Tra innovazione e sostenibilità: nuovi algoritmi terapeutici nel mieloma

multiplo

Alessandro CorsoBolzano 26 ottobre 2017

Mieloma Multiplo

Il mieloma multiplo è una neoplasia ematologica incurabilecaratterizzata dalla presenza di cellule tumorali nel midollo osseo edi una componente monoclonale sierica e/o urinaria

Rappresenta l’1.3% di tutti i tumori e il 13% delle neoplasieematologiche con un’incidenza media ogni anno di 9,5 casi ogni100.000 uomini e 8,1 ogni 100.000 donne

L’età mediana alla diagnosi è di 70 anni

L’incidenza negli ultimi anni è stabile mentre la prevalenza è inaumento per l’allungamento della sopravvivenza dei pazienti con inuovi farmaci

Multiple myeloma

Continued improvement in survival in multiple myeloma:

changes in early mortality and outcomes in older patientsKumar et al. Leukemia 2013

PeriodMedian

OS

2001-2005 4,6 yrs

2006-20106,2 yrs

P=0,002

Period Median OS

2001-2005 3,2 yrs

2006-20105 yrs

P=0,01

Talidomide 1999

Velcade 2004Lenalidomide 2008MPT 2008VMP 2009VTD 2011Pomalidomide 2015KRD 2016EloRd 2017Daratumumab 2017

Multiple Myeloma Treatment Transformed: A Population-Based Study of

changes in Initial Management Approaches in the United StatesWarren et al. J Clin Oncol 31:1984-1989; 2013

Patients (n. 1,976) with newly diagnosed myeloma in 1999, 2003, and 2007

were examined.

From 1999 to 2007, use of melphalan alone dropped from 32.0% to 4.1%,

and vincristine and doxorubicin use declined from 18.2% to 0.4%. The

percentage of patients receiving any novel agent rose from 3.9% in 1999 to

75.5% in 2007. HSCT increased from 11.1% in 1999 to 21.7% in 2007.

For white patients, use of novel agents was lower for those with Medicare

only (42.6%) than for those with private insurance (50.2%). For patients of

other races, those with Medicare only or Medicaid were less likely to receive

novel agents or transplantation compared with those with private insurance

Early Mortality in Multiple MyelomaCosta LJ et al. Leukemia 29:1616-1618, 2015

Among 30324 cases included in the analysis, a significant reduction of

EM was observed for younger patients from 19.8 to 13.9% and for

older patients from 33.9 to 26.9%. The most likely explanation for

reduction in EM is the early use of more active therapies both

preventing and at time reversing potentially fatal complications

Natural History of MM

MGUS or

smoldering

myeloma

Asymptomatic Symptomatic

ACTIVE

MYELOMA

M P

rote

in (

g/L

)

20

50

100

1. RELAPSE

2. RELAPSE

REFRACTORY

RELAPSE

First-line therapy

Plateau

remission

Second-line Third-line

Diagnosis

10 months

1° Relapse

7 months

2° Relapse

6 months

≥3° Relapse

3-4 months

Therapeutic response in patients not transplant

candidates in pre-novel eraKumar et al, Mayo Clin Proc, 2004

Diagnosis

30 months

1° Relapse

15 months

2° Relapse

7 months

≥3° Relapse

4 months

Current therapeutic scenario in MM

MM: Epidemiologia

AIRTUM – 2014

31%

<65 anni

35%

> 75 anni

34%

65-74 anni

INCIDENZA (nord-centro-sud: 6.1-5-4.3/100.000

Regione Piemonte 2006

31%

<65 anni

33%

> 75 anni

36%

65-74 anni

INCIDENZA: 8.9/100.000

Registro Marchigiano MM 2010

32%

< 65 anni

30%

65-75 anni

38%

> 75 anni

INCIDENZA: 7.3/100.000

Trattamento del paziente con mieloma

Eleggibilità a un trattamento intensivo?

Età: fino a 70 e se FIT anche fino a 75 anni (circa il 30% dei pazienti oltre i

70aa)

Età > 70Circa il 50% dei pazienti

osservati

Sì No

Induzione con tripletta (VTD) per 4 cicliTrattamento intensivo con Melphalan

200 mg/m² ed autotrapiantoTrattamento di mantenimento

con lenalidomide

MVP, Rd

AGING HETEROGENEITY

•Older adult are underrepresented in cancer registration trials

•Only 30% of patients are over 65 yrs old

•Older adults included in clinical trials are not the mirror of

what we usually see in clinical practice

Improved survival in myeloma patients: starting to close in on the gapbetween elderly patients and a matched normal population.

