ANCO%20ASH%20Highlights%202007:%20Multiple%20Myeloma

1

• ANCO ASH Highlights 2007Multiple Myeloma
• Joseph M. Tuscano, MD
• University of California, Davis

2
Abstracts

• 73 Bortezomib (Velcade )-Thalidomide-Dexamethaso
  ne (VTD) vs Thalidomide-Dexamethasone (TD) in
  Preparation for Autologous Stem-Cell (SC)
  Transplantation (ASCT) in Newly Diagnosed
  Multiple Myeloma
• 76 MMY-3002 A Phase 3 Study Comparing
  Bortezomib Melphalan Prednisone (VMP) with
  Melphalan Prednisone (MP) in Newly Diagnosed MM
• 74 A Randomized Trial of Lenalidomide Plus
  High-Dose Dexamethasone (RD) Versus Lenalidomide
  Plus Low-Dose Dexamethasone (Rd) in Newly
  Diagnosed Multiple Myeloma (E4A03) A Trial
  Coordinated by the Eastern Cooperative Oncology
  Group.
• 2716 The Efficacy and Toxicity of the RAD
  Regimen (Revlimid , Adriamycin , Dexamethasone)
  in Relapsed and Refractory Multiple Myeloma
• 310 A Prospective, Randomized, Phase III Study
  of Enoxaparin Versus Aspirin Versus
  Low-Fixed-Dose of Warfarin in Newly Diagnosed
  Myeloma Patients Treated with Thalidomide-Containi
  ng Regimens
• 2714 Lenalidomide, Bortezomib, and
  Dexamethasone (Rev/Vel/Dex) in Patients with
  Relapsed or Relapsed/Refractory Multiple Myeloma
  (MM) Preliminary Results of a Phase II Study

3
73 Bortezomib (Velcade )-Thalidomide-Dexamethaso
ne (VTD) vs Thalidomide-Dexamethasone (TD) in
Preparation for Autologous Stem-Cell (SC)
Transplantation (ASCT) in Newly Diagnosed
Multiple Myeloma (MM). Session Type Oral
SessionMichele Cavo, Francesca Patriarca, Paola
Tacchetti, Monica Galli, Giulia Perrone, Maria
Teresa Petrucci, Annamaria Brioli, Sara Bringhen,
Lucia Pantani, Patrizia Tosi, Claudia Crippa,
Elena Zamagni, Francesco Di Raimondo, Franco
Narni, Claudia Cellini, Michela Ceccolini,
Norbert Pescosta, Maria Cecilia Goldaniga,
Vittorio Montefusco, Vincenzo Callea, Valerio De
Stefano, Tommaso Caravita, Mario Boccadoro,
Michele Baccarani Seragnoli Institute of
Hematology, University of Bologna, Bologna,
Italy Italian Myeloma Network, GIMEMA, Italy
4
Newly Diagnosed
INDEX
VTD vs TD for SCT Induction
Phase III study Planned interim analysis

• Endpoints Primary include CRnCR post-induction
  Secondary includeCRnCR post-consolidation, TTP,
  EFS, OS, Stem cell yield, and Safety
• Patients 450 planned patients 256 enrolled
  (Arm A n129, Arm B n127)
• Dose Three 21-day cycles

R A N D O M I Z E

• DVT Prophylaxis Pts randomized to LMWH
  (enoxaparin 40mg/d), Aspirin (100mg/d), or
  wafarin 1.25mg/d

Cavo M, et al. ASH 2007, abstract 73
5
Newly Diagnosed
VTD vs TD for SCT Induction
Base-Line Patient Characteristics VTD (n129) TD (n127)
Median age yrs (range) 58 (34-66) 57 (29-65)
ISS () I II III 47 34 19 47 34 19
Median ?2-m mg/L (range) 2.9 (0.2-15) 3.0 (1.3-12)
Median albumin g/dL (range) 3.9 (0.38-17.3) 3.9 (1.3-59.9)
Median creatinine mg/dL (range) 1.0 (0.5-2.0) 1.0 (0.46-2.3)
Genetic abnormality Del13 pos () t(414) pos () Del17 pos () 49 23 10 44 19 8
Cavo M, et al. ASH 2007, abstract 73
6
Newly Diagnosed
VTD vs TD for SCT Induction
Response Induction Induction Induction Post-SCT Post-SCT
VTD (n129) TD (n127) P value VTD (n74) TD (n79)
CRnCR 36 9 lt0.001 57 28
? VGPR 60 27 lt0.001 77 54
lt PR 7 20 0.003 - -
Modified EBMT criteria

