Mieloma Multiplo Michele Cavo Seràgnoli Institute of Hematology, Bologna University School of Medicine, Italy Florence, September 19 th , 2014
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Mieloma Multiplo
Michele Cavo
Seràgnoli Institute of Hematology,
Bologna University School of Medicine, Italy
Florence, September 19th, 2014
Newly Diagnosed ASCT eligible
Prognostic relevance of 18F-FDG PET/CT negativity after autologous stem
cell transplantation (ASCT) in newly diagnosed multiple myeloma patients
Zamagni E.1, Nanni C.2, Pezzi A.1, Mancuso K.1, Tacchetti P.1,
Pantani L.1, Zannetti B.1, Brioli A.1, Rocchi S.1, Marzocchi G.1,
Testoni N.1, Terragna C.1, Martinelli G.1, Fanti S.2, Cavo M.1
1 “Seragnoli” Institute of Hematology, University of Bologna2 Institute of Nuclear Medicine, University of Bologna
UNIVARIATE ANALYSIS OF PROGNOSTIC
FACTORS FOR PFS AND OS
Variables PFS OS
HR 95% CI p HR 95% CI p
ISS 3 1.63 1.05-2.52 0.029 2.32 1.11-4.87 0.025
Failure CR at 1° line
therapy2.78 1.99-3.89 <0.001 1.54 0.89-2.66 0.119
FLs > 3 1.85 1.24-2.76 0.002 2.60 1.30-5.20 0.007
SUV max > 4,2 2.39 1.51-3.77 <0.001 4.47 1.81-11.04 0.001
EMD 2.88 1.19-6.99 0.019 3.41 1.01-11.55 0.049
All the variables retained prognostic relevance independently of
the treatment received (ASCT or not, Bortezomib or not)
SCORE: ISS 3 - Failure CR - FLs PET
SCORE ISS 3 - < CR - FLs > 3
n° of risk factors % of ptsPFS
median (mo)
OS
at 60 mo (%)
0 30.38 75 94.41
1 37.34 58 90.39
2 25.32 40 80.90
3 6.96 17 51.95
Log rank test P < 0.0001 P < 0.001
Trend test P < 0.0001 P < 0.001
PREDICTIVE VALUE OF PET/CT AFTER TREATMENT IN PATIENTS
ACHIEVING CONVENTIONALLY- DEFINED CR
29% of the patients in conventionally-defined CR had PET/CT still positive
MULTIVARIATE ANALYSIS OF POST TREATMENT FACTORS
FAVORABLY INFLUENCING PFS AND OS IN PATIENTS
ACHIEVING CONVENTIONALLY- DEFINED CR
COX model PFS OS
HR 95% CI p HR 95% CI p
FLs=0 0.43 0.24-0.77 0.004 0.33 0.13-0.86 0.023
No EMD 0.16 0.03-1.04 0.054 0.13 0.02-0.98 0.048
Newly Diagnosed ASCT ineligible
Lenalidomide and Dexamethasone in
Transplant-Ineligible Patients with Myeloma
Lofti Benboubker, Meletios A. Dimopoulos, Angela Dispenzieri, John Catalano,
Andrew R. Belch, Michele Cavo, AntonelloPinto, Katja Weisel, Heinz Ludwig, Nizar
Bahlis, Anne Banos, Mourad Tiab, Michel Delforge, Jamie Cavenagh, Catarina
Geraldes, Je-Jung Lee, Christine Chen, Albert Oriol, Javier De La Rubia, Lugui
Qiu, Darrell J. White, Daniel Binder, Kenneth Anderson, Jean-Paul Fermand,
Philippe Moreau, Michel Attal, Robert Knight, Guang Chen, Jason Van
Oostendorp, Christian Jacques, Annette Ervin-Haynes, Hervé Avet-Loiseau,
Cyrille Hulin, and Thierry Facon for the Frontline Investigation of Revlimid and
Dexamethasone versus Standard Thalidomide (FIRST®) Trial Team
Benboubker L, et al. NEJM. 2014;371:xxx-xxx. doi: 10.1056.
