Como escolher o tratamento certo para o doente certo no …

Como escolher o tratamento certo para o doente certo no MM R/R?

How to choose the right treatment for the right patient in R/R MM?

EstaapresentaçãoconstituiumserviçoprestadoàTakeda,tendosidosujeitaahonoráriosPT/IXZ/1019/0052

Oconteúdodestaapresentaçãoédaautoriadopalestrante,refletindoasuaperspetivaclínicae/outrabalhosseusnãopublicados

Mª Victoria Mateos, MD, PhD

Conflict of Interest

• Honoraria from lectures and participation in advisory boards: Janssen, Celgene, Amgen, Takeda, GSK, EDO, Pharmamar, Adaptive

Oconteúdodestaapresentaçãoédaautoriadopalestrante,refletindoasuaperspetivaclínicae/outrabalhosseusnãopublicadosThecontentofthispresentationisauthor`sown,reflectinghisclinicalperspectiveandorhisunpublishedworks.

EstaapresentaçãoconstituiumserviçoprestadoàTakeda,tendosidosujeitaahonorários.ThispresentationconstitutesaserviceprovidedtoTakedaandhasbeensubjecttohonoraria.

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

RemissionMGUS or smouldering

myeloma

Active myeloma

Relapse

Time

M p

rote

in

SYMPTOMATICASYMPTOMATIC 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

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

RRMM: relapsed/refractory multiple myeloma.

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

Relapse/Refractory MM patients ESMO guidelines 2017

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 RdX

EfficacyPOLLUX

DaraRd vs Rd1-3ASPIRE

KRd vs Rd4,5ELOQUENT-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 14DOR, 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

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; Cross-trial comparisons are potentially confounded by differences in trial design and study population

Which patients do they fit today in the ESMO guidelines 2017

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 7812 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

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 monthsRd:Lenalidomideanddexamethasone;KRd:Carfilzomib,lenalidomideanddexamethasone;CR:Completeresponse;OS:OverallSurvival;HR:HazarRatio;CI:ConfidenceintervalPFS:Progressionfreesurvival

Carfilzomib + lenalidomide and dexamethasone vs lenalidomide and dexamethasone in RRMM: ASPIRE

Daratumumab + lenalidomide and dexamethasone vs lenalidomide and dexamethasone in RRMM: POLLUX 3-year follow-up

Bahlisetal.,ASH2018;abstract1996

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,lenalidomideanddexamethasone;Rd:Lenalidomideanddexamethasone;HR:HazardratioORR:Overallresponserate;CR:Completeresponse;MRD;Minimalresidualdisease;NE:Not-estimeated;CI:ConfidenceInterval;PFS:Progressionfreesurvival;ITT:Intentiontotreat

A29%reductionintheriskofprogressionordeath(sustainedovertime)50%inthePFSrateat4years(21%vs14%)infavorofELoRd

ELOQUENT-2: EloRd vs Rd 4-year follow-up: Progression-free survivala

DimopoulosMA,etal.PresentedatEHA2017(AbstractS456),oralpresentation.

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-yearPFS 2-yearPFS 3-yearPFS 4-yearPFS

Prob

abilityofP

FS

Time(months)

Patientsatrisk

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

aAllrandomizedpatientsDatacut-offOct18,2016

● Minimumfollow-up:48months

EloRd/Eld:Elotuzumab,lenalidomideanddexamethasone;Rd/Ld:Lenalidomideanddexamethasone;HR:Hazardratio;CI:ConfidenceInterval;PFS:Progressionfreesurvival;

Ixazomib-Rd vs Rd in RRMM patients: Tourmaline-MM1: PFS with IRd vs placebo-Rd

Number of pts at risk:IRdPlacebo-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 10 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

MoreauPetal.NEJM2016;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

DimopoulosMA,etal.PresentedatEHA2017(AbstractS456),oralpresentation.

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 trxMateos MV et al. Haematologica. 2017 Oct;102(10):1767-1775.

Pl:Previousline;Trx:transplant;Pts:patients;HR:Hazardratio;CI:ConfidenceInterval

• 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

EfficacyPOLLUX

DaraRd vs Rd2-4ASPIRE

KRd vs Rd5-7ELOQUENT-2

ERd vs Rd8TOURMALINE-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 14DOR, 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

WhichpatientsfittheESMOguidelines2017?

