De la Gammapatia Monoclonal de Significat Incert (GMSI) al ... · Clonal proliferation of mature B lymphocytes (plasma cells and/or lymphoplasmocytoid cells) resulting in a monoclonal

De la Gammapatia Monoclonal de Significat Incert (GMSI) al Mieloma Múltiple (MM)

Joan BladéServei d’Hematologia

Unitat d’Amiloïdosi i MielomaHospital Clínic de Barcelona

Sessió inaugural, l’AcadèmiaBarcelona, Novembre de 2015

Concept

• Clonal proliferation of mature B lymphocytes (plasma

cells and/or lymphoplasmocytoid cells) resulting in a

monoclonal production of an homogenous

immunoglobulin (M component)

Classification

1. Multiple myeloma (MM) and variants

─ Smoldering myeloma─ Plasma cell leukemia─ Osteosclerotic myeloma (POEMS)─ Non-secretory myeloma─ Solitary plasmacytoma (bone or extramedullary)

2. Waldenström`s Macroglobulinemia (WM)

3. Ig light chain amyloidosis or primary amyloidosis (AL)

4. MG of undetermined significance (MGUS)

Gammapatía monoclonal de significado incierto (MGUS)

GMSI MQ MM

CPMO (%) <10y

≥10y/o

≥10*

CM (g/L) <30 ≥ 30 Presente

Manifestaciones clínicas No No Si**

GMSI. Concepto

*Clonales**Hipercalcemia, insuficiencia renal, anemia, lesiones líticas, infecciones bacterianas recurrentes y/o plasmocitomas extramedulares

§> 50 años à 3%

§> 70 años à 5.3%

Kyle et al, N Engl J Med 2006;354:1362-69

GMSI. Prevalencia

Transformación maligna de la GMSI

• Probabilidad actuarial:• 1% anual (30% a los 25 años)

• Probabilidad real(considerando causas competitivas de muerte): • 11% a los 25 años

Kyle et al; N Engl J Med 2002; 346:564-9

GMSI. Predictores de transformación maligna

Característica RR 95% Intervalo Confidencia p

Evolving vs non-evolving

12.14 5.80-25.40 <0.0001

IgA vs otros 2.92 1.36-6.28 0.006

CM(≥15 g/L)

2.18 1.02-4.66 0.044

Rosiñol et al, Mayo Clin Proc 2007

GMSI. Cociente de cadenas liberas libres en suero (FLC): factor de riesgo independiente de progresión

Riesgo a los 20 añosALTO RIESGO

Cociente FLC anormal, tipo no-IgG y CM ³15g/L 58%

BAJO-RIESGO

Cociente FLC normal, tipo IgG y CM <15 g/L 5%

Rajkumar et al. Blood 2005; 106: 812-7.

Mortalidad a los 20 años de seguimiento en 1384 pacientes con GMSI

• Gammapatía monoclonal: 10%

• Causa no relacionada: 72%

Kyle et al, NEJM 2002; 346: 564-9

Mieloma múltiple quiescente(Mieloma asintomático)

MIELOMA QUIESCENTE (MQ)

• Criterios diagnósticos de mieloma múltiple (MM)(componente monoclonal (CM) >30 g/L y > 10% decélulas plasmáticas en médula ósea).

• Ausencia de anemia, insuficiencia renal,hipercalcemia y lesiones osteolíticas

Kyle and Greipp, NEJM 1980; 302: 1347-49

Mieloma quiescente.Criterios diagnósticos IMWG

§CM sérico ≥30 g/Ly/o CM orina ³ 1g/24 horasy/o células plasmáticas clonales en médula ósea ≥10%

§ Ausencia de daño orgánico o síntomas

* The International Myeloma Working Group. Br J Haematol 2003; 121: 749-57.