• Cytogenetic abnormalities Del 13q and t(414)
  had no adverse impact on CRnCR post-induction a
  significantly improved CRnCR rate with VTD was
  seen in these patients (Del 13q Plt0.001 and
  t(414) P0.002) vs with TD

PBSC Harvest VTD (n112) TD (n108) P-value
Median CD34 cells (x106 /kg) (range) ? 4.0 x106 /kg ( pts) 9.2 (0-29) 94 10.6 (0-37) 93 NS
Median of apheresis 1 (0-5) 2 (0-4) NS
Cavo M, et al. ASH 2007, abstract 73
7
Newly Diagnosed
VTD vs TD for SCT Induction
Safety Grade 3-4 AE () VTD (n129) TD (n127) P-value
PN 7 2 0.03
Skin rash 6.5 1 0.01
Constipation 4 2 NS
Infection(s) excluding HZ 3 3
DVT 3 6.5 0.01
Liver toxicity 2.5 3 NS
Vomiting/diarrhea 2 0 NS
Herpes Zoster infection 1 0 NS
Cardiac 0 2 NS
Other 9 10.5 NS

• Discontinuation due to toxicity 3 VTD vs 2 TD
• Deaths due to toxicity 0 VTD vs 1 TD
• 91 of pts received gt90 of planned bortezomib
  administrations

Cavo M, et al. ASH 2007, abstract 73
8
Newly Diagnosed
VTD vs TD for SCT Induction

• Conclusions

• VTD as primary therapy for MM significantly
  increased the rate of CR nCR and ?VGPR
  compared to TD and was not adversely influenced
  by t(414) or chromosome 13 deletion
• Significant response benefit by VTD induction
  translated into a significantly higher
  probability of CRnCR or ?VGPR post-SCT
• Grade 3-4 AE, including SAE, was similar in the
  two treatment arms Exception higher rate of PN
  and rash with VTD, and higher rate DVT with TD
• Relatively low toxicity profile of VTD was
  reflected by low discontinuation rate, high
  probability of receiving gt90 planned dose, and
  absence of early deaths
• Primary therapy with VTD did not adversely impair
  the efficiency of PBSC harvest

Cavo M, et al. ASH 2007, abstract 73
9
76 MMY-3002 A Phase 3 Study Comparing
Bortezomib Melphalan Prednisone (VMP) with
Melphalan Prednisone (MP) in Newly Diagnosed
Multiple Myeloma. Session Type Oral
SessionJ.F. San Miguel, R. Schlag, N. Khuageva,
O. Shpilberg, M. Dimopoulos, M. Kropff, I.
Spicka, M. Petrucci, O. Samoilova, A. Dmoszynska,
K. Abdulkadyrov, R. Schots, B. Jiang, A. Palumbo,
M. Mateos, K. Liu, A. Cakana, H. Van de Velde, P.
Richardson Hospital Universitario de Salamanca,
Spain Praxisklinik Dr. Schlag, W rzburg,
Germany SP Botkin Moscow City Clinical Hospital,
Russian Federation Rabin Medical Center,
Petah-Tiqva, Israel University of Athens School
of Medicine, Greece University of M nster,
Germany University Hospital Prague, Czech
Republic University La Sapienza, Rome, Italy
Nizhnii Novgorod Region Clinical Hospital,
Russian Federation Medical University of Lublin,
Poland St Petersburg Clinical Research Institute
of Hematology Transfusiology, Russian
Federation Myelome Study Group Belgian
Hematological Society, Belgium People s
Hospital, Peking University, China Universita di
Torino, Italy Johnson Johnson PRD, Raritan,
USA Johnson Johnson PRD, Beerse, Belgium
Dana-Farber Cancer Institute, Boston, USA
10
Newly Diagnosed
INDEX
VMP vs MP VISTA Phase III
Randomized, international phase 3 study Planned
interim analysis of VMP vs MP in previously
untreated MM patients, not candidates for SCT

• Endpoints Primary TTP Secondary CR rate, ORR,
  TTR, DOR, PFS, TNT, OS, QoL

• Study Schema

Assessment of Efficacy and Safety
R A N D O M I Z E
ARM A (VMP) VMP Four 6-week cycles Cycles
1-4 Bortezomib 1.3mg/m2 days 1, 4, 8, 11, 22,
25, 29, 32 Melphalan 9mg/m2 and prednisone
60mg/m2 days 1-4 Followed by five 6-week cycles
Cycles 5-9 Bortezomib 1.3mg/m2 days 1, 8, 22,
29 Melphalan 9mg/m2 and prednisone 60mg/m2 once
daily on days 14