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 RdX

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; Cross-trial comparisons are potentially confounded by differences in trial design and study population

• 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 RiskHigh 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 (17p) and t(4;14)

Avet Loiseau Blood 2017

DK/IXA/1606/00033

IRd: Ixazomib, lenalidomide and dexamethasone; Rd: Lenalidomide and dexamethasone PFS: Progression free survival; HR: Hazard ratio

• 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 DaraRdRoute 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 required

Hospital/clinic visit Every 4 weeks Twice a week Weekly x 8 then twice weekly

Weekly 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.MoreauP,etal.NEnglJMed2016;374:1621–34.2.RichardsonPG,etal.BloodCancerJ.2018;8(11):1093.RichardsonPG,etalBlood.2014123(10):1461-94.StewartAK,etal.NEnglJMed2015;372:142–52.5.DimopoulosMA,etal.LancetOncol.2016;17(1):27-38

PFS*/TTNT**(patientswith1-3previoustreatmentlines)

*RealworlddatapresentedasPFS/TTNTintervals.PFS,progressionfreesurvival;PI,proteassomeinhibitor;RRMM,relapsed/refractorymultiplemyeloma;RWE,realworldevidence;TTNT,timetonexttreatment;VRd,bortezomib,lenalidomideanddexamethasone;Rd,Lenalidomideanddexamethasone

DOTandTTNTofVRd,KRd,orIRdinpatientswithRRMM:ClinicalpracticeintheUSvsclinicaltrialexperience

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

HigherDOTandTTNTvaluesinIRdvsKRdandVRdpatients

VRd KRd IRd

n 343 139 49

Medianage(years) 69 65 73

Medianfollow-up(months) 17.3 8.3 5.2

MedianDOT(months)

PIcomponentalone 5.4 6.1 NR

Entireregimen 8.7 6.3 NR

MedianTTNT(months) 12.9 8.7 NR

DiscontinuationratesforPIcomponent(%)

9months 63 71 40

12months 72 76 NR

18months 83 89 NR

DOT (PI component)

Month from start of regimen

100

80

60

40

20

00 6 12 21 24

Trea

tmen

t con

tinua

tion

prob

abili

ty (%

)

3 9 15 18

IRdKRdVRd

TTNT

Month from start of regimen

100

80

60

40

20

00 6 12 21 24

Eve

nt-fr

ee p

roba

bilit

y (%

)

3 9 15 18

IRdKRdVRd

VRd–Bortezomib,lenalidomidedexamethasone;KRd–Carfilzomib,lenalidomide,dexamethasone;IRd–Ixazomib,lenalidomide,dexamethasone;DOT–Durationoftreatment;TTNT–Timetonexttreatment;PI–ProteassomeInhibitor;Rd-Lenalidomideanddexamethasone 1.ChariP,etal.Blood2017;132(suppl):1818

ComparativeEffectivenessofTripletsContainingBortezomib(B),Carfilzomib(C),Daratumumab(D),orIxazomib(I)inRelapsed/RefractoryMultipleMyeloma(RRMM)inRoutineCareintheUS

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

TTNTwaslongerforIxazomibbasedregimensvsbortezomib,carfilzomib,anddaratumumab-based

≥2Linesoftherapy 2or3Linesoftherapy

• InRRMMpatients,medianTTNTwaslongerforIxazomibbasedregimensvsB-,C-,andD-basedtriplets.• ThemedianTTNT(months)resultswere11.1forI-,and9.8forB-,6.7forC-,and7.2forD-basedtriplets.DOT–Durationoftreatment;TTNT–Timetonexttreatment

AdaptedfromDaviesFetal.EHAPoster#PS1419

Ixazomib-basedBortezomib-basedDaratumumab-basedCarfilzomib-based

Ixazomib-basedBortezomib-basedDaratumumab-basedCarfilzomib-based

Real-worlddataontheefficacyandsafetyofIRdinRRMM:DatafromtheCzechRMG1

Characteristic Allpatients(N=127)

Medianage(range),years 66(41–84)