Liwing et al. British Journal of Haematology, 2014, 164, 684–693

62%

39%

1638 pts observed between 2001 and 2011

Fig 4. Relationships betweenindividual response categories in thefirst and second lines of therapy

Fig 3. Response distribution nCR/VGPR/PR/NR in thefirst, second, third and fourth lines of therapy.Comparing the population treated with B, T or L to thepopulation treated with conventional drugs

Improved survival in myeloma patients: starting to close in on the gapbetween elderly patients and a matched normal population.

Liwing et al. British Journal of Haematology, 2014, 164, 684–693

Mieloma Multiplo scenario 2015-2019

2015 2016 2017 2018 2019

Revlimid 1L (Lenalidomide) (3Q 2016)

IMID

Celgene

Velcade MCL 1L

Imnovid (Pomalidomide)(3Q 2015)

IMID

Celgene

Farydak(Panobinostat)(2Q 2016)

HDAC

Novartis Kyprolis RR (Carfilzomib)(3Q 2016)

PI

Amgen

Ninlaro RR (Ixazomib)(4Q 2016)

PI

Takeda

Empliciti RR(Elotuzumab)(4Q 2016)

MAb SLAM F7

BMS

Darzalex BT(Daratumumab)2017

Darzalex +VD/RD(Daratumumab)(2017)

Empliciti 1L(Elotuzumab)(2Q 2018)

MAb SLAM F7

Takeda

Kyprolis 1L (Carfilzomib)(3Q 2018)

PI

Amgen

Isatuximab BT(2Q 2019)

MAb CD38

SanofiImnovid RR (Pomalidomide)(3Q 2019)

IMID

Celgene

Empliciti 1L (elotuzumab)(4Q 2019)

MAb SLAM F7

BMS

Ninlaro 1L(ixazomib)(4Q 2019)

PI

Takeda

HDAC

IMIDs

MAbPI

Innovazione nel trattamento

del mieloma multiplo

Incremento costi dei farmaciIncremento sopravvivenza

Miglioramento qualità della vita

Incremento reale dei costi?Diretti (sanitari, non sanitari) e indiretti

Direct Hospital resource utilization and costs of treating patients with multiple myeloma in southwest sweden: a 5-

year retrospective analysis.Ghatnekar O et al, Clinical Therapeutics/Volume 30, Number 9, 2008

The cost of treating Swedish patients with MM

varied greatly between individuals but, overall,

chemotherapy drugs constituted only a minor part

of the total monthly cost (2%), whereas costs for

inpatient stays and therapy-induced adverse

events or comorbidity-related events accounted

for 35% and 42%, respectively. There was no

significant difference in monthly cost between

treatment lines.

Direct Hospital resource utilization and costs of treating patients with multiple myeloma in southwest sweden: a 5-year

retrospective analysis.Ghatnekar O et al, Clinical Therapeutics/Volume 30, Number 9, 2008

o Total healthcare costs per patient over the maximum

follow-up period were estimated to be 78,020 € for the

younger group and 23,096 € for the older one

o The cost per patient related to the first year after

diagnosis was 42,948 € in the under 70 group and

14,669 € in the over 70’s…The vast majority of the

total costs estimated, either in the first year after

diagnosis and during the entire follow-up, can be

attributed to hospital care

The burden of multiple myeloma: assessment on occurrence, outcomes and cost using a retrospective

longitudinal study based on administrative claims databaseDe Portu S. et al, Italian J Public Health, 2011

Patterns of total cost of economic consequences of progression for patientswith newly diagnosed multiple myeloma patients Arikian SR et al, CMRO 2015

Direct Healthcare Costs of Treated Multiple Myeloma: Results From a Population-Based StudyA. Corso et al. ASH meeting 2014

A retrospective study based on around 10 million people of theItalian Lombardy region performed through an administrativehealthcare databases. The study population was made up of allLombardy residents who, during the period 2003-2009, received adiagnosis of multiple myeloma. The study population was followedup until 31 December 2010.

Myeloma patients were grouped in those treated with CHT(chemotherapy) and SCT (stem cell transplant). Direct healthcarecosts were grouped into three categories: inpatient hospitalizations,outpatient visits, and drug prescriptions.

