR: Complete response; DOR: Duration of treatment; OS: Overall Survival ; CI: Confidence interval ; MRDneg: Minimal residual disease; NE: Non-estimated;
KRd (n=396)
244 (61.6%) 26.1
Rd (n=396)
272 (68.7) 16.6
0.66 (0.55–0.78) 1-sided P<0.0001
1.0
0.8
0.6
0.4
0.2
0
Prop
ortio
n Su
rviv
ing
W
ithou
t Pro
gres
sion
0
Months Since Randomization
KRd Rd
6 24
42
54
78
12
18
30
36
48
60
66
72
396 396
337 291
282 211
227 154
178 118
136 99
109 81
94 61
65 45
45 30
32 21
17 13
2 4
0 0
KRd Rd
Number of patients at risk:
HR (95% CI) at 18 months = 0.55 (0.44–0.69)
Siegel D et al. JCO 2017
Carfilzomib + lenalidomide and dexamethasone vs lenalidomide and dexamethasone in RRMM: ASPIRE
KRd vs Rd: ORR 87% vs 66.7%; ≥CR 32% vs 9%
PFS OS
Stewart K et al. NEJM2015
KRD in first relapse resulted in median PFS of 29 months
Rd: Lenalidomide and dexamethasone; KRd: Carfilzomib, lenalidomide and dexamethasone; CR: Complete response; OS: Overall Survival; HR: Hazar Ratio; CI: Confidence interval PFS: Progression free survival
Daratumumab + lenalidomide and dexamethasone vs lenalidomide and dexamethasone in RRMM: POLLUX
3-year follow-up
Bahlis et al., ASH 2018; abstract 1996
Updated PFSa
Median follow-up: 44.3 months D-Rd significantly prolonged PFS vs Rd
in the ITT population (median: 44.5 months vs 17.5 months; HR, 0.44; 95% CI, 0.35-0.55; P<0.0001)
56% reduction in the risk of progression or death in patients receiving D-Rd
aThe upper bound 95% CI is currently not estimable; median PFS may change with additional follow-up once the upper bound 95% CI estimate is reached.
DRd vs Rd: ORR 93% vs 76%; ≥CR 57% vs 23%. MRD neg rate: 30% vs 5%
Median PFS has not been reached with DRd in first relapse
DRd: Daratumumab, lenalidomide and dexamethasone; Rd: Lenalidomide and dexamethasone; HR: Hazard ratio ORR: Overall response rate; CR: Complete response; MRD; Minimal residual disease; NE: Not-estimeated; CI: Confidence Interval ; PFS: Progression free survival; ITT: Intention to treat
A 29% reduction in the risk of progression or death (sustained over time) 50% in the PFS rate at 4 years (21% vs 14%) in favor of ELoRd
ELOQUENT-2: EloRd vs Rd 4-year follow-up: Progression-free survivala
Dimopoulos MA, et al. Presented at EHA 2017 (Abstract S456), oral presentation.
ELd n=321
Ld n=325
HR=0.71 (95% CI: 0.59–0.86); p=0.0004
Median PFS (95% CI)
19.4 mo (16.6–22.3)
14.9 mo (12.1–17.3) 0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62
1-year PFS 2-year PFS 3-year PFS 4-year PFS
Prob
abili
ty o
f PFS
Time (months) Patients at risk
ELd
Ld
69%
41%
27% 21%
57%
28%
19% 14%
ELd
Ld
321 304 280 260 233 216 196 180 160 147 132 125 111 103 94 91 79 70 63 60 55 52 49 46 36 31 24 17 13 6 2 0
325 295 249 216 192 173 158 141 124 108 91 76 68 64 61 54 47 41 39 37 33 31 30 27 22 13 9 6 3 1 1 0
aAll randomized patients Data cut-off Oct 18, 2016
Minimum follow-up: 48 months
EloRd/Eld: Elotuzumab, lenalidomide and dexamethasone; Rd/Ld: Lenalidomide and dexamethasone; HR: Hazard ratio ; CI: Confidence Interval ; PFS: Progression free survival;
Ixazomib-Rd vs Rd in RRMM patients: Tourmaline-MM1: PFS with IRd vs placebo-Rd
Number of pts 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
Time from randomization (months)
Median follow-up: 14.8 months in the IRd group and 14.6 months in the placebo-Rd group
1.0
0.8
0.6
0.4
0.2
0.0 0 1 2 3 4 5 6 7 8 9 1
0 11
12
13
14
15
16
17
18
19
20
21
22
23
24
Prob
abili
ty o
f pro
gres
sion
-free
sur
viva
l
Log-rank test p=0.01 Hazard ratio (95% CI): 0.74 (0.59, 0.94)
Number of events: IRd 129; placebo-Rd 157
Median PFS: IRd: 20.6 months
Placebo-Rd: 14.7 months
Moreau P et al. NEJM 2016;374(17):1621-34 IRd: Ixazomib, lenalidomide and dexamethasone; Rd: Lenalidomide and dexamethasone
Frailty Disease morbidity
Risk assessment
Treatment history Lifestyle
ISS, International Staging System. Clegg A et al. Lancet 2013;381:752–762; Handforth C et al. Ann Oncol 2015;26:1091–1101; Chen X et al. Clin Interv Aging 2014;9:433–441; Palumbo A et al. Blood 2015;125:2068–2074; Jhaveri D et al. Haematologica 2016;101:1–881 (Abstract E1312); Sonneveld P et al. Leukemia 2013;27:1959–1969; Faiman BM et al. Clin J Oncol Nurs 2011;15(Suppl):66–76; Miceli TS et al. Clin J Oncol Nurs 2011;15:9–23; Greipp PR et al. J Clin Oncol 2005;23:3412–3420; Binder M et al. Haematologica 2016;101:P665; Merz M et al. Haematologica 2016;101:P650; Chng WJ et al. Leukemia 2016;30:1071–1078; Chung TH et al. PLoS One 2013;20:e66361; Sonneveld P et al. Leukemia 2013;27:1959–1969; Ramsenthaler C et al. BMC Cancer 2016;16:427; Williams LA et al. J Clin Oncol 2016;34:e18127; Ramasamy K et al. Haematologica 2017;102:E1457.