MQ: Factores predictivos de progresion*

§CM ≥ 30 g/L y ≥10% CPMO

§Cociente anormal de cadenas ligeras libres en suero (sFLC)

§ Fenotipo aberrante (>95%)

§ Inmunoparesia

§ Patrón de la RM

§ “Evolving” vs “Non-evolving”

§ Alteraciones citogenéticas

MONTHS

25

35

45

55

65

75

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90MONTHS

20

30

40

50

60

70

80

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90

SMM. Pattern of Evolution

Rosiñol et al, Br J Haematol 2003

Evolving Non-evolving

Smoldering Multiple Myeloma

Evolving SMM(n=22)

Non-Evolving SMM(n=26)

M-protein Progressive increase Long-lasting stable

Previously MGUS 59% 4%

IgA type 36% 7%

Cytogenetics Chromosomal losses (71%)1q gains (57%)

Chromosomal gains(100%) (except 1q+)

TTP 1.3 yrs 3.9 yrs

• 53 patients with SMMSerum MP >30 g/L or Urine MP > 1000 mg/24h + BMPC ³ 10%

Rosiñol et al, BJH 2003; BJH 2005

Monoclonal Gammopathies: Evolution Pattern

MM

SMM

MGUS

“EVOLVING”

“NON EVOLVING”

“NON EVOLVING”

Rosiñol et al. Br J Haematol 2003; 123: 631-36. Rosiñol et al. Mayo Clin Proc 2007; 82: 428-34.

Riesgo de progresión: “evolving” vs. “no-evolving”

• N=207

• Probabilidad progresión 2 años: 45%

• Probabilidad de progresión 5 años: 78%

• Asociado más frecuentemente al isotipo IgA (41,2% frente 23,8%, p=0,02)

Mediana TTP 3 años

Mediana TTP 19,4 años

p < 0,001

Isola et al; sesión plenaria #abstract 1

0

20%

40%

60%

80%

100%

Inci

de

nci

a a

cum

ula

da

0 5 10 15 20 25 30 35 40Años desde el diagnóstico

Bajo Intermed-1 Intermed-2 Alto

Progresión según los factores de riesgo: “evolving”, inmunoparesia y CM >30 g/L

Progresión 2 años

Progresión 5 años

Bajo 2,4% 4,9%

Intermedio-1 11% 31%

Intermedio-2 11% 52%

Alto 57% 80%

Isola et al; sesión plenaria #abstract 1

Mieloma quiescente de muy alto riesgo

CPMO ³ 60%

Mediana TTP 7 meses

> 1 IMÁGEN FOCAL EN RMN

Mediana TTP 13 meses

COCIENTE sFLC ≥ 100

Mediana TTP 15 meses

Rajkumar SV et al. NEJM, 2011

Riesgo de progresión >80% a los dos años

Rajkumar et al, Lancet Oncol 2014

Hillengass J et al. JCO, 2011 Larsen JT et al. Leukemia, 2012

Mateos et al, N Engl J Med 2013; 369:438-47

QUIREDEX: SLP y SG

SLP: NR vs 21 m SG

Mateos et al, N Engl J Med 2013;369:438-47

¿Cuando tratar el mieloma quiescente?

• Nuevos criterios diagnósticos

─ Muy alto riesgo Þ MM sintomático

• Tratamiento precoz

─ NO: auténtico MQ (no evolving)

─ A considerar: alto riesgo (↑ CM, ↓Hb, inmunoparesia)

Indicators of Increasing Disease and/or End-organ Dysfunction MM-related (CRAB)

§HyperCalcemia (> 11.5 mg/dL)

§Renal failure ( serum creatinine by ≥ 2 mg/dL)

§Anemia (¯ Hb by > 2 g/dL or < 10 g/dL)

§ Increase (> 50% and at least 1 cm) in size of existingBone lesions or plasmacytomas

§Other: hyperviscosity, development of new soft tissueplasmacytomas or bone lesions

*Rajkumar et al, Blood 2011; 117: 4691-5.