RA
ND
OM
IZA
TIO
N 1
:1:1
Arm B
Ld18
Arm C
MPT
LEN + LoDEX: 18 Cycles (72 wks) LENALIDOMIDE 25 mg D1-21/28
LoDEX 40 mg D1,8,15, & 22/28
MEL + PRED + THAL 12 Cycles (72 wks)MELPHALAN 0.25 mg/kg D1-4/42
PREDNISONE 2 mg/kg D1-4/42
THALIDOMIDE 200 mg D1-42/42
PD
, O
S,
an
d
Su
bseq
ue
nt
an
ti-M
M T
x
PD
or
Un
accep
tab
le T
oxic
ity
Active Treatment + PFS Follow-up PhaseScreening LT Follow-Up
Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL (100 mg D1-42/42); MEL 0.2 mg/kg D1–4
• Stratification: age (≤ 75 y vs. > 75 y), country, and ISS stage (I or II vs. III)
• Thromboprophylaxis was mandatory
FIRST Trial: Study Design
LEN + LoDEX: ContinuouslyLENALIDOMIDE 25 mg D1-21/28
LoDEX 40 mg D1,8,15, & 22/28
Arm A
Continuous Ld
FIRST, Frontline Investigation of Revlimid and Dexamethasoneversus Standard Thalidomide; ISS, International Staging System; Ld, lenalidomide plus low-dose dexamethasone;
Ld18, lenalidomide plus low-dose dexamethasone for 18 cycles; LEN, lenalidomide; LoDEX, low-dose dexamethasone; LT, long-term; MEL, melphalan; MM, multiple myeloma;
MPT, melphalan, prednisone, thalidomide; OS, overall survival; PD, progressive disease; PFS, progression-free survival; Pred, prednisone; pt, patient; THAL, thalidomide; Tx,
treatment.
Benboubker L, et al. NEJM. 2014;371:xxx-xxx. doi: 10.1056.
Continuous Ld
(n= 535)
RANDOMIZATION 1:1:1
(N= 1,623)
Median follow-up of 37 months as of May 24, 2013
Continuous Ld Ld18 MPT
Pts still on study Tx, n (%) 121 (23) 0 (0) 0 (0)
Ld18 (72 weeks)
(n= 541)
MPT (72 weeks)
(n= 547)
FIRST, Frontline Investigation of Revlimid and Dexamethasoneversus Standard Thalidomide; Ld, lenalidomide plus low-dose dexamethasone; Ld18, lenalidomide plus low-dose
dexamethasone for 18 cycles; NR, not reported; pt, patient; Tx, treatment.
Benboubker L, et al. NEJM. 2014;371:xxx-xxx. doi: 10.1056.
FIRST Trial: Patient Disposition
Median PFS
Ld (n= 535) 25.5 mos
Ld18 (n= 541) 20.7 mos
MPT (n= 547) 21.2 mos
Ld 535 400 319 265 218 168 105 55 19 2 0
Ld18 541 391 319 265 167 108 56 30 7 2 0
MPT 547 380 304 244 170 116 58 28 6 1 0
Hazard ratio
Ld vs. MPT: 0.72; P< 0.001
Ld vs. Ld18: 0.70; P< 0.001
Time (months)
Pa
tie
nts
(%
)100
80
60
40
20
00 6 12 18 24 30 36 42 48 54 60
FIRST Trial: Final Progression-Free Survival
FIRST, Frontline Investigation of Revlimid and Dexamethasoneversus Standard Thalidomide; Ld, lenalidomide plus low-dose dexamethasone; Ld18, lenalidomide plus low-dose
dexamethasone for 18 cycles; MPT, melphalan, prednisone, thalidomide; PFS, progression-free survival.
Benboubker L, et al. NEJM. 2014 ;371:xxx-xxx. doi: 10.1056.
a High risk defined as t(4;14), t(14;16), or del(17p).
β2M, β2 microglobulin; CrCl, creatinine clearance; del, deletion; ECOG PS, Eastern Cooperative Oncology Group Performance Status; FIRST, Frontline Investigation of Revlimid and
Dexamethasoneversus Standard Thalidomide; HR, hazard ratio; ISS, International Staging System; Ld, lenalidomide plus low-dose dexamethasone; LDH, lactate dehydrogenase; MPT, melphalan,
prednisone, thalidomide; PFS, progression-free survival; t, translocation.