Patient-based factors are highly influential in treatment decision-making
Quality of life
Age
Performance status
Disability
Co-morbidities
Refractory disease
Renal impairment
Bone disease
ISS
Cyto-genetics
Previous therapies
Patient preference
Travel / infusion time
• Type of relapse: Indolent/biochemical relapse vs aggressive relapse All combinations are feasible in both situations • Age of the patients: All combinations are effective and well tolerated by elderly patients • Number and type of prior lines: All studies were conducted in lenalidomide-naïve or sensitive patients and we are seeing now more patients lenalidomide-refractory
Treatment sequencing
Aspire: PFS by prior lines of therapy
HR, hazard ratio; KRd, carfilzomib with lenalidomide and dexamethasone; PFS, progression-free survival; Rd, lenalidomide and dexamethasone. Dimopoulos MA, et al. Blood Cancer Journal 2017; 7:e554; doi:10.1038/bcj.2017.31.
KRd (n=184) Rd (n=157)
Progression/Death, n (%) 91 (49.5) 88 (56.1)
Median PFS, mo 29.6 (95% CI, 23.2-33.5) 17.6 (95% CI, 15.0-22.2)
Hazard ratio (KRd/Rd) (95% CI) 0.713 (0.532-0.957)
P value (1-sided) 0.0118
KRd (n=212) Rd (n=239)
Progression/Death, n (%) 116 (54.7) 136 (56.9)
Median PFS, mo 25.8 (95% CI, 22.2-31.0) 16.7 (95% CI, 13.9-22.0)
Hazard ratio (KRd/Rd) (95% CI) 0.720 (0.561-0.923)
P value (1-sided) 0.0046
1 previous line of therapy
⩾2 previous lines of therapy
Phase 3 POLLUX study: DRd vs Rd in RRMM Subgroup analyses
DRd improved PFS versus Rd regardless of the number of prior lines of therapy
HR, hazard ratio; CI, confidence interval. PFS: Progression free survival DRd: Daratumumab,, lenalidomide and dexamethasone Rd: Lenalidomide and dexamethasone aKaplan-Meier estimate.
PFS Median follow-up: 32.9 months
Philippe Moreau, et al. Poster presentation at ASH 2017. Abstract 1883.
Eloquent-2: PFS in patients with ≥ median time from diagnosis (≥ 3.5 yrs) after 1PL or > 1PL
After 1PL After >1PL
Dimopoulos MA, et al. Presented at EHA 2017 (Abstract S456), oral presentation.
Pl: previous line; Eld: Elotuzumab, lenalidomide and dexamethasone Ld:lenalidomide and dexamethasone
TOURMALINE-MM1: PFS according to the number of prior lines of therapy
After 1PL After 2-3PL
Pts with 2 or 3 PL or 1PL without trx seemed to have greater benefit than pts after 1PL and trx
Mateos MV et al. Haematologica. 2017 Oct;102(10):1767-1775. Pl: Previous line; Trx: transplant; Pts: patients; HR: Hazard ratio;CI: Confidence Interval
• Type of relapse: Indolent/biochemical relapse vs aggressive relapse All combinations are feasible in both situations • Age of the patients: All combinations are effective and well tolerated by elderly patients • Number and type of prior lines: All studies were conducted in lenalidomide-naïve or sensitive patients and we are seeing now more patients lenalidomide- refractory Would it be possible to use Rd-based combinations in patients already exposed to len but no len-refractory?
Rd: Lenalidomide and dexamethasone
Treatment sequencing
Efficacy POLLUX
DaraRd vs Rd2-4 ASPIRE
KRd vs Rd5-7 ELOQUENT-2 ERd vs Rd8
TOURMALINE-MM1 IRd vs Rd9,10
PFS HR (95% CI) 0.44 (0.35–0.55) 44.5 m vs 17.5 m
0.69 (0.57-0.83) 26.3 m vs 17.6 m
0.71 (0.59–0.86) 19.4 m vs 14.9 m
0.74 (0.59–0.94) 20.6 m vs. 14.7 m
ORR, % 93 87 79 78 ≥ CR, % 57 (MRDneg 30%) 32 5 14 DOR, months NE 28.6 21.2 20.5
OS HR (95% CI) 0.63 (0.42–0.95) 0.79 (0.63–0.99) 48 m vs. 40 m
0.78 (0.63–0.96) 48.3 m vs 39.6 m NE
PFS HR (95% CI), median In len-exposed
0.38 (0.21–0.66) 38.8 m vs 18.6 m
0.796 (0.522–1.215) 19.4 m vs 13.9 m Only 5 pts 0.58
NR vs 17.5 m
1st line • Bortezomib-based combinations • Exposed or not to lenalidomide but not progressing under lenalidomide therapy
Which patients fit the ESMO guidelines 2017?
1. Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61; 2. Bahlis NJ, et al. ASH 2018, abstract 1996, poster presentation. 3. Usmani SZ, et al. ASH 2016, abstract 1151, oral presentation; 4. Usmani SZ, et al. ASH 2018, abstract 3288; 5. Stewart AK, et al. N Engl J Med. 2015;372:142-52; 6. Siegel DS, et al. J Clin Oncol 2018;36(8):728-734; 7. Dimopoulos MA, et al. Blood Cancer Journal 2017;7:e554; 8. Dimopoulos MA, et al., Cancer 2018;124(20):4032-4043; 9. Moreau P, et al. N Engl J Med. 2016;374:1621-34; 10. Mateos MV, et al. Haematalogica 2017;102(10):1767-
1775.
First relapse after Bortezomib-based induction1
Triplets based on Rd DaraRd or KRd or IxaRd or EloRd
Doublets Rd X
Rd: Lenalidomide and dexamethasone; DaraRd: Daratumumab, lenalidomide and dexamethasone; KRd: Carfilzomib, lenalidomide and dexamethasone; IxaRd: Ixazomib, lenalidomide and dexamethasone; EloRd: Elotuzumab, lenalidomide and dexamethasone PFS: Progression free survival; HR: Hazard ratio; ORR: Overall response rate; CR: Complete response; DOR: Duration of treatment; OS: Overall Survival ; CI: Confidence interval ; MRDneg: Minimal residual disease; NE: Non-estimated;
• Type of relapse: Indolent/biochemical relapse vs aggressive relapse All combinations are feasible in both situations • Age of the patients: All combinations are effective and well tolerated by elderly patients • Number and type of prior lines: All studies were conducted in lenalidomide-naïve or sensitive patients and we are seeing now more patients lenalidomide-refractory • Cytogenetic abnormalities: Combination of PIs and IMiD’s is the optimal choice
PIs: Proteasome inhibitor; IMiDs: Immunomodulatory imide drugs
Treatment sequencing
Aspire study: KRd vs Rd: PFS by Cytogenetic Risk Status at Baseline
KRd (n = 48)
Rd (n = 52)
KRd (n = 147)
Rd (n = 170)
PFS, median months 23.1 13.9 PFS, median months 29.6 19.5
Hazard ratio (95% CI) 0.70 (0.43–1.16) Hazard ratio (95% CI) 0.66 (0.48–0.90)
CI, confidence interval; KRd, carfilzomib, lenalidomide, and dexamethasone; PFS, progression-free survival; Rd, lenalidomide and dexamethasone. Avet-Loiseau H, et al. Blood 2016;128(9):1174-1180.
High Risk Standard Risk High Risk
Avet-loiseau. blood 2017
Tourmaline MM1: IRd vs Rd: PFS in patients according to the cytogenetic risk
DK/IXA/1606/00033
IRd: Ixazomib, lenalidomide and dexamethasone; Rd: Lenalidomide and dexamethasone; PFS: Progression free survival; HR: Hazard ratio
Tourmaline MM1: IRd vs Rd: PFS in patients according to the cytogenetic risk
In the Tourmaline – MM1 the median PFS benefit with IRd versus placebo-Rd was consistent using different positivity cut-offs of del (17/17p) and t(4;14)
Richardson P et al. ASCO 2016
DK/IXA/1606/00033
IRd: Ixazomib, lenalidomide and dexamethasone; Rd: Lenalidomide and dexamethasone
• Type of relapse: Indolent/biochemical relapse vs aggressive relapse All combinations are feasible in both situations • Age of the patients: All combinations are effective and well tolerated by elderly patients • Number and type of prior lines: All studies were conducted in lenalidomide-naïve or sensitive patients and we are seeing now more patients lenalidomide-refractory • Cytogenetic abnormalities: Combination of PIs and IMiD’s is the optimal choice • Toxicity profile/comorbidities: Renal impairment: K/I/Elo/Dara can be used in renal impairment and R should be adjusted. Cardiovascular toxicity/severe COPD/ skin sensitivity….... • Patients preferences/lifestyle/ visits to the hospital....
Treatment sequencing
Pis: Proteasome inhibitor; IMiDs: Immunomodulatory drugs; COPD: Chronic Obstructive Pulmonary Disease
• Minimum number of planned hospital visits required for administration/collection of MM treatments over 18 cycles1–5*
*Patients are treated until progression or unacceptable toxicity. Calculation excludes visits for monitoring. Standard carfilzomib (IV) regimen is 18 cycles; number of administrations of carfilzomib per cycle: cycle 1-12 = 6 doses (2 consecutive doses each week for 3 weeks), cycle 13-18 = 4 doses (2 consecutive doses during 1st and 3rd week). Treatment with carfilzomib + Rd for longer than 18 cycles should be based on an individual benefit-risk assessment, as the data on the tolerability and toxicity of carfilzomib beyond 18 cycles are limited;2–4 Daratumumab is administered (IV) in, weekly for the first 8 weeks, then once every two weeks throughout weeks 9–24, followed by every 4 weeks from week 25 until disease progression or unacceptable toxicity. Calculation: 18 x 4 =72 weeks in 18 cycles. (1 x 8) + (1 x 16/2) + (1 x 64/2) = 28 doses.5
IRd, ixazomib-lenalidomide-dexamethasone; MM, multiple myeloma; Rd, lenalidomide-dexamethasone. 1. NINLARO® Summary of Product Characteristics; 2. REVLIMID® 25 mg Summary of Product Characteristics. 3. Dexamethasone 2 mg Tablets Summary of Product Characteristics; 4. KYPROLIS® Summary of Product Characteristics; 5. DARZALEX® Summary of Product Characteristics.
Administration of combination treatments can have lifestyle implications for patients
Rd: Lenalidomide and dexamethasone
Burden to patient, caregiver, and healthcare system reduced
IRd KRd ERd DaraRd Route of administration PO IV IV IV
Minimum clinic visits based on 18 cycles
18 96 44 28
Dosing schedule Days 1, 8, and 15 of 28-day cycle
Days 1, 2, 8, 9, 15, and 16 of 28-day cycle.