• Independent data monitoring committee (IDMC)
  monitored safety data monthly
• Safety assessed using NCI Common Toxicity
  Criteria
• Response and progression assessed q3 weeks per
  EBMT1 using central laboratory for M-protein
  quantification results reported in real time to
  the investigator for evaluation

Max of 9 cycles (total 54 weeks) in both Arms
ARM B (MP) MP Nine 6-week cycles Cycles
1-9 Melphalan 9mg/m2 and prednisone 60mg/m2 days
1-4
1. Bladé et al. Br J Haematol 19981021115-23.
San Miguel J, et al. ASH 2007, abstract 76
11
VMP vs MP
Newly Diagnosed
INDEX
IDMC recommended study stop in September 2007
based on protocol-specified interim analysis
(data cut-off 15 June 2007) VMP was significantly
superior across all efficacy endpoints
Statistical Methods

• Intent to treat analysis (all subjects
  randomized)
• Designed to show a 33 improvement in TTP and
  42 in OS
• Statistical tests two-sided ? 0.05
• Stratification ß2microglobulin, albumin, region
• Time-to-event measurements
• Time to progression (TTP) randomization to first
  evidence of PD/relapse
• Progression free survival (PFS) randomization
  to first evidence of PD/relapse or death
• Time to next therapy (TNT) randomization to
  first dose of subsequent anti-myeloma therapy,
  including treatment free interval (TFI)
• TFI last dose of study drug to first dose of
  subsequent anti-myeloma therapy

San Miguel J, et al. ASH 2007, abstract 76
12
VMP vs MP
Newly Diagnosed
INDEX
Patient Demographics and Disease Characteristics
Characteristics VMP n344 MP, n338
Median age, years 71 71
Aged 75 years, 31 30
KPS 70, 35 33
ISS Stage I / II / III, 19 / 47 / 35 19 / 47 / 34
IgG / IgA / Light chain, 64 / 24 / 8 62 / 26 / 8
ß2M lt2.5/2.5 - 5.5/gt5.5 mg/L, 12 / 55 / 33 12 / 55 / 33
Median ß2M, mg/L 4.2 4.3
CrCl 30/gt30 - 60/gt60 (ml/min), 6 / 48 / 46 5 / 50 / 46
Median serum Cr, mg/dL 1.1 1.1
Albumin lt3.5 g/dL, Median albumin, g/dL 58 (3.3) 59 (3.3)
Lytic bone lesions, 65 66
Median plasma cells in bone marrow biopsy 40 41
San Miguel J, et al. ASH 2007, abstract 76
13
VMP vs MP
Newly Diagnosed
INDEX
Response VMP (n336) VMP (n336) MP (n331) MP (n331) P-value
Response M-Protein EBMT1 M-Protein EBMT1 P-value
CRIF- 35 30 5 4 lt0.000001
PR 46 40 45 31
VGPR 10 N/A 5 N/A
ORR (CRPR) 82 71 50 35 lt0.000001
Time to Response1
All Responders 1.4 mos 1.4 mos 4.2 mos 4.2 mos lt10-10
Time to CR 4.2 mos 4.2 mos 5.3 mos 5.3 mos lt10-10
Duration of Response1
All Responders 20 mos 20 mos 13 mos 13 mos
CR 24 mos 24 mos 13 mos 13 mos

• Response rates, PFS and OS were not influenced
  by age ( lt75 vs ?75 yrs), CrCl (lt60 vs ?60
  ml/min), or cytogenetics (FISH) (any t4-14,
  t14-16, 17p Del vs none))

• Measured in serum or urine by central laboratory
• 1. Bladé et al. Br J Haematol 19981021115-23.