Benboubker L, et al. NEJM. 2014;371:xxx-xxx. doi: 10.1056.
0 .1 2 5 0 .2 5 0 .5 1 2 4 8
SubgroupAge > 75 yearsAge ≤ 75 years
Sex: femaleSex: male
WhiteAsian
AsiaEurope
North America and PacificISS stage: I or II
ISS stage: IIICrCI < 30 mL/min
CrCI 30-50 mL/minCrCI 50-80 mL/min
CrCI ≥ 80 mL/minβ2M > 5.5 mg/Lβ2M ≤ 5.5 mg/L
Albumin > 35 g/LAlbumin ≤ 35 g/L
ECOG PS score 0ECOG PS score 1ECOG PS score 2
LDH < 200 U/lLDH ≥ 200 U/l
High-risk cytogeneticsa
Non-high-risk cytogenetics
Hazard ratio (HR) and 95% CI HR (95% Cl)0.81 (0.62-1.05)0.68 (0.56-0.83)0.73 (0.58-0.93)0.71 (0.57-0.88)0.72 (0.61-0.85)0.64 (0.35-1.14)0.61 (0.33-1.14)0.77 (0.63-0.93)0.64 (0.46-0.89)0.70 (0.57-0.87)0.75 (0.59-0.95)0.76 (0.44-1.30)0.66 (0.48-0.91)0.74 (0.58-0.95)0.71 (0.51-1.01)0.79 (0.62-1.00)0.67 (0.54-0.83)0.68 (0.55-0.84)0.83 (0.65-1.06)0.54 (0.39-0.74)0.81 (0.65-1.01)0.80 (0.57-1.12)0.69 (0.58-0.83)0.96 (0.66-1.39)1.23 (0.78-1.93)0.69 (0.53-0.90)
FIRST Trial: Consistent PFS Benefit Across Subgroups
Favoring Ld Favoring MPT
MPT114/188220/359153/260181/287301/49126/4423/40
234/37477/133
191/323143/22437/5583/126
135/22279/144
149/234184/312188/324146/22386/156
172/27572/111
265/43468/11239/47
124/206
Ld107/186171/349119/241159/294244/47420/4018/36
197/36963/130
154/319124/21623/4574/126
125/24156/123
133/224144/309162/343116/19263/155
148/25765/119
229/44849/8637/4399/205
Side Effects of Tx
Fewer side
effects
More
sideeffects
• Rd resulted in a significant reduction in patient-reported Side Effects
of Tx vs. MPT at most time points
Visit
Ch
an
ge F
rom
Baselin
e
** *
* **
* * *
20
15
10
5
0
−5
C2D1 Mo 3 Mo 6 Mo 12 Mo 18
Rd
MPT
•• •
•
* P ≤ 0.05 vs. baseline (1-sample t-test)
• P ≤ 0.05 Rd vs. MPT (2-sample t-test)
FIRST Trial: EORTC QLQ-MY20 Results
EORTC, European Organisation for the Research and Treatment of Cancer; FIRST, Frontline Investigation of Revlimid and Dexamethasoneversus Standard Thalidomide;
Ld, lenalidomide plus low-dose dexamethasone; Mo, month; MPT, melphalan, prednisone, thalidomide; QLQ-MY20, Quality of Life Questionnaire Myeloma Module; Tx,
treatment.
Facon T. Haematologica. 2014;99(s1):220 [oral presentation, abstract S643].
E1A06An Intergroup Phase III Randomized Controlled Trial Comparing Melphalan, Prednisone and
Thalidomide (MPT-T) versus Melphalan, Prednisone and Lenalidomide (mPR-R) in Newly
Diagnosed Multiple Myeloma Patients Who Are Not Candidates for High Dose Therapy
A. Keith Stewart, Susanna Jacobus, Rafael Fonseca, Matthias Weiss,
Natalie Callander, Asher Chanan-Khan, S. Vincent Rajkumar
Induction Maintenance(Planned twelve cycles)
(until disease progression)
Enrollment
N=306
Treatment A (MPT-T)
•Melphalan 9 mg/m2 po days 1 - 4
•Prednisone 100 mg po days 1 - 4
•Thalidomide 100 mg po days 1 - 28
Treatment B (mPR-R)
•Melphalan 5 mg/m2 po days 1 - 4
•Prednisone 100 mg po days 1 - 4
•Lenalidomide 10 mg po days 1 - 21
Thal 100 mg po daily
Len 10 mg po daily
All patients received EC aspirin 325 mg po daily
Progression-Free Survival: ITT
Overall Survival: Results
Results: Quality of Life
QoL analysis favored mPR-R by induction end
– Mean QoL change over Induction: MPT-T -2.8 vs. mPR-R 3.3;
p=0.007.
