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seus não publicados The content of this presentation is author`s own, reflecting his clinical perspective and or his unpublished works.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 DSO-PT@takeda.com