Additional IV hydration needed especially before each dose in Cycle 1, but
may be in other cycles also
Days 1, 8, 15, 22 of 28-day cycles 1 & 2 then
Days 1 and 15 cycle 3+. Premedication required 45-90 minutes prior to
Elo
Days 1,8,15, 22 of 28-day cycles 1&2 then Days 1 and 15 cycles 3-6 then
Day 1 of each cycle. Premedication rquired
Hospital/clinic visit Every 4 weeks Twice a week Weekly x 8 then twice weekly
Weejly x 8 then twice weekly cycles 3-6 then
monthly
Premedication N N Y Y
Prehydration N Y N N
Minimum administration time in clinic/ hospital per visit
0 hours Over 2 hours (130 minutes)
About 5 hours (290 minutes)
About 8 hours 1st infusion (3-4 hours the
subsequent-ones)
• IV treatments require regular clinic visits and involve infusion times which place a substantial burden on patients. • IV regimens are associated with substantially higher administration costs than oral regimens
DaraRd: Daratumumab, lenalidomide and dexamethasone; KRd: Carfilzomib, lenalidomide and dexamethasone; IRd: Ixazomib, lenalidomide and dexamethasone; ERd: Elotuzumab, lenalidomide and dexamethasone; iv: Intravenous administration ; PO: Oral administration
1- RCM Ixazomib, 2- RCM carfilzomib; 3 – RCM elotuzumab; 4- RCM Daratumumab
Personal experience
There are significant resource implications of combination treatments
Median time from check-in to
administration
120 minutes
Median travel time
120 minutes
Median travel distance
100 Kms
Patients requiring hospital transport
40%
University Hospital of Salamanca
PFS/TTNT of PI-based regimens in RRMM: Results of phase 2/3 studies vs RWE
1. Moreau P, et al. N Engl J Med 2016;374:1621–34. 2. Richardson PG, et al. Blood Cancer J. 2018; 8(11):109 3. Richardson PG, et al Blood. 2014 123(10):1461-9 4. Stewart AK, et al. N Engl J Med 2015;372:142–52. 5. Dimopoulos MA, et al. Lancet Oncol. 2016; 17(1):27-38
PFS*/TTNT** (patients with 1-3 previous treatment lines)
*Real world data presented as PFS/TTNT intervals. PFS, progression free survival; PI, proteassome inhibitor; RRMM, relapsed/refractory multiple myeloma; RWE, real world evidence; TTNT, time to next treatment; VRd, bortezomib, lenalidomide and dexamethasone; Rd, Lenalidomide and dexamethasone
DOT and TTNT of VRd, KRd, or IRd in patients with RRMM: Clinical practice in the US vs clinical trial experience Retrospective cohort study design: Patients who initiated KRd, VRd, or IRd (index regimen) as treatment line 2, 3, or 4 between January 2008 and December 2016 in Humedica, a large US-based EMR database Endpoints: DOT, TTNT, discontinuation rates
• This study suggests that patients were able to stay on the PI component of an oral PI-Rd triplet for longer than patients receiving IV PI-Rd triplets; this may translate into improved TTNT
Higher DOT and TTNT values in IRd vs KRd and VRd patients
VRd KRd IRd
n 343 139 49
Median age (years) 69 65 73
Median follow-up (months) 17.3 8.3 5.2
Median DOT (months)
PI component alone 5.4 6.1 NR
Entire regimen 8.7 6.3 NR
Median TTNT (months) 12.9 8.7 NR
Discontinuation rates for PI component (%)
9 months 63 71 40
12 months 72 76 NR
18 months 83 89 NR
DOT (PI component)
Month from start of regimen
100
80
60
40
20
0 0 6 12 21 24
Trea
tmen
t con
tinua
tion
prob
abilit
y (%
)
3 9 15 18
IRd KRd VRd
TTNT
Month from start of regimen
100
80
60
40
20
0 0 6 12 21 24
Eve
nt-fr
ee p
roba
bilit
y (%
)
3 9 15 18
IRd KRd VRd
VRd – Bortezomib, lenalidomide dexamethasone; KRd – Carfilzomib, lenalidomide, dexamethasone; IRd – Ixazomib, lenalidomide, dexamethasone; DOT – Duration of treatment; TTNT – Time to next treatment; PI – Proteassome Inhibitor; Rd- Lenalidomide and dexamethasone
1. Chari P, et al. Blood 2017;132(suppl):18
Comparative Effectiveness of Triplets Containing Bortezomib (B), Carfilzomib (C), Daratumumab (D), or Ixazomib (I) in Relapsed/Refractory Multiple Myeloma (RRMM) in Routine Care in the US
Retrospective cohort study design: 1432 adults with RRMM with at least 1 prior line of therapy (LOT) and initiating a triplet regimen containing B, C, D, or I. Endpoints: DOT, TTNT
TTNT was longer for Ixazomib based regimens vs bortezomib, carfilzomib, and daratumumab-based
≥2 Lines of therapy 2 or 3 Lines of therapy
• In RRMM patients, median TTNT was longer for Ixazomib based regimens vs B-, C-, and D-based triplets.
• The median TTNT (months) results were 11.1 for I-, and 9.8 for B-, 6.7 for C-, and 7.2 for D-based triplets.