01
02
03
04
05
06
07
08
09
01
00
FA
CT
Ntx
TO
I
0 6 12 18 24 30 36Month from registration
MPR-R MPT-T
+/- 1 SD
E1A06 FACT-Ntx TOI: On Treatment
IMPACT OF CONTINUOUS TREATMENT
VS FIXED DURATION OF THERAPY IN
NEWLY DIAGNOSED MYELOMA
PATIENTS: PFS1, PFS2, OS ENDPOINTS.
Francesca Gay* 1, Federica Cavallo1, Francesco Di Raimondo2, Izhard Hardan3, Arnon Nagler4,
Maria T. Petrucci2, Paolo Corradini2, Roman Hajek5, Sara Pezzati2, Michel Delforge6, Francesca
Patriarca2, Francesca Donato1, Lucia Pantani2, Chiara Nozzoli2, Zhinuan Yu7, Luana
Boccadifuoco1, Tommaso Caravita2, Christian Jacques 7, Giulia Benevolo2, Meletios A.
Dimopoulos8, Tommasina Guglielmelli2, Donatella Vincelli2, Giovannino Ciccone9, Pellegrino
Musto2, Mario Boccadoro1 , Antonio Palumbo1 .
1Myeloma Unit, Division of Hematology, University of Torino, Torino, 2Italian Multiple Myeloma Network, GIMEMA,
Italy, 3 Hematology Division, Meir Medical Center, Kfar-Saba, 4Director Division of Hematology Chaim Sheba
Medical Center, Tel Hashomer, Israel, 5University Hospital Brno and Faculty of Medicine OU, Ostrava, Czech
Republic, 6University Hospital Leuven, Leuven, Belgium, 7Celgene Corporation, Summit, United States,
8Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra Hospital, Athens,
Greece, 9Unit of Clinical Epidemiology, University of Torino, Torino, Italy
VMPT-VT vs VMP1
N= 511MPR/Mel200-R vs
MPR/Mel2002
N= 402
MPR-R vs MPR vs MP3
N= 459
PATIENTS INCLUDED
N= 1218
CONTINUOUS THERAPY
N= 604
VMPT-VT1
Rd-MPR/Mel200-R2
MPR-R3
FIXED DURATION OF THERAPY
N= 614
VMP1
Rd-MPR/Mel2002
MPR3
MP
N=154
Study design
To compare novel agent based- CT vs FDT
CT, continuous therapy; FDT, Fixed duration of therapy, VMPT, bortezomib-melphalan-prednisone-thalidomide, VT, bortezomib-thalidomide maintenance, VMP,
bortezomib-melphalan-prednisone; MPR, melphalan-prednisone-lenalidomide; Mel200, melphalan 200 mg/mq followed by autologous transplant; R, lenalidomide
maintenance; MP, melphalan-prednisone.
1. GIMEMA MM-03-05 trial, Palumbo A, et al, JCO 2014 ; 32: 634-40 2. GIMEMAM RV-MM-209 trial, Gay F, Blood 2013; 122: 21 (abstr 2089) 3. MM-015 trial Palumbo
A, et al N Engl J Med 2012; 366: 1759–69.