Bortezomib-refractory,% 18.9

Lenalidomide-refractory,% 7.9

1stlinetreatment† Patients,%

Bortezomib 94.5

Thalidomide 40.9

Lenalidomide 18.9

Carfilzomib 5.5

IRduseperlineoftreatment Patients,%

Second 58.5

Third 23.7

Fourth 7.6

Fifthandbeyond 10.1

Efficacyoutcomes

ORR(≥PR),% 67.1

CR 11.4

VGPR 16.5

PR 39.2

MR 10.1

≤SD 22.8

PFSafter1line,months Notreached

After2lines 23.1

After3lines 8.7

After≥4lines 4.6Grade≥3toxicities Patients,%

Neutropenia 35.1

Thrombocytopenia 22.8

Anaemia 12.3

Infection 19.3

*Riskstatusundeterminablein34patients.†Byindividualdrugs.CR,completeresponse;IRd,ixazomib,lenalidomide,dexamethasone;MR,minimalresponse;ORR,overallresponserate;PFS,progression-freesurvival;PR,partialresponse;RMG,registryofmonoclonalgammopathies;RRMM,relapsed/refractorymultiplemyeloma;SD,stabledisease;VGPR,verygoodPR1.Minariketal,Blood2018;132(suppl):1959.

CASE REPORT

EstecasoclínicofoidesenvolvidoporumperitoemHematologiaparafinsformaçãomédicacontínuarefletindoasuaexperienciaclinicaepessoal.

Patient history*

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

*Thispatientcaserepresentsanindividualpatientexperienceonlyanddoesnotrepresentallpatients.Hb,haemoglobin;IgG,immunoglobulinG;ISS,InternationalStagingSystem;MM,multiplemyeloma;R-ISS,RevisedInternationalStagingSystem.

First-line therapy

• 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,adverseevent;MRD,minimalresidualdisease;Rd,lenalidomide-dexamethasone;SAE,seriousadverseevent;sCR,stringentcompleteresponse;VMP,bortezomib-melphalan-prednisone.

Biochemical relapse

• 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.

Clinical relapse

• 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,Positronemissiontomography–computedtomography.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:Overallsurvival;RRMM,relapsed/refractorymultiplemyeloma;m,months;2L,secondline.

Prolonged duration of therapy is associated with improved OS in patients undergoing second-line therapy

Real-world US data in RRMM1,2

HariP,etal.ClinLymphomaMyelomaLeuk2018;18:152–160.

Dur

atio

n of

ther

apy

in 2

L (m

onth

s)

% Increase in 1-year OS relative to median duration of therapy in 2L

0,0% 3,5% 7,0% 10,5% 14,0%

6.9 months

7m to <8m8m to <9m9m to <10m10m to <11m11m to <12m≥12m

3.7%

6.7%

9.2%

11.1%

12.7%

14.0%

Treatment at first relapse: What is the best choice for Alexander?

• 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,immunomodulatoryimidedrugs;PI,proteosomeinhibitor.VMP:Bortezomib,Melfalan,Prednisolone;Rd:Lenalidomideanddexamethasone

EfficacyPOLLUX

DaraRd vs Rd2-4ASPIRE

KRd vs Rd5-7ELOQUENT-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 14DOR, 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 RdX

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.CleggA,etal.Lancet2013;381:752–762;2.HandforthC,etal.AnnOncol2015;26:1091–1101;3.DimopoulosMA,etal.CancerTreatRev2015;41:827–835;4.FaimanBM,etal.ClinJOncolNurs2011;15suppl:66–76;5.MiceliTS,etal.ClinJOncolNurs2011;15:9–23;6.GreippPR,etal.JClinOncol2005;23:3412–3420;7.ChngWJ,etal.Leukemia2016;30:1071–1078;8.TarimanJD,etal.CancerTreatCommun2014;2:34–47;9.BarbeeMS,etal.AnnPharmacother2013;47:1136–1142;10.SonneveldP,etal.Leukemia2013;27:1959–69;11.RamsenthalerC,etal.BMCCancer2016;16:427.ISS:Internationalstagingsystem