Frontline Therapy of Symptomatic Multiple Myeloma

Transplant Candidates

Pre and Post-ASCT CR Rate with “old” Regimens*

Regimen Pre-ASCT Post-ASCT

Dexa/VAD 5% 35%

Cyclophosphamide/Dexa 7% 32%

VBMCP/VBAD 10% 35%

*Bladé et al. Blood 2010;115:3655-63; Bladé et al. Haematologica2010;95:702-4; Harousseau et al. ASH 2009 (abstract 353); Mellqvist et al. Cancer 2008;112:129-35

Pre and Post-ASCT CR Rate with “Novel” Induction Regimens*

Regimen Pre-ASCT Post-ASCT

Thal/Dex 6% 23-34%

Vel/Dex 12% 33%

PAD-1 24% 43%

VRD 23% 42%

VTD 21-30% 43-52%

Total Therapy III** - 56% at 2 yrs

*Cavo et al, ASH 2009 (abstract 351); Rosiñol et al, Blood 2012;120: 1589-96; Harousseau et al, Haematologica 2006; 91: 1498-05; Rosiñol et al, JCO 2007; 25:1498-05; Popat et al, BJH 2008; 141: 512-6; Barlogie et al, BJH 2007; 138:176-85, Roussel et al;Blood 2011; 118(abstract 1872).

**VTD-PACE + Tandem ASCT + VTD/TD

VTD: Response rates according to the number of cycles and dose of Velcade

Trial Nº cycles CR (%)

GIMEMA1 3 19%

PETHEMA/GEM2 6 35%

vtD3 4 13%

1Cavo et al, The Lancet 2010;376:2075-20852Rosiñol et al, Blood 2012;120:1589-15963Moreau et al, Blood 2011;118:5752-5758

0102030405060708090

100

1 2 3 4 5 6

CR

GEM05: CR rate over induction(in patients who achieved CR)

4%

16%

40%

53%

71%

100%

VTD: Post-transplant CR, PFS and OS

Trial Post-Tx CR (%)

GIMEMA1 35%

PETHEMA/GEM2 46%

vtD3 31%

1Cavo et al, The Lancet 2010;376:2075-20852Rosiñol et al, Blood 2012;120:1589-15963Moreau et al, Blood 2011;118:5752-5758

GEM05. PFS and OS from diagnosis

VTD

TD

QT+V

56.1 m

29.2 m

39.9m

Rosiñol et al, IMW 2015

IFM 2013-04 trialMulti-center, Phase III, Randomized, Open-label, Prospective

VTD x 4 versus VCD x 4as induction therapy prior to ASCT

Symptomatic de novo MMless than 66 years

Primary end-point : VGPR rate340 patients overall (170 per arm)

VTD > VCD to be presented at ASH 2015

Consolidation therapyConcept

─ Full drug dosing─ Short period of therapy

• 2-6 months?• Longer?

Aim

─ Further decrease of tumor burden

Indu

ctio

nVR

Dx6 R

Mel-200

Bu-MelC

onso

lidat

ion

Man

inte

nanc

e

R

GEM12MENOS65

VRDconx 2

MRD MRD MRD

Concept

Low drug(s) dosingLong-term period of therapy: 1-3 years?, indefinite?

Aim

Maintain a low tumor burden

Maintenance therapy

Maintenance Therapy. Thalidomide

• Significant prolongation of EFS/PFS

• Controversial results in OS

Attal et al. Blood 2006; Spencer et al. J Clin Oncol 2009; Barlogie et al. N Engl J Med 2006; Lokhorst et al. Blood 2010; Morgan et al, Blood 2012; Stewart et al, Blood 2013

• Significant prolongation of PFS

─ IFM-2005-02: 41 vs 23 m─ CALGB100104: 50 vs 27m─ GIMEMA: 42 vs 21m

• Significant prolongation of OS in one study(CALGB100104)

Maintenance Therapy. Lenalidomide

Attal et al, NEJM 2012;366:1782-91McCarthy et al, NEJM 212;366:1770-81; IMW 2013Palumbo et al, NEJM 2014;371:895-905

GEM

12m

enos

65

R

Arm ALena/dexaLena 15 mg/d x 21dDexa 20 mg d 1-4 y 9-12

Arm BLena/dexa + MLN9708

Lena/dexa + MLN9708 4mg d 1,8,15EM

R e

valu

atio

n 2

year

s

EMR pos

End of ttoEMR neg

Lena/dexaX 3 years

GEM2014

Annual EMR

Frontline Therapy of Symptomatic Multiple Myeloma

Non-Transplant Candidates

Multiple myeloma in the elderly.Results with “old” regimens

• MP• CR: <5%• Median overall survival: 2-3 yrs

• Dex-based• CR <5%• Median overall survival: 2-3 yrs

MPT vs. MPCR (%)