4-year OS
CT 69%
FDT 60%
CT, continuous therapy; FDT, fixed duration of therapy; OS, overall survival; N, number; ITT, intention to treat
1-year Landmark analysis
P
F
S
1
P
F
S
2
O
S
N= 1218
N= 687
2nd
P
F
S
Induction-
consolidationMaintenance
0.00
0.25
0.50
0.75
1.00
0 12 24 36 48 60
CT
FDT
HR 0.69, 95% CI 0.54-0.88, P =.003
% o
f p
ati
en
ts
Months
CONTINUOUS vs FIX DURATION: OS
Median PFS2
CT 55 months
FDT 40 months
CT, continuous therapy; FDT, fixed duration of therapy; PFS, progression-free survival; OS, overall survival, N°number; N, number
1-year Landmark analysis
P
F
S
1
P
F
S
2
O
S
N= 1218
N= 687
2nd
P
F
S
Induction-
consolidationMaintenance
Months
0.00
0.25
0.50
0.75
1.00
0 12 24 36 48 60
CT
FDT
HR 0.61, 95% CI 0.50-0.75, P <.001
% o
f p
ati
en
ts
CONTINUOUS vs FIX DURATION: PFS2
Relapsed/Refractory
Jesús F. San-Miguel, Vânia T.M. Hungria, Sung-Soo Yoon,
Meral Beksac, Meletios Athanasios Dimopoulos, Ashraf Elghandour,
Wieslaw W. Jedrzejczak, Andreas Guenther, Thanyaphong Na Nakorn,
Noppadol Siritanaratkul,
Robert L. Schlossman, Jian Hou, Philippe Moreau, Sagar Lonial, Jae
Hoon Lee, Hermann Einsele, Hans Salwender, Monika Sopala,
Bourras-Rezki Bengoudifa, Claudia Corrado, Florence Binlich, and
Paul G. Richardson
on behalf of the PANORAMA 1 investigators
Randomized, Double-blind, Placebo-controlled Phase
3 Study of Panobinostat or Placebo Plus Bortezomib
And Dexamethasone In Relapsed Or Relapsed And
Refractory Multiple
Myeloma (PANORAMA 1)
PANORAMA 1 Study DesignRandomized, Double-Blind, Phase 3 Study in
Relapsed or Relapsed and Refractory MM
Follow-up
Treatment Phase 1 Treatment Phase 2
Eight 21-Day cycles (24 wks) Four 42-Day cycles (24 wks)
Panobinostat +
bortezomib +
dexamethasone
Placebo + bortezomib + dexamethasone
Panobinostat + bortezomib + dexamethasone
Placebo + bortezomib + dexamethasone
Pts with clinical benefita in Treatment
Phase I, can proceed to Treatment Phase II
• Primary endpoint: PFS (per modified EBMT criteria; confirmed by IRC)1,2
• Key secondary endpoint: OS
• Other secondary endpoints: ORR, nCR/CR rate, DOR, TTR, TTP, QoL, and safety
Study conducted at 215 centers across 34 countries
Pts(N = 768)
•Rel or Rel/Ref MM (BTZ-ref excluded)
•1-3 prior lines of therapy
•Stratification factors
–Prior lines of therapy
–Prior BTZ
a Achieving ≥ no change according to
modified EBMT criteria (SD or better)
1. Blade J, et al. Br J Haematol. 1998;102:1115-11232. Richardson PG, et al. N Engl J Med. 2003; 348:2609-2617
PANORAMA 1 Treatment Schedule
Week 1 Week 2 Week 3
Treatment Phase 1 (Cycles 1-8)
PAN/Pbo
BTZ
Dex
Week 1 Week 2 Week 3
Treatment Phase 2 (Cycle 9-12)
PAN/Pbo
BTZ
Dex
Week 4 Week 5 Week 6
PAN: Panobinostat 20 mg oral
BTZ: Bortezomib 1.3 mg/m2 IV
Dex: Dexamethasone 20 mg oral
• Primary endpoint was met (P < .0001), with clinically relevant