Patient-based factors are highly influential in treatment decision making

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.CleggA,etal.Lancet2013;381:752–762;2.HandforthC,etal.AnnOncol2015;26:1091–1101;3.DimopoulosMA,etal.CancerTreatRev2015;41:827–835;4.FaimanBM,etal.ClinJOncolNurs2011;15suppl:66–76;5.MiceliTS,etal.ClinJOncolNurs2011;15:9–23;6.GreippPR,etal.JClinOncol2005;23:3412–3420;7.ChngWJ,etal.Leukemia2016;30:1071–1078;8.TarimanJD,etal.CancerTreatCommun2014;2:34–47;9.BarbeeMS,etal.AnnPharmacother2013;47:1136–1142;10.SonneveldP,etal.Leukemia2013;27:1959–69;11.RamsenthalerC,etal.BMCCancer2016;16:427.ISS:Internationalstagingsystem;VMP:Bortezomib,melphalanprednisolone;Rd:Lenalidomideanddexamethasone

Patient-based factors are highly influential in treatment decision making

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 time9PS-0

No disabilities

Controlled co-morbidities

72 years old VMP, Rd

Sports, Family

Treatment at first relapse

• Patient received IRd: • VGPR achieved for over 2 years • ECOG PS 0 • Patient visits clinic on monthly basis • Active lifestyle maintained on treatment

January2016

ECOGPS,EasternCooperativeOncologyGroupPerformanceStatus;VGPR,verygoodpartialresponse.IRd:Ixazomib,lenalidomideanddexamethasone

Experience with treatment regimens can enhance practical guidance and management recommendations

• 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:

InformationisbasedonthepersonalexperienceofDrMateos.

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

Patient history*

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

*Thispatientcaserepresentsanindividualpatientexperienceonlyanddoesnotrepresentallpatients.Hb,haemoglobin;IgG,immunoglobulinG;ISS,InternationalStagingSystem;MM,multiplemyeloma;R-ISS,RevisedInternationalStagingSystem.