PFS(months)

OS (months)

Palumbo et al, 2008 16 vs. 4 21.8 vs 14.545 vs. 47.6

(p=NS)

Facon et al, 200713 vs. 2 27.5 vs. 17.8

51.6 vs. 33.2(p=0.0006)

Hulin et al, 2009 7 vs. 1 24.1 vs. 18.544 vs. 29.1

(p=0.03)

Wijermans et al, 2010 2 vs. 215 vs. 11 (PFS)13 vs. 9 (EFS)

40 vs. 31(p=0.05)

Waage et al, 2010 13 vs. 4 15 vs. 1429 vs. 32(p=NS)

Beksac et al, 2011 9 vs. 9 8.8 vs. 8.928 vs. 26(p=NS)

Palumbo et al. Blood 2008Facon et al. Lancet 2007Hulin et al. J Clin Oncol 2009

Wijermans et al. JCO 2010 Waage et al. Blood 2010

Beksac et al, Eur J Haematol 2011

MPT vs. MP

Fayers P M et al. Blood 2011

VISTA trial: VMP vs. MPVMP MP

ORR (%) 71 35

CR rate (%) 30 4

Median time to first response (mos.) 1.4 4.4

Median duration of response

• all responders (mos.) 19.9 13.1

• patients achieving CR (mos.) 24 12.8

San Miguel et al. N Engl J Med. 2008; 359:906-17

Confirmed survival (OS) benefit with VMP ~31% reduced risk of death with VMP

Mateos et al. J Clin Oncol 2010San Miguel et al. J Clin Oncol 2013

Median follow-up: 60.1 months

PETHEMA. VMP vs. VTPGIMEMA. VMP vs. VMPT (weekly bortezomib dosing)

• ß Peripheral neuropathy• Maintain efficacy

IFM:• Subcutaneous administration

Mateos et al. Blood 2012Palumbo et al. Blood 2011Moreau et al, Lancet Oncol 2011

Facon T, et al. N Engl J Med 2014;371:906-17

RAN

DO

MIZ

ATI

ON

1:1

:1

Arm BRd18

Arm CMPT

LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

MEL + PRED + THAL 12 Cycles1 (72 wks)MELPHALAN 0.25mg/kg D1-4/42PREDNISONE 2mg/kg D1-4/42THALIDOMIDE 200mg D1-42/42

PD, O

S an

d Su

bseq

uent

ant

i-MM

Tx

PD o

r Una

ccep

tabl

e To

xici

ty

Active Treatment + PFS Follow-up PhaseScreening LT Follow-Up

Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL2 0.2 mg/kg D1–4

47

• Stratification: age, country and ISS stage

1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.

FIRST Trial: Study Design

LEN + Lo-DEX ContinuouslyLENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

Arm AContinuous Rd

ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival

Facon T, et al. N Engl J Med 2014; 371:906-17

Median PFSRd (n=535) 25.5 mosRd18 (n=541) 20.7 mosMPT (n=547) 21.2 mos

Rd 535 400 319 265 218 168 105 55 19 2 0Rd18 541 391 319 265 167 108 56 30 7 2 0MPT 547 380 304 244 170 116 58 28 6 1 0

Hazard ratioRd vs. MPT: 0.72; P = 0.00006Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349

Time (months)

Patie

nts

(%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

48

42% (Rd)

23% (Rd18) 23% (MPT)

FIRST Trial: Final Progression-free Survival

mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone.