DOT – Duration of treatment; TTNT – Time to next treatment Adapted from Davies F et al. EHA Poster #PS1419
Ixazomib-based Bortezomib-based Daratumumab-based Carfilzomib-based
Ixazomib-based Bortezomib-based Daratumumab-based Carfilzomib-based
Real-world data on the efficacy and safety of IRd in RRMM: Data from the Czech RMG1
Characteristic All patients (N=127)
Median age (range), years 66 (41–84)
Bortezomib-refractory, % 18.9
Lenalidomide-refractory, % 7.9
1st line treatment† Patients, %
Bortezomib 94.5
Thalidomide 40.9
Lenalidomide 18.9
Carfilzomib 5.5
IRd use per line of treatment Patients, %
Second 58.5
Third 23.7
Fourth 7.6
Fifth and beyond 10.1
Efficacy outcomes
ORR (≥PR), % 67.1
CR 11.4
VGPR 16.5
PR 39.2
MR 10.1
≤SD 22.8
PFS after 1 line, months Not reached
After 2 lines 23.1
After 3 lines 8.7
After ≥4 lines 4.6
Grade ≥3 toxicities Patients, %
Neutropenia 35.1
Thrombocytopenia 22.8
Anaemia 12.3
Infection 19.3
*Risk status undeterminable in 34 patients. †By individual drugs. CR, complete response; IRd, ixazomib, lenalidomide, dexamethasone; MR, minimal response; ORR, overall response rate; PFS, progression-free survival; PR, partial response; RMG, registry of monoclonal gammopathies; RRMM, relapsed/refractory multiple myeloma; SD, stable disease; VGPR, very good PR 1. Minarik et al, Blood 2018;132(suppl):1959.
Este caso clínico foi desenvolvido por um perito em Hematologia para fins formação médica contínua refletindo a sua experiencia clinica e pessoal.
Initial diagnosis • Diagnosed with MM IgG-kappa (ISS-2; R-ISS-2) in April 2012 • Myeloma-defining event: anaemia (Hb: 10.9 g/dL) • No high-risk cytogenetic abnormalities • No extramedullary disease
Patient name:
Sex:
Age:
Alexander
Male
69 years old
Prior medical history • Medication for hypertension and hypercholesterolaemia
Lifestyle • Generally active; plays tennis and golf • Regularly looked after two grandsons
* This patient case represents an individual patient experience only and does not represent all patients. Hb, haemoglobin; IgG, immunoglobulin G; ISS, International Staging System; MM, multiple myeloma; R-ISS, Revised International Staging System.
• Patient received VMP x 9 cycles, followed by Rd x 9 cycles (Spanish trial GEM-2010): • He was able to continue playing tennis and golf • He achieved sCR after 18 cycles, but MRD remained positive • Good tolerability without significant AE/SAEs
May 2012
AE, adverse event; MRD, minimal residual disease; Rd, lenalidomide-dexamethasone; SAE, serious adverse event; sCR, stringent complete response; VMP, bortezomib-melphalan-prednisone.
• In a follow-up visit (1 year and 2 months after treatment end), while the patient was asymptomatic, IF results tested positive (confirmed twice)
January 2015
• Serum protein electrophoresis showed an M-spike of 0.6 g/dL • 2 months later, M-spike was still 0.5 g/dL
May 2015
IF, immunofixation.
• In a follow-up visit (1 year and 2 months after treatment end), while the patient was asymptomatic, IF results tested positive (confirmed twice)
January 2015
• Serum protein electrophoresis showed an M-spike of 0.6 g/dL • 2 months later, M-spike was still 0.5 g/dL
May 2015
December 2015
• Mild fatigue: • Hb level decreased to 11 g/dL • PET-CT positive uptake observed in right hip with no lytic lesions • No high-risk features
PET-CT, Positron emission tomography–computed tomography. Hb: Hemoglobin
The first question Alexander asked us was about the duration of the treatment
1. Continuous therapy 2. Fixed-duration therapy (as per first-line therapy)
OS: Overall survival ;RRMM, relapsed/refractory multiple myeloma; m, months; 2L, second line.
Real-world US data in RRMM1,2
Hari P, et al. Clin Lymphoma Myeloma Leuk 2018;18:152–160.
0,0% 2,0% 4,0% 6,0% 8,0% 10,0% 12,0% 14,0% 16,0%% Increase in 1-year OS
relative to median duration of therapy in 2L
Dur
atio
n of
ther
apy
in 2
L (m
onth
s)
6.9 months
7m to <8m 8m to <9m 9m to <10m 10m to <11m 11m to <12m ≥12m
3.7%
6.7%
9.2%
11.1%
12.7%
14.0%
• The patient agreed with the recommendation to receive continuous therapy:
• As he previously received VMP and Rd for 18 months with subsequent treatment-free interval, he could be a candidate for either PI- or IMiD-based combinations
• Alexander stated a preference for an IMiD-based regimen for convenience, and because he had a more positive experience with the last 9 cycles than with the first 9 cycles of his first-line therapy
• He also wanted to maintain an active lifestyle
IMiD, immunomodulatory imide drugs; PI, proteosome inhibitor. VMP: Bortezomib, Melfalan, Prednisolone; Rd: Lenalidomide and dexamethasone
Efficacy POLLUX
DaraRd vs Rd2-4 ASPIRE
KRd vs Rd5-7 ELOQUENT-2 ERd vs Rd8
TOURMALINE-MM1 IRd vs Rd9,10
PFS HR (95% CI) 0.44 (0.35–0.55) 44.5 m vs 17.5 m
0.670 (0.558–0.803) 26.3 m vs 17.6 m
0.71 (0.59–0.86) 19.4 m vs 14.9 m
0.74 (0.59–0.94) 20.6 m vs. 14.7 m
ORR, % 93 87 79 78 ≥ CR, % 57 (MRDneg 30%) 32 5 14 DOR, months NE 28.6 21.2 20.5
OS HR (95% CI) 0.63 (0.42–0.95) 0.79 (0.63–0.99) 48 m vs. 40 m
0.78 (0.63–0.96) 48.3 m vs 39.6 m NE
PFS HR (95% CI), median In len-exposed
0.38 (0.21–0.66) 38.8 m vs 18.6 m
0.796 (0.522–1.215) 19.4 m vs 13.9 m Only 5 pts 0.58
NR vs 17.5 m
1st line • Bortezomib-based combinations • Exposed to lenalidomide but no progressing under lenalidomide therapy
How to make the right choice?