IECRCM de NINLARO®

Estemedicamentoestásujeitoamonitorizaçãoadicional.NOMEDOMEDICAMENTO:NINLARO2,3mg,3mge4mg,cápsulasCOMPOSIÇÃOQUALITATIVAEQUANTITATIVA:NINLARO2,3mgcápsulas:Cadacápsulacontém2,3mgdeixazomib(3,3mgcomocitratodeixazomib).NINLARO3mgcápsulas:Cadacápsulacontém3mgdeixazomib(4,3mgcomocitratodeixazomib).NINLARO4mgcápsulas:Cadacápsulacontém4mgdeixazomib(5,7mgcomocitratodeixazomib).FORMAFARMACÊUTICA:Cápsulas.NINLARO2,3mgcápsulas:Cápsulasdegelatinaduracor-de-rosaclaras,tamanho4,gravadascom“Takeda”nacabeçae“2,3mg”nocorpocomtintapreta.NINLARO3mgcápsulas:Cápsulasdegelatinaduracinzentasclaras,tamanho4,gravadascom“Takeda”nacabeçae“3,0mg”nocorpocomtintapreta.NINLARO4mgcápsulas:Cápsulasdegelatinaduracor-de-laranjaclaras,tamanho3,gravadascom“Takeda”nacabeçae“4,0mg”nocorpocomtintapreta.INDICAÇÕESTERAPÊUTICAS:NINLARO,emcombinaçãocomlenalidomidaedexametasona,éindicadoparaotratamentodedoentesadultoscommielomamúltiplo,quetenhamrecebidopelomenosuma terapêuticaanterior.POSOLOGIAEMODODEADMINISTRAÇÃO:O tratamentodeve ser iniciadoemonitorizadosob supervisãodeummédicoexperienteno tratamentodemielomamúltiplo.Posologia:Adose inicial recomendadade ixazomibéde4mgadministradaporviaoralumavezporsemana,nosDias1,8e15deumciclodetratamentode28dias.Adoseinicialrecomendadadelenalidomidaéde25mgadministradadiariamentenosDias1a21deumciclodetratamentode28dias.Adoseinicialrecomendadadedexametasonaéde40mgadministradanosDias1,8,15e22deumciclodetratamentode28dias.Parainformaçãoadicionalrelacionadacomlenalidomidaedexametasona,consultaroRCMparaestesmedicamentos.Antesdeiniciarumnovociclodeterapêutica:•Acontagemabsolutadeneutrófilosdeveser≥1000/mm3;•Acontagemdeplaquetasdeveser≥75000/mm3;•Astoxicidadesnão-hematológicasdevem,noparecerdomédico,sergeralmenterecuperadasparaacondiçãoinicialdodoenteou≤Grau1.Otratamentodevesercontinuadoatéprogressãodadoençaoutoxicidadeinaceitável.Otratamentocomixazomibemcombinaçãocomlenalidomidaedexametasonapormaisde24ciclosdeverábasear-senumaavaliaçãodebenefício-riscoindividual,poisosdadossobreatolerabilidadeetoxicidadealémdos24ciclossãolimitados.Dosesatrasadasoufalhadas:Emcasodeatrasooufalhadeumadosedeixazomib,adoseapenasdeverásertomadaseapróximadoseprevistafora≥72horas.Umadosefalhadanãodevesertomadaduranteas72horasqueantecedemapróximadoseprevista.Nãodeverásertomadaumadoseadobrarparacompensarumadose falhada.Seumdoentevomitarapósa tomadeumadose,odoentenãodeverá repetiressa toma,massimretomara tomadapróximadosenaalturaprevista.Alteraçõesàdose:Passosde reduçãodedose ixazomib:Dose inicial recomendada:4mg (Érecomendadaumadosereduzidade3mgnapresençadecompromissohepáticomoderadoougrave,compromissorenalgraveoudoençarenalemfaseterminal(DRT)queexijadiálise).Primeirareduçãopara:3mg.Segundareduçãopara:2,3mg.Depoisdescontinuar.Érecomendadaumaabordagemalternativadealteraçãoàdoseparaixazomibelenalidomidaparatoxicidadessobrepostasdetrombocitopenia,neutropeniaeerupçãocutânea.Paraestastoxicidades,oprimeiropassodealteraçãoàdoseédesuspensão/reduçãodelenalidomida.ConsultaroRCMdalenalidomidaparainformaçãosobreospassosdereduçãodedoseparaestastoxicidades.Medicamentosconcomitantes:Aprofilaxiaantiviraldeveráserconsideradaemdoentesemtratamentocomixazomibparadiminuiroriscodereativaçãodoherpes-zóster.Osdoentesincluídosemestudos com ixazomib,que receberamprofilaxia antiviral, tiveramuma incidênciamenorde infeçãoporherpes-zóster, emcomparação comdoentesquenão receberamprofilaxia.A tromboprofilaxiaé recomendadaemdoentesem tratamento com ixazomib, emcombinação comlenalidomidaedexametasona,edevebasear-senumaavaliaçãodosriscossubjacenteseestadoclínicododoente.Paraoutrosmedicamentosconcomitantesquepossamsernecessários,consultarRCMdalenalidomidaedexametasona.Populaçõesdedoentesespeciais:Idosos:Nãoénecessárioajustededosedeixazomibparadoentescommaisde65anosdeidade.Foramnotificadasdescontinuaçõesemdoentescom>75anosem13doentes(28%)noregimedeixazomibeem10doentes(16%)noregimedeplacebo.Foramobservadasarritmias,emdoentescom>75anos, 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 aspartatoaminotransferase(AST)>LNSoubilirrubinatotal>11,5xLNSequalquerAST].