FIRST Trial: Overall Survival Interim Analysis574 deaths (35% of ITT)

Facon T, et al.. N Engl J Med 2014;371:906-17

Pat

ient

s (%

)

RdRd18MPT

535541547

488505484

457465448

433425418

403393375

338324312

224209205

121124106

434430

563

000

4-year OSRd (n= 535) 59.4%Rd18 (n= 541) 55.7%MPT (n= 547) 51.4%

Overall survival (months)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

Hazard ratioRd vs. MPT: 0.78; P = 0.0168Rd vs. Rd18: 0.90; P = 0.307Rd18 vs. MPT: 0.88; P = 0.184

49

GEM2010MAS65.Schedule of therapySymptomatic newly diagnosed MM pt > 65 y

* Half of the patients will start on VMP and half on Rd

MPV x 9 cycles Lendex x 9 cycles

MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPVRd MPV Rd

Sequential scheme

Alternating scheme*

N: 240 pts74 weeks

Hypothesis: - Higher efficacy for the alternating scheme- Less probability of cell escape- Lower cumulative toxicity

Ongoing Large Phase III Trials

• MP-based• MPV vs. MP-CFZ (CLARION)

• MPV vs MPV-Daratumumab (Alcyone)

• LEN/DEX-based

• RD vs. RD-MLN9708 (TOURMALINE-MM2)

• RD vs. RD-Elotuzumab (ELOQUENT-1)

Clinicaltrials.gov

Treatment of Refractory or Relapsed Multiple Myeloma

Main randomized trials on treatment of relapsed/refractory myeloma

Regimen ORR(%) CR(%) TTP OS

Bort. vs. Dex1 38 vs. 18 6 vs. 1 6.2 vs. 3.580 vs. 66%

at 1 yr

Bort.+ Doxil vs. Bort2 44 vs. 41 4 vs. 2 9.3 vs. 6.5

76 vs. 65% at 15 months

Len/Dex vs. Dex3 61 vs. 19.9 14.1 vs. 0.6 11.1 vs. 4.7 29.6 vs. 20.2 months

Len/Dex vs. Dex4 60.2 vs. 24 15.9 vs. 3.4 11.3 vs. 4.7 Not reached vs. 20.6 months

1Richardson et al, NEJM 2005; 2Orlowski et al, JCO 2007; 3Weber et al, NEJM 2007; 4Dimopoulos et al, NEJM 2007

Recent Phase III Trials in Refractory/Relapsed Myeloma

• Carfilzomib (second generation proteasome inhibitor)

- Carfilzomib versus best supportive care regimen (FOCUS trial)- KRd versus Kd (ASPIRE trial)- Kd versus Vd (ENDEAVOR trial)

• Panobinostat (oral pan-deacetylase inhibitor):

─ Panobinostat-Vd versus Vd (PANORAMA1 trial)

• Elotuzumab (monoclonal antibody targeting SLAMF7 or CS1):

─ Elo-Rd versus Rd (ELOQUENT-2 trial)

• Pomalidomide (second generation IMID):

─ Poma/dexa versus dexa alone (NIMBUS trial)










Carfilzomib, Lenalidomide, and Dexamethasone vs Lenalidomide and

Dexamethasone in Patients withRelapsed Multiple Myeloma:

Interim Results from ASPIRE, a Randomized, Open-Label, Multicenter Phase

3 Study

A. Keith Stewart, S. Vincent Rajkumar, Meletios A. Dimopoulos, TamásMasszi, Ivan Spicka, Albert Oriol, Roman Hájek, Laura Rosiñol, David S.

Siegel, Georgi G. Mihaylov, Vesselina Goranova-Marinova, Péter Rajnics, Aleksandr Suvorov, Ruben Niesvizky, Andrzej Jakubowiak, Jesus F. San Miguel, Heinz Ludwig, Naseem Zojwalla, Margaret E. Tonda, Biao Xing,

Philippe Moreau and Antonio Palumbo

Stewart et al, NEJM 2015;372:142-52

ASPIRE Study Design

RdLenalidomide 25 mg Days 1–21

Dexamethasone 40 mg Days 1, 8, 15, 22

KRdCarfilzomib 27 mg/m2 IV (10 min)

Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only) Lenalidomide 25 mg Days 1–21

Dexamethasone 40 mg Days 1, 8, 15, 22

Randomization N=792

Stratification:• β2-microglobulin• Prior bortezomib • Prior lenalidomide

After cycle 12, carfilzomib given on days 1, 2, 15, 16After cycle 18, carfilzomib discontinued