First relapse after Bortezomib-based induction1
Triplets based on Rd DaraRd or KRd or IxaRd or
EloRd
Doublets Rd X
1. Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61; 2. Bahlis NJ, et al. ASH 2018, abstract 1996, poster presentation. 3. Usmani SZ, et al. ASH 2016, abstract 1151, oral presentation; 4. Usmani SZ, et al. ASH 2018, abstract 3288; 5. Stewart AK, et al. N Engl J Med. 2015;372:142-52; 6. Siegel DS, et al. J Clin Oncol 2018;36(8):728-734; Dimopoulos MA, et al. Blood Cancer Journal 2017;7:e554; 8. Dimopoulos MA, et al., Cancer 2018;124(20):4032-4043; 9. Moreau P, et al. N Engl J Med. 2016;374:1621-34; 10. Mateos MV, et al. Haematalogica 2017;102(10):1767-1775.
Rd: Lenalidomide and dexamethasone; DaraRd: Daratumumab, lenalidomide and dexamethasone; KRd: Carfilzomib, lenalidomide and dexamethasone; IxaRd: Ixazomib, lenalidomide and dexamethasone; EloRd: Elotuzumab, lenalidomide and dexamethasone PFS: Progression free survival; HR: Hazard ratio; ORR: Overall response rate; CR: Complete response; DOR: Duration of treatment; OS: Overall Survival ; CI: Confidence interval ; MRDneg: Minimal residual disease; NE: Non-estimated;
1. Clegg A, et al. Lancet 2013;381:752–762; 2. Handforth C, et al. Ann Oncol 2015;26:1091–1101; 3. Dimopoulos MA, et al. Cancer Treat Rev 2015;41:827–835; 4. Faiman BM, et al. Clin J Oncol Nurs 2011;15 suppl:66–76; 5. Miceli TS, et al. Clin J Oncol Nurs 2011;15:9–23; 6. Greipp PR, et al. J Clin Oncol 2005;23:3412–3420; 7. Chng WJ, et al. Leukemia 2016;30:1071–1078; 8. Tariman JD, et al. Cancer Treat Commun 2014;2:34–47; 9. Barbee MS, et al. Ann Pharmacother 2013;47:1136–1142; 10. Sonneveld P, et al. Leukemia 2013;27:1959–69; 11. Ramsenthaler C, et al. BMC Cancer 2016;16:427.
Treatment history
Previous therapies3
Frailty
Age1,2
Performance status3
Disability1
Comorbidities1,2
Disease morbidity
Refractory disease3
Renal impairment4
Bone disease5
Risk assessment
ISS6
Cytogenetics6,7
Lifestyle
Quality of life10,11
Patient preference8
Travel/ infusion time9
1. Clegg A, et al. Lancet 2013;381:752–762; 2. Handforth C, et al. Ann Oncol 2015;26:1091–1101; 3. Dimopoulos MA, et al. Cancer Treat Rev 2015;41:827–835; 4. Faiman BM, et al. Clin J Oncol Nurs 2011;15 suppl:66–76; 5. Miceli TS, et al. Clin J Oncol Nurs 2011;15:9–23; 6. Greipp PR, et al. J Clin Oncol 2005;23:3412–3420; 7. Chng WJ, et al. Leukemia 2016;30:1071–1078; 8. Tariman JD, et al. Cancer Treat Commun 2014;2:34–47; 9. Barbee MS, et al. Ann Pharmacother 2013;47:1136–1142; 10. Sonneveld P, et al. Leukemia 2013;27:1959–69; 11. Ramsenthaler C, et al. BMC Cancer 2016;16:427. ISS: International staging system
Treatment history
Previous therapies3
Frailty
Age1,2
Performance status3
Disability1
Comorbidities1,2
Disease morbidity
Refractory disease3
Renal impairment4
Bone disease5
Risk assessment
ISS6
Cytogenetics6,7
Lifestyle
Quality of life10,11
Patient preference8
Travel/ infusion time9 PS-0
No disabilities
Controlled co-morbidities
72 years old VMP, Rd
Sports, Family
• Patient received IRd: • VGPR achieved for over 2 years • ECOG PS 0 • Patient visits clinic on monthly basis • Active lifestyle maintained on treatment
January2016
ECOG PS, Eastern Cooperative Oncology Group Performance Status; VGPR, very good partial response.
• Experience in routine clinical practice can identify practical challenges that are not present in the trial setting, thereby helping to optimise treatment in real-world practice
• Practical learnings from experience with IRd include:
Information is based on the personal experience of Dr Mateos.
Use following indolent or biochemical relapses
Use at first relapse in elderly after bortezomib-based combinations
Use at second and third relapses in patients who received ASCT in the first line
The extension of PFS irrespective of cytogenetic profile
Opportunities for patients who want to maintain their regular activity
Options for patients who do not want to or cannot come to the hospital every week
When patients are asked for their preference they
usually prefer the oral administration
Initial diagnosis • Diagnosed with MM IgG-kappa (ISS-2; R-ISS-2) in April 2012 • Myeloma-defining event: anaemia (Hb: 10.9 g/dL) • No high-risk cytogenetic abnormalities • No extramedullary disease
Patient name:
Sex:
Age:
Alexander
Male
69 years old
Prior medical history • Medication for hypertension and hypercholesterolaemia
Lifestyle • Generally active; plays tennis and golf • Regularly looked after two grandsons
* This patient case represents an individual patient experience only and does not represent all patients. Hb, haemoglobin; IgG, immunoglobulin G; ISS, International Staging System; MM, multiple myeloma; R-ISS, Revised International Staging System.