Érecomendadaadosereduzidade3mgemdoentescomcompromissohepáticomoderado(bilirrubinatotal>1,53xLNS)ougrave(bilirrubinatotal>3xLNS).Compromissorenal:Nãoénecessárioajustededosedeixazomibparadoentescomcompromissorenalligeirooumoderado(depuraçãodecreatinina≥30ml/min).Érecomendadaadosereduzidade3mgemdoentescomcompromissorenalgrave(depuraçãodecreatinina<30ml/min)oudoençarenalemfaseterminal(DRT)queexijadiálise.Ixazomibnãoédialisávele,porconseguinte,podeseradministradosemconsideraçãoàhoradediálise.ConsultaroRCMdalenalidomidapararecomendaçõesdeposologiaemdoentescomcompromissorenal.Populaçãopediátrica:Asegurançaeeficáciadeixazomibemcriançascomidadeinferiora18anosdeidadenãoforamestabelecidas.Nãoexistemdadosdisponíveis.Mododeadministração:ixazomibéadministradoporviaoral.Ixazomibdevesertomadoaproximadamenteàmesmahoranosdias1,8e15decadaciclodetratamento,pelomenos1horaantesoupelomenos2horasapósa ingestãodealimentos.A cápsuladeve serengolida inteira comágua.Nãodeve seresmagada,mastigadaouaberta.Contraindicações:Hipersensibilidadeà substância ativaouaqualquerumdosexcipientes.ConsultarRCMsda lenalidomidaedexametasonaparacontraindicaçõesadicionais.EFEITOSINDESEJÁVEIS:ConsultarRCMsdalenalidomidaedexametasonaparaefeitosindesejáveisadicionais.Resumodoperfildesegurança:OsdadosapresentadosabaixosãodadosdesegurançaagrupadosdoensaioclínicopilotodeFase3globalC16010(n=720)edoC16010-estudodecontinuaçãonaChina(n=115),emduplaocultação,controladoporplacebo(n=115).Asreaçõesadversasmaisfrequentementecomunicadas(≥20%)em417doentestratadosnoregimedeixazomibe418doentesnoregimedeplaceboforamdiarreia(39%vs.32%),trombocitopenia(33%vs.21%),neutropenia(33%vs.30%),obstipação(30%vs.22%),neuropatiaperiférica(25%vs.20%),náuseas(23%vs.18%),edemaperiférico(23%vs.17%),vómitos(20%vs.10%),einfeçãodotratorespiratóriosuperior(21%vs.16%).Asreaçõesadversasgravescomunicadasem≥2%dosdoentesincluíramtrombocitopenia(2%)ediarreia(2%).Reaçõesadversasemdoentestratadoscomixazomibemcombinaçãocomlenalidomidaedexametasona(todososgraus,Grau3eGrau4):Reaçõesadversas(todososgraus):Infeçõeseinfestações:Muitofrequentes:Infeçõesdotratorespiratóriosuperior;Frequentes:Herpes-zóster.Doençasdosangueesistemalinfático:Muitofrequentes:Trombocitopenia(representaumconjuntodetermospreferenciais),neutropenia.Doençasdosistemanervoso:Muitofrequentes:Neuropatiasperiféricas (representaumconjuntodetermospreferenciais).Doençasgastrointestinais:Muito frequentes:Diarreia,náuseas,vómitos,obstipação.Afeçõesdostecidoscutâneosesubcutâneos:Muito frequentes:Erupçãocutânea(representaumconjuntodetermospreferenciais).Afeçõesmúsculo-esqueléticasedostecidosconjuntivos:Muitofrequentes:Dorsalgia.Perturbaçõesgeraisealteraçõesnolocaldeadministração:Muitofrequentes:Edemaperiférico.ReaçõesadversasdeGrau3:Poucofrequentes:Infeçõesdotratorespiratóriosuperior; 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 termospreferenciais).Doençasgastrointestinais:Frequentes:Diarreia,náuseas;Poucofrequentes:Vómitos,obstipação.Afeçõesdostecidoscutâneosesubcutâneos:Frequentes:Erupçãocutânea(representaumconjuntodetermospreferenciais).Afeçõesmúsculo-esqueléticasedostecidosconjuntivos:Poucofrequentes:Dorsalgia.Perturbaçõesgeraisealteraçõesno localdeadministração:Frequentes:Edemaperiférico.ReaçõesadversasdeGrau4:Doençasdosangueesistema linfático:Frequentes:Trombocitopenia (representaumconjuntodetermospreferenciais),neutropenia.Dataderevisão:setembrode2018.EstádisponívelinformaçãopormenorizadasobreestemedicamentonosítiodainternetdaAgênciaEuropeiadeMedicamentos:http://www.ema.europa.eu.Medicamentosujeitoareceitamédicarestrita-Alíneaa)doArtigo118ºdoD.L.176/2006.MedicamentoaprovadoporavaliaçãopréviaaoabrigodoDL97/2015,de1dejunho.ParamaisinformaçõesdeverácontactarorepresentantelocaldotitulardaAutorizaçãodeIntroduçãonoMercado:Takeda-FarmacêuticosPortugal,Lda.,Av.daTorredeBelém,nº19–R/CEsq.–1400-342LisboaNIPC:502801204RegistadanaCRCdeCascaissobmesmonúmero;T+351211201457;F+351211201456.Paranotificaçãodereacçõesadversascontactar:[email protected]