28-day cycles


Response ratesP

erce

ntag

e of

Pat

ient

s

P<.0001

P<.0001

sCR 14.1% vs 4.3%

P<.0001

ó Median duration of response was 28.6 months in the KRd group and 21.2 months in the Rd group


Progression-Free Survival (ITT Population, N=792)

1.0

0.8

0.6

0.4

0.2

0.0

Pro

porti

on S

urvi

ving

With

out P

rogr

essi

on

KRdRd

0 6 12 18 24 30 36 42 48Months Since Randomization

KRd Rd(n=396) (n=396)

Median PFS, mo 26.3 17.6HR (KRd/Rd) (95% CI) 0.69 (0.57–0.83)P value (one-sided) <0.0001

No. at Risk:KRd

Rd396 332 279 222 179 112 24 1396 287 206 151 117 72 18 1


Interim Overall Survival AnalysisMedian Follow-Up 32 Months

ó Median OS was not reached; results did not cross the prespecified stopping boundary (P=0.005) at the interim analysis

1.0

0.8

0.6

0.4

0.2

0.0

Pro

porti

on S

urvi

ving

KRdRd

0 6 12 18 24 30 36 42 48Months Since Randomization

KRd Rd(n=396) (n=396)

Median OS, mo NE NEHR (KRd/Rd) (95% CI) 0.79 (0.63–0.99)P value (one-sided) 0.018

No. at Risk:KRd

Rd396 369 343 315 280 191 52 2396 356 313 281 237 144 39 3











1School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 2University of Nantes, Nantes, France; 3University of Torino, Torino, Italy; 4Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; 5University Hospital Brno, Brno, Czech Republic; 6University Hospital Brno and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic; 7CHRU Lille Hôpital Claude Huriez, Lille, France; 8Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria; 9Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Barcelona, Spain; 10Heidelberg Medical University, Heidelberg, Germany; 11Hospital Clínic de Barcelona, Barcelona, Spain; 12Vseobecna fakultni nemocnice v Praze, Prague, Czech Republic; 13Hematological Department, First Republican Clinical Hospital of Udmurtia, Izhevsk, Russia; Bayonne, France; 14Department of Hematooncology, University Hospital Olomouc, Olomouc, Czech Republic; 15Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; 16Universitatsklinikum Tubingen, Tubingen, Germany; 17Hematology Clinic University Multiprofile Hospital for Active Treatment, Plovdiv, Bulgaria; 18Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA; 19National University Cancer Institute, National University Health System, Singapore and Cancer Science Institute, National University of Singapore, Singapore

Carfilzomib is not approved in EU Amgen EUROPE GmbH, Dammstrasse 23, CH-8301, Zug, Switzerland. EUHQ-NP-CARF-0615-106844

Carfilzomib and Dexamethasone vs Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma: Results From the Phase 3 Study ENDEAVOR

Meletios A. Dimopoulos,1 Philippe Moreau,2 Antonio Palumbo,3 Douglas Joshua,4Ludek Pour,5 Roman Hájek,6 Thierry Facon,7 Heinz Ludwig,8 Albert Oriol,9Hartmut Goldschmidt,10 Laura Rosiñol,11 Jan Straub,12 Aleksandr Suvorov,13

Tomas Pika,14 Gianluca Gaidano,15 Katja Weisel,16 Vesselina Goranova-Marinova,17

Heidi Gillenwater,18 Wee-Joo Chng,19 on behalf of the ENDEAVOR investigators

ENDEAVOR Study Design

63

VdBortezomib 1.3 mg/m2 (IV bolus or subcutaneous injection)

Days 1, 4, 8, 11Dexamethasone 20 mg

Days 1, 2, 4, 5, 8, 9, 11, 1221-day cycles until PD or unacceptable toxicity

KdCarfilzomib 56 mg/m2 IV

Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)Infusion duration: 30 minutes for all doses

Dexamethasone 20 mg Days 1, 2, 8, 9, 15, 16, 22, 23

28-day cycles until PD or unacceptable toxicity

Randomization 1:1 N=929

Stratification:

• Prior proteasome inhibitor therapy

• Prior lines of treatment

• ISS stage

• Route of V administration

ISS, International Staging System; IV, intravenous; Kd, carfilzomib and dexamethasone; PD, progressive disease; Vd, bortezomib and dexamethasone; V, bortezomib. Carfilzomib is not approved in EU

Response Rates

64CI, confidence interval; CR, complete response; DOR, duration of response; ORR, overall response rate; Kd, carfilzomib and dexamethasone; NE, not estimable; PR, partial response; Vd, bortezomib and dexamethasone; VGPR, very good partial response.