IECRCM de NINLARO® Este medicamento está sujeito a monitorização adicional. NOME DO MEDICAMENTO: NINLARO 2,3 mg, 3 mg e 4 mg, cápsulas COMPOSIÇÃO QUALITATIVA E QUANTITATIVA: NINLARO 2,3 mg cápsulas: Cada cápsula contém 2,3 mg de ixazomib (3,3 mg como citrato de ixazomib). NINLARO 3 mg cápsulas: Cada cápsula contém 3 mg de ixazomib (4,3 mg como citrato de ixazomib). NINLARO 4 mg cápsulas: Cada cápsula contém 4 mg de ixazomib (5,7 mg como citrato de ixazomib). FORMA FARMACÊUTICA: Cápsulas. NINLARO 2,3 mg cápsulas: Cápsulas de gelatina dura cor-de-rosa claras, tamanho 4, gravadas com “Takeda” na cabeça e “2,3 mg” no corpo com tinta preta. NINLARO 3 mg cápsulas: Cápsulas de gelatina dura cinzentas claras, tamanho 4, gravadas com “Takeda” na cabeça e “3,0 mg” no corpo com tinta preta. NINLARO 4 mg cápsulas: Cápsulas de gelatina dura cor-de-laranja claras, tamanho 3, gravadas com “Takeda” na cabeça e “4,0 mg” no corpo com tinta preta. INDICAÇÕES TERAPÊUTICAS: NINLARO, em combinação com lenalidomida e dexametasona, é indicado para o tratamento de doentes adultos com mieloma múltiplo, que tenham recebido pelo menos uma terapêutica anterior. POSOLOGIA E MODO DE ADMINISTRAÇÃO: O tratamento deve ser iniciado e monitorizado sob supervisão de um médico experiente no tratamento de mieloma múltiplo. Posologia: A dose inicial recomendada de ixazomib é de 4 mg administrada por via oral uma vez por semana, nos Dias 1, 8 e 15 de um ciclo de tratamento de 28 dias. A dose inicial recomendada de lenalidomida é de 25 mg administrada diariamente nos Dias 1 a 21 de um ciclo de tratamento de 28 dias. A dose inicial recomendada de dexametasona é de 40 mg administrada nos Dias 1, 8, 15 e 22 de um ciclo de tratamento de 28 dias. Para informação adicional relacionada com lenalidomida e dexametasona, consultar o RCM para estes medicamentos. Antes de iniciar um novo ciclo de terapêutica: • A contagem absoluta de neutrófilos deve ser ≥ 1000/mm3; • A contagem de plaquetas deve ser ≥ 75000/mm3; • As toxicidades não-hematológicas devem, no parecer do médico, ser geralmente recuperadas para a condição inicial do doente ou ≤ Grau 1. O tratamento deve ser continuado até progressão da doença ou toxicidade inaceitável. O tratamento com ixazomib em combinação com lenalidomida e dexametasona por mais de 24 ciclos deverá basear-se numa avaliação de benefício-risco individual, pois os dados sobre a tolerabilidade e toxicidade além dos 24 ciclos são limitados. Doses atrasadas ou falhadas: Em caso de atraso ou falha de uma dose de ixazomib, a dose apenas deverá ser tomada se a próxima dose prevista for a ≥ 72 horas. Uma dose falhada não deve ser tomada durante as 72 horas que antecedem a próxima dose prevista. Não deverá ser tomada uma dose a dobrar para compensar uma dose falhada. Se um doente vomitar após a toma de uma dose, o doente não deverá repetir essa toma, mas sim retomar a toma da próxima dose na altura prevista. Alterações à dose: Passos de redução de dose ixazomib: Dose inicial recomendada: 4 mg (É recomendada uma dose reduzida de 3 mg na presença de compromisso hepático moderado ou grave, compromisso renal grave ou doença renal em fase terminal (DRT) que exija diálise). Primeira redução para: 3 mg. Segunda redução para: 2,3 mg. Depois descontinuar. É recomendada uma abordagem alternativa de alteração à dose para ixazomib e lenalidomida para toxicidades sobrepostas de trombocitopenia, neutropenia e erupção cutânea. Para estas toxicidades, o primeiro passo de alteração à dose é de suspensão/redução de lenalidomida. Consultar o RCM da lenalidomida para informação sobre os passos de redução de dose para estas toxicidades. Medicamentos concomitantes: A profilaxia antiviral deverá ser considerada em doentes em tratamento com ixazomib para diminuir o risco de reativação do herpes-zóster. Os doentes incluídos em estudos com ixazomib, que receberam profilaxia antiviral, tiveram uma incidência menor de infeção por herpes-zóster, em comparação com doentes que não receberam profilaxia. A tromboprofilaxia é recomendada em doentes em tratamento com ixazomib, em combinação com lenalidomida e dexametasona, e deve basear-se numa avaliação dos riscos subjacentes e estado clínico do doente. Para outros medicamentos concomitantes que possam ser necessários, consultar RCM da lenalidomida e dexamethasone. Populações de doentes especiais: Idosos: Não é necessário ajuste de dose de ixazomib para doentes com mais de 65 anos de idade. Foram notificadas descontinuações em doentes com > 75 anos em 13 doentes (28%) no regime de ixazomib e em 10 doentes (16%) no regime de placebo. Foram observadas arritmias, em doentes com > 75 anos, em 10 doentes (21%) no regime de ixazomib e em 9 doentes (15%) no regime de placebo. Compromisso hepático: Não é necessário ajuste de dose de ixazomib para doentes com compromisso hepático ligeiro [bilirrubina total ≤ limite superior normal (LSN) e aspartato aminotransferase (AST) > LNS ou bilirrubina total > 1-1,5 x LNS e qualquer AST]. É recomendada a dose reduzida de 3 mg em doentes com compromisso hepático moderado (bilirrubina total > 1,5-3 x LNS) ou grave (bilirrubina total > 3 x LNS). Compromisso renal: Não é necessário ajuste de dose de ixazomib para doentes com compromisso renal ligeiro ou moderado (depuração de creatinina ≥ 30 ml/min). É recomendada a dose reduzida de 3 mg em doentes com compromisso renal grave (depuração de creatinina < 30 ml/min) ou doença renal em fase terminal (DRT) que exija diálise. Ixazomib não é dialisável e, por conseguinte, pode ser administrado sem consideração à hora de diálise. Consultar o RCM da lenalidomida para recomendações de posologia em doentes com compromisso renal. População pediátrica: A segurança e eficácia de ixazomib em crianças com idade inferior a 18 anos de idade não foram estabelecidas. Não existem dados disponíveis. Modo de administração: ixazomib é administrado por via oral. Ixazomib deve ser tomado aproximadamente à mesma hora nos dias 1, 8 e 15 de cada ciclo de tratamento, pelo menos 1 hora antes ou pelo menos 2 horas após a ingestão de alimentos. A cápsula deve ser engolida inteira com água. Não deve ser esmagada, mastigada ou aberta. Contraindicações: Hipersensibilidade à substância ativa ou a qualquer um dos excipientes. Consultar RCMs da lenalidomida e dexametasona para contraindicações adicionais. EFEITOS INDESEJÁVEIS: Consultar RCMs da lenalidomida e dexametasona para efeitos indesejáveis adicionais. Resumo do perfil de segurança: Os dados apresentados abaixo são dados de segurança agrupados do ensaio clínico piloto de Fase 3 global C16010 (n=720) e do C16010 - estudo de continuação na China (n=115), em dupla ocultação, controlado por placebo (n=115). As reações adversas mais frequentemente comunicadas (≥ 20%) em 417 doentes tratados no regime de ixazomib e 418 doentes no regime de placebo foram diarreia (39% vs. 32%), trombocitopenia (33% vs. 21%), neutropenia (33% vs. 30%), obstipação (30% vs. 22%), neuropatia periférica (25% vs. 20%), náuseas (23% vs. 18%), edema periférico (23% vs. 17%), vómitos (20% vs. 10%), e infeção do trato respiratório superior (21% vs. 16%). As reações adversas graves comunicadas em ≥ 2% dos doentes incluíram trombocitopenia (2%) e diarreia (2%). Reações adversas em doentes tratados com ixazomib em combinação com lenalidomida e dexametasona (todos os graus, Grau 3 e Grau 4): Reações adversas (todos os graus): Infeções e infestações: Muito frequentes: Infeções do trato respiratório superior; Frequentes: Herpes-zóster. Doenças do sangue e sistema linfático: Muito frequentes: Trombocitopenia (representa um conjunto de termos preferenciais), neutropenia. Doenças do sistema nervoso: Muito frequentes: Neuropatias periféricas (representa um conjunto de termos preferenciais). Doenças gastrointestinais: Muito frequentes: Diarreia, náuseas, vómitos, obstipação. Afeções dos tecidos cutâneos e subcutâneos: Muito frequentes: Erupção cutânea (representa um conjunto de termos preferenciais). Afeções músculo-esqueléticas e dos tecidos conjuntivos: Muito frequentes: Dorsalgia. Perturbações gerais e alterações no local de administração: Muito frequentes: Edema periférico. Reações adversas de Grau 3: Pouco frequentes: Infeções do trato respiratório superior; Frequentes: herpes-zóster. Doenças do sangue e sistema linfático: Muito frequentes: Trombocitopenia (representa um conjunto de termos preferenciais), neutropenia. Doenças do sistema nervoso: Frequentes: Neuropatias periféricas (representa um conjunto de termos preferenciais). Doenças gastrointestinais: Frequentes: Diarreia, náuseas; Pouco frequentes: Vómitos, obstipação. Afeções dos tecidos cutâneos e subcutâneos: Frequentes: Erupção cutânea (representa um conjunto de termos preferenciais). Afeções músculo-esqueléticas e dos tecidos conjuntivos: Pouco frequentes: Dorsalgia. Perturbações gerais e alterações no local de administração: Frequentes: Edema periférico. Reações adversas de Grau 4: Doenças do sangue e sistema linfático: Frequentes: Trombocitopenia (representa um conjunto de termos preferenciais), neutropenia. Data de revisão: setembro de 2018. Está disponível informação pormenorizada sobre este medicamento no sítio da internet da Agência Europeia de Medicamentos: http://www.ema.europa.eu. Medicamento sujeito a receita médica restrita - Alínea a) do Artigo 118º do D.L. 176/2006. Medicamento não comparticipado. Para mais informações deverá contactar o representante local do titular da Autorização de Introdução no Mercado: Takeda - Farmacêuticos Portugal, Lda., Av. da Torre de Belém, nº19 – R/C Esq. – 1400-342 Lisboa NIPC: 502 801 204 Registada na CRC de Cascais sob mesmo número; T +351 21 120 14 57; F +351 21 120 14 56. Para notificação de reacções adversas contactar: +351 21 120 14 57 ou [email protected]