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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)
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
Stewart et al, NEJM 2015;372:142-52
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
Stewart et al, NEJM 2015;372:142-52
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
Stewart et al, NEJM 2015;372:142-52
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
Stewart et al, NEJM 2015;372:142-52
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)
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
Carfilzomib is not approved in EU
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
Carfilzomib is not approved in EU
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)
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
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)
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
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)
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
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)
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