3,043 patients, observed for 8 years, were included in the analysis:• 925 (30%) treated with SCT, median survival 7.5 years,average cost 125,202• 2118 treated with CHT, median survival 2.8, average cost38,443• hospitalizations and drugs were the drivers of costs in bothgroups• no increase of average costs per patient groups was observedover time, even considering the availability of new and moreexpensive MM specific drugs.

Direct Healthcare Costs of Treated Multiple Myeloma: Results From a Population-Based StudyA. Corso et al. ASH meeting 2014

SCT vs CHT patients: mean cost (€) per patient

during the study period

1,9232,801

66,068

17,042

24,462

10,93414,624

10,336

14,898

10,034

15,597

9,31712,624

8,556

15,939

7,72611,050

6,381

Mean cost (euro) for SCT and CHT patients

by type of cost and year of observation

Baseline FU1 FU2 FU3 FU4 FU5 FU6 FU7 FU8

N. patients 3,043 3,043 2,513 1,840 1,305 881 609 331 146

€/patient 2,534 31,945 15,790 12,061 12,137 12,212 10,492 11,671 8,939

The average cost for SCT patients during the 8 years of study period was 125,202,

72% of which spent during the first 2 years after the index date.

Baseline FU1 FU2 FU3 FU4 FU5 FU6 FU7 FU8

N. patients 2,118 2,118 1,611 1,100 741 475 319 172 66

€/patient 2,800 17,042 10,935 10,336 10,035 9,318 8,555 7,726 6,381

The average cost for CHT patients during the 8 years of study period was 38,443,

73% of which spent during the first 2 years after the index date.

Trends in overall survival and costs of multiple myeloma, 2000–2014 Fonseca R et al. Leukemia (2017) 31, 1915–1921

Trends in overall survival and costs of multiple myeloma, 2000–2014 Fonseca R et al. Leukemia (2017) 31, 1915–1921

The Role of Bortezomib, Thalidomide and Lenalidomide in the Management of Multiple Myeloma

An Overview of Clinical and Economic Information Messori A et al. Pharmacoeconomics 2011; 29 (4): 269-285

Spesa per i farmaciCosto per paziente

(Messori)Spesa, mediana

LENA in recidiva da 32000 a 70000 33723 € (16574- 60152 €)

BOR in recidiva 24000 17145 € (9479 - 28468 €)

BOR in prima linea 48000 19257 € (9912 – 26885 €)

Analisi dei costi in «real life» di una popolazione

di pazienti con mieloma multiplo

TMO (2008-15) No TMO (2008-15)

Spesa totale della I

linea di terapia60546 (51909-68451) 19257 (9912-26885)

Spese farmaci 623 (23-12220) 8304 (1137-18385)

Spese ambulatoriali 2833 (1674-4059) 1658 (680-3193)

Spese ricoveri 50627 (48371-53192) 3941 (0-8218)

Analisi dei costi in «real life» di una popolazione

di pazienti con mieloma multiplo

Trattamento del paziente con mieloma

Eleggibilità a un trattamento intensivo?

Circa il 50% dei pazientiosservati

Circa il 50% dei pazientiosservati

Sì No

Debating the Oncologist’s role in defining the value in cancer care: we have duty to society

Jagsi R, J Clin Oncol 2008, vol 32, N 36: 4035-38

“Physicians have a societal responsibility to provide care that minimizes waste. They should develop a culture of financial

stewardship developing explicit standard and norms for professional behavior in order to ensure an appropriate

delivery of high value cancer care to all patients”

Debating the Oncologist’s role in defining the value in cancer care: our duty is to our patients

Sulmasy D, J Clin Oncol 2008, vol 32, N 36: 4039-41

“Physicians should still be free to fulfil their primary duty to act in the best interest of their individual patients within the

practical limits established by society”

Nell’ultima decade la storia del mieloma è cambiata completamente. Le possibilitàterapeutiche sono aumentate in modo esponenziale raddoppiando la sopravvivenzanon solo dei più giovani ma anche di quelli non candidati a terapie ad alte dosi

La disponibilità di nuovi farmaci e la prospettiva di averne molti altri nel giro di pochianni, non solo in ambito ematologico, sollevano problemi di sostenibilità eappropriatezza

Questi per essere affrontati nel modo più corretto dovranno tener conto:

• Diritto alla tutela della salute

• Complessità del paziente e della malattia

• Costi in real life e non su modelli basati sugli studi

• Costo del paziente in toto e mai solo costo dei farmaci

• Ruolo centrale dell’ematologo

Conclusioni