increase in median PFS of 3.9 months for PAN-BTZ-Dex arm
Primary Endpoint Met (PFS)
100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
387 288 241 202 171 143 113 89 69 52 44 35 26 18 13 10 5 3 0
381 296 235 185 143 114 89 64 42 32 24 18 12 5 5 3 2 0 0
MonthsNumber of patients at riskPAN-BTZ-Dex
Pbo-BTZ-Dex
Pro
gre
ss
ion
-fre
e s
urv
iva
l P
rob
ab
ilit
y (
%)
Events
Median PFS
(95% CI)
months
HR
(95% CI)P value
PAN-BTZ-Dex 207/38712.0
(10.3, 12.9) 0.63 (0.52-0.76)
< .0001Pbo-BTZ-Dex
260/3818.1
(7.6, 9.2)
PAN-BTZ-Dex
Pbo-BTZ-Dex
PANORAMA 1
Efficacy: Response
PAN-BTZ-Dex
(n = 387)
Pbo-BTZ-Dex
(n = 381)P value
ORR (PR or better)
[95% CI]
60.7%
[55.7, 65.6]
54.6%
[49.4, 59.7].087
CR/nCR rate
[95% CI]
27.6%
[23.2, 32.4]
15.7%
[12.2, 19.8].00006*
Median DoR
[95% CI]
13.1 mos
[11.8, 14.9]
10.9 mos
[9.2, 11.8]N/A
Median TTR
[95% CI]
1.5 mos
[1.4, 1.6]
2.0 mos
[1.6, 2.8]N/A
Median TTP
[95% CI]
12.7 mos
[11.8-14.9]
8.5 mos
[7.7-9.7]N/A
• CR/nCR rate was nearly doubled vs control arm (sCR in PAN arm
2%, vs 0% Pbo arm)
• Clinically meaningful improvements in median DoR and TTP
*Post-hoc analysis
PANORAMA 1
Non-Hematologic AEsGrade 3/4 Diarrhea and Asthenia/Fatigue Observed
aCombined incidence of hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, polyneuropathy.
PAN-BTZ-Dex (n = 381) Pbo-BTZ-Dex (n = 377)
Preferred term – % All grades Grade 3/4 All grades Grade 3/4
Diarrhea 68.2 25.5 41.6 8.0
Peripheral neuropathya 60.6 17.6 67.1 14.6
Asthenia/fatigue 57.0 23.9 40.6 11.9
Nausea 36.2 5.5 20.7 0.5
Peripheral edema 28.6 2.1 19.1 0.3
Decreased appetite 28.1 3.1 12.5 1.1
Constipation 26.8 1.0 32.6 1.1
Pyrexia 26.0 1.3 14.9 1.9
Vomiting 25.7 7.3 13.0 1.3
Cough 21.3 1.0 18.6 0
• Discontinuation due to diarrhea (4.5%) and fatigue (2.9%) on PAN arm
PANORAMA 1
Safety and Efficacy of Daratumumab
with Lenalidomide and Dexamethasone
in Relapsed or Relapsed and Refractory Multiple Myeloma.
Torben Plesner1, Hendrik-Tobias Arkenau2, Henk M. Lokhorst3, Peter Gimsing4, Jakub Krejcik1,Charlotte Lemech2, Monique Minnema3, Ulrik Niels Lassen3, Tahamtan Ahmadi5, Howard Yeh5, MaryGuckert5, Huaibao Feng5, Nikolai C. Brun6, Steen Lisby6, Linda Basse6, Antonio Palumbo7, Paul G.Richardson8
1Vejle Hospital, Vejle, Denmark; 2Sarah Cannon Research Institute, London, United Kingdom; 3Department of Hematology, University MedicalCenter Utrecht, Utrecht, Netherlands; 4Rigshospitalet, Copenhagen, Denmark; 5Janssen Research & Development, USA; 6Genmab A/S,Copenhagen, Denmark; 7University of Torino, Azienda Ospedaliero-Universitaria (AOU) S. Giovanni Battista Torino, Torino, Italy; 8Dana-FarberCancer Institute, Boston, MA
Background
Daratumumab
A human CD38 mAb with broad-spectrum killing activity of CD38-expressing tumor cells
DARA+LEN enhanced killing of MM cells in vitro and is hypothesized to lead to synergistically higher efficacy
in clinical setting.