KdVd

P<0.0001

P<0.0001

P<0.0001

• Median DOR: 21.3 months (95% CI, 21.3–NE) for Kd vs 10.4 months (95% CI, 9.3–13.8) for Vd

n=58 n=29 n=252 n=133 n=357 n=291

Pat

ient

s (%

)

(95% CI, 73–81)

(95% CI, 58–67)

Carfilzomib is not approved in EU

Progression-Free Survival (N=929)

65

1.0

0.8

0.6

0.4

0.2

0

Pro

porti

on S

urvi

ving

W

ithou

t Pro

gres

sion

0

Months Since Randomization

KdVd

Kd(n=464)

171 (37)18.7

Vd(n=465)

243 (52)9.4

0.53 (0.44–0.65)1-sided P<0.0001

Disease progression or death – n (%)Median PFS – monthsHR for Kd vs Vd (95% CI)

CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; Kd, carfilzomib and dexamethasone; PFS, progression-free survival; Vd, bortezomib and dexamethasone.

• Median follow-up: 11.2 months

6 12 18 24 30


OS data were immature; the study will continue until the final OS analysis is performed

Pro

porti

on S

urvi

ving

Kd(n=464)

75 (16)NE

Death – n (%)Median OS – monthsHR for Kd vs. Vd (95% CI)

Vd(n=465)

88 (19)24.3

0.79 (0.58–1.08)1-sided P=0.066

CI, confidence interval; HR, hazard ratio; ITT, intent to treat; Kd, carfilzomib and dexamethasone; NE, not estimable; OS, overall survival; Vd, bortezomib and dexamethasone.

Overall Survival (N=929)

66

0

Months Since Randomization

KdVd

6 12 18 24 30

1.0

0.8

0.6

0.4

0.2

0











PFS and OS Panobinostat-Vd versus Vd (median FU: 6.4 vs. 5.5 mos.)

San Miguel et al, Lancet Oncol 2014;11:1195-206










Progression-Free SurvivalElotuzumab-Rd versus Rd (median follow-up: 24.5 mos.)

Lonial et al, NEJM 2015;373:621-31

Median PFS: 19.4 vs. 14.9 months, p<0.001










NIMBUS: CC-4047-MM-003:Pomalidomide/dexa vs Dexa

PFS: 4 vs 1.9 m; p<0.0001

OS: 12.7 vs 8.1 m; p=0.02

San Miguel et al, Lancet Oncol 2013










Daratumumab: Maximal change in M-Component

Plesner. ASH 2012 & Lokhorst EHA 2013 & ASCO 2014

AA A AA A

AA AA AA AA AAB

B

B B

C C

C

2 mg/kg

4 mg/kg

8 mg/kg

16 mg/kg

24 mg/kg

< 1 mg/kg

A: serum M-component B: urine M-component C: FLC

Expansion phase @ 16 mg/Kg à 46% ≥ PR (3 VGPR + 3 PR)

n=32 with median of 6 prior lines (2-12)

Daratumumab + LD 11 pts … 4 prior lines à 5 VGPR; 3 PR; 2 MR Plesner. ASCO 2014

0

5

10

15

20

25

30

35

40

45

1 2 3 4 5 6 7 8 9 10

Serum M-spike (g/L)

Thal/Dex

Bort CHOP

Len/Dex

2013

ASCT(2008)

General Considerations in the Treatment of Refractory MM

• Doubtful clinical benefit of “stable disease” in clinical trials unless that evident PD is controlled

• Comparator arm in clinical trials: best supportive care with Cyclo/Predni

• Synergistic / additive effect in drug combinations

• Clinical judgement: when to offer only palliative care

MOLTES GRÀCIES

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