Presented by: Torben Plesner
Antibody-dependent cell-
mediated cytotoxicity (ADCC)
Antibody-dependent cellular
phagocytosis (ADCP)
Complement-dependent
cytotoxicity (CDC)
Apoptosis
Study Objective To evaluate safety and efficacy of DARA+LEN+DEX in patients with
relapsed, or relapsed and refractory (RR) MM
Presented by: Torben Plesner
Study Design
2 mg/kg
(N=3)
4 mg/kg
(N=3)
8 mg/kg
(N=4)
16 mg/kg Total
(N=22)Part 1
(N=3)
Part 2
(N= 9)
Total
(N=12)
Infusions per patient,
Median (range)
21.0
(13; 26)
23.0
(22; 24)
20.0
(17; 21)
11.0
(10; 16)
2.0
(1; 4)
2.5
(1; 16)
12.0
(1; 26)
Duration of infusion
(hours),
n,
Median (range)
60
7.25
(5.8; 11.9)
69
7.22
(5.7; 10.3)
78
5.92
(5.6; 9.3)
36
6.31
(5.8; 8.5)
19
6.92
(5.8; 12.2)
55
6.53
(5.8; 12.2)
262
6.42
(5.6; 12.2)
Presented by:Torben Plesner
Results
Demographics and Baseline Characteristics
•Data from 22 patients (16 men, 6 women) are evaluable to date.
•Median age 62 (48-76) years
•Median prior therapies: 2.5 (1-4)
•13 patients had ECOG status 0; 8 patients had ECOG status 1
•3 patients (1 in 4 mg/kg group and 2 in 8 mg/kg group) LEN refractory.
Safety
•AEs (>30% patients): neutropenia, diarrhea
•MTD not reached
•No DLTs reported in any dose cohort
•Infusion reactions (grade 1 and 2) reported in 4 patients
Presented by: Torben Plesner
Efficacy
•All patients followed up for at least 2 weeks
•Marked decrease in M-protein
•PR or better: 15/20 patients
•3 CR, 6 VGPR
•Median time to response-4.3 weeks (2.1-11.3)
Results
Best Response and Duration of Follow-upMaximum % Change in Para-protein from Baseline
Twice-weekly Oral MLN9708, an Investigational
Proteasome Inhibitor, in Combination with
Lenalidomide (Len) and Dexamethasone (Dex)
in Patients (Pts) with Newly Diagnosed Multiple
Myeloma (MM): Final Phase 1 Results and
Phase 2 Data
Paul G. Richardson,1 Craig C. Hofmeister,2 Cara A. Rosenbaum,3
Myo Htut,4 David H. Vesole,5 Jesus G. Berdeja,6 Michaela Liedtke,7
Ajai Chari,8 Stephen D. Smith,9 Daniel Lebovic,10 Deborah Berg,11
Eileen Liao,11 Neeraj Gupta,11 Alessandra Di Bacco,11 Jose Estevam,11
Ai-Min Hui,11 Rachid Baz12
1Dana-Farber Cancer Institute, Boston, MA; 2The Ohio State University, Columbus, OH; 3University of Chicago,
Chicago, IL; 4City of Hope National Medical Center, Duarte, CA; 5The John Theurer Cancer Center at Hackensack
UMC, Hackensack, NJ; 6Sarah Cannon Research Institute, Nashville, TN; 7Stanford Cancer Institute, Stanford,
CA; 8Mount Sinai School of Medicine, New York, NY; 9Oregon Health & Science University / now University of
Washington Fred Hutchinson Cancer Research Center, Seattle, WA; 10University of Michigan, Ann Arbor, MI; 11Takeda Pharmaceuticals International Co., Cambridge, MA;
12H. Lee Moffitt Cancer Center, Tampa, FL
Study design
• Phase 1: oral MLN9708 dose-escalation
– Standard 3+3 schema, 33% dose increments, based on cycle 1 DLTs
• Phase 2: oral MLN9708 at the RP2D from phase 1
• Protocol allows for stem cell collection after cycle 4, with ASCT deferred
until after 8 cycles
• MLN9708 maintenance continued at the last tolerated dose until
progression or unacceptable toxicity
1 8 15 21
MLN9708
maintenance
Days 1, 4, 8, 11
21-day cycles
Induction: up to 16 x 21-day treatment cycles Maintenance
MLN9708 MLN9708 MLN9708
Dex* Dex* Dex*
Lenalidomide 25 mg, days 1–14
MLN9708
Dex*
4 11
*Dex 20/10 mg cycles 1–8 / 9–16
All patients required thromboembolism prophylaxis with aspirin 81–325 mg QD or
LMWH while receiving len-dex
2 5 9 12
Phase 1: DLTs and RP2D
• Two dose levels in this study:
– 7 pts enrolled to MLN9708 3.0 mg
– 7 pts enrolled to MLN9708 3.7 mg
• No AEs met DLT criteria in cycle 1 at either dose of MLN9708
• RP2D was chosen as 3.0 mg
– Determined based on consideration of the balance between overall
tolerability, including rate of rash that was higher than expected with either
single-agent MLN9708 or lenalidomide, and efficacy across multiple cycles
• All 7 pts enrolled to MLN9708 3.7 mg reported rash-related AEs
(including 4 pts with grade 3 AEs)
DLTs, dose-limiting toxicites; RP2D, recommended phase 2 dose
3224 20
50
4846
27
8
9 16 21
0
10
20
30
40
50
60
70
80
90
100
After 4 cycles (n=56) After 8 cycles (n=56) Overall (n=56)
sCR
CR
VGPR
PR
Preliminary response data show
deepening responses over course of
treatment (pts treated at RP2D)
%
≥VGPR
61%
ORR 93% ORR 95% ORR 95%
• Depth of response increased over the course of treatment
− Median time to 1st response: 0.69 months
− Median time to best response to date: 1.96 months
• Median DOR to date is 13.8 months, ranging up to 18.8+ months
≥VGPR
71% ≥VGPR
75%
sCR/CR
11%sCR/CR
23%sCR/CR
29%
(incl. nCR)
Safety profile
AE,* n (%)
Phase 1
(n=14)
RP2D†
(n=57)
Total
(N=64)
Any AE 14 (100) 57 (100) 64 (100)
Any drug-related AE# 14 (100) 56 (98) 63 (98)
Any grade ≥3 AE 11 (79) 44 (77) 49 (77)
Any grade ≥3 drug-related AE# 9 (64) 32 (56) 37 (58)
Any serious AE (SAE) 7 (50) 28 (49) 30 (47)
Any drug-related SAE† 4 (29) 16 (28) 18 (28)
Dose reduction due to AEs 10 (71) 32 (56) 37 (58)
Discontinuation due to AEs 3 (21) 7 (12) 9 (14)
*AEs graded using NCI-CTCAE v4.03; †Includes 7 phase 1 pts treated at MLN9708 3.0 mg; #Drug-related is defined as
related to any drug in the combination
• One pt (phase 2) died due to cardio-respiratory arrest, likely a pulmonary embolism, considered by the
investigator to be unrelated to MLN9708 or dex but probably len
Drug-related* AEs, all grades (≥20% of total)
AE, n (%) Phase 1 (n=14) RP2D (n=57)† Total (n=64)
Rash-related AEs# 10 (70) 25 (44) 32 (50)
Peripheral neuropathies‡ 9 (64) 30 (53) 34 (53)
Fatigue 9 (64) 27 (47) 31 (48)
Peripheral edema 7 (50) 22 (39) 25 (39)
Dysgeusia 3 (21) 18 (32) 20 (31)
Diarrhea 5 (36) 17 (30) 19 (30)
Insomnia 6 (43) 15 (26) 19 (30)
Constipation 4 (29) 14 (25) 17 (27)
Nausea 4 (29) 15 (26) 17 (27)
Dizziness 2 (14) 14 (25) 14 (22)
*Drug-related defined as related to any drug in the combination; †Includes 7 phase 1 pts treated at MLN9708 3.0 mg;#Any rash-related AE within the MedDRA System Organ Class, includes rash maculo-papular (n=17), rash , rash
macular (n=7), pruritis, rash papular (n=5), rash pruritic, dermatitis acneiform, dry skin (n=3), dermatitis exfoliative,
rash erythematous, acne, erythema multiforme, rash vesicular, Stevens-Johnson syndrome; ‡Includes peripheral
neuropathy and peripheral sensory neuropathy
Spunti di discussione
Ruolo del trapianto autologo: in induzione o alla
ricaduta?
Terapia continuativa nel paziente non eleggibile a
trapianto?
Mieloma Smoldering: Osservazione o Terapia?
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