San Miguel J, et al. ASH 2007, abstract 76
14
VMP vs MP
Newly Diagnosed
INDEX

• Overall survival 40 reduced risk of death on
  VMP

• Time to progression52 reduced risk of
  progression on VMP

VMP MP

• VMP
• MP

Median follow-up 16.3 mos VMP not reached (45
deaths) MP not reached (76 deaths) HR 0.607, p
0.0078
VMP 24.0 months (83 events) MP 16.6 months (146
events) HR 0.483, p lt 0.000001
MP 338 320 301 280 220
157 116 69 29
7 VMP344 315 300 290 235
168 115 72 36 4
Number of patients at risk
MP 338 296 241 206 152
86 53 22 5 VMP344
295 272 245 185 111
65 31 17 Number of patients
at risk

• VMP shows benefit in TTP across sub-groups
  analyzed
• Time to Next Therapy (TTNT) not reached for VMP
  vs 21 mos for MP (p0.000009) pts on VMP were
  48 less likely to start second-line therapy
• Treatment Free Interval (TFI) not reached for
  VMP vs 9 mos for MP (p0.0001)

VMP MP
OS _at_ 2-years 83 70
lt75 year 84 74
75 years 79 60
Treatment related deaths 1 2
San Miguel J, et al. ASH 2007, abstract 76
15
VMP vs MP
Newly Diagnosed
INDEX

Grade 3/4 AE () VMP (n340) VMP (n340) MP (n337) MP (n337)
Grade 3/4 AE () Gr 3 Gr 4 Gr 3 Gr 4
Neutropenia 30 10 23 15
Thrombocytopenia 20 17 16 14
Anemia 16 3 20 8
GI 19 1 5 lt1
Peripheral Sensory Neuropathy 13 lt1 0 0
Fatigue 7 1 2 0
Asthenia 6 lt1 3 0
Pneumonia 5 2 4 1
Herpes Zoster 3 0 2 0

• Serious AE 46 for VMP vs 36 for MP
• Transfusion (26 vs 35) and EPO support (34 vs
  42) were somewhat lower on VMP arm vs MP
  respectively
• PN resolved or improved in 75 of cases in a
  median of 64 days
• DVT was low (1) and similar on both arms

San Miguel J, et al. ASH 2007, abstract 76
16
VMP vs MP
Newly Diagnosed
INDEX

• Conclusions

• VMP significantly prolongs survival and is
  superior across all pre-specified efficacy
  endpoints in the largest MP-based phase III study
• Rapid and durable responses with unprecedented CR
  rate (35)
• Prolonged TTP, time to next therapy (TTNT) /
  treatment-free interval (TFI), and OS
• Data are robust and consistently superior across
  all prognostic subgroups
• VMP was well tolerated, with patients on therapy
  for 46 weeks
• Discontinuations due to AE were low and identical
  for both arms

San Miguel J, et al. ASH 2007, abstract 76
17
74 A Randomized Trial of Lenalidomide Plus
High-Dose Dexamethasone (RD) Versus Lenalidomide
Plus Low-Dose Dexamethasone (Rd) in Newly
Diagnosed Multiple Myeloma (E4A03) A Trial
Coordinated by the Eastern Cooperative Oncology
Group. Session Type Oral SessionS. Vincent
Rajkumar, Susanna Jacobus, Natalie Callander,
Rafael Fonseca, David Vesole, Michael Williams,
Rafat Abonour, David Siegel, Philip Greipp Mayo
Clinic, Rochester, MN, USA Dana Farber Cancer
Institute, Boston, MA, USA University of
Wisconsin, Madison, WI, USA Mayo Clinic,
Scottsdale, AZ, USA St. Vincent s Comprehensive
Cancer Center, New York, NY, USA University of
Virginia, Charlottesville, VA, USA Indiana
University Medical Center, Indianapolis, IN, USA
Hackensack University Medical Center, Hackensack,
NJ, USA
18
Lenalidomide Plus Standard- or Low-Dose
Dexamethasone in Newly Diagnosed MM
ECOG-E4A03 Phase III, Randomized Study
Courses repeat q 28 days 1 yr in absence of PD
or unacceptable toxicity
If PD within 4 mo
Arm I. Lenalidomide 25 mg/day po, days
121 Standard-dose dexamethasone 40 mg/day po,
days 14, 912, 1720 (n223)
Arm III. Salvage therapy Thalidomide 200 mg/day
po, days 128 Standard-dose dexamethasone 40
mg/day po, days 14, 912, 1720
Newly diagnosed, untreated MM (N445)
Arm IV. Salvage therapy Thalidomide 200 mg/day
po, days 128 Lower-dose dexamethasone 40
mg/day po, days 1, 8, 15, 22
Arm II. Lenalidomide 25 mg/day po, days
121 Lower-dose dexamethasone 40 mg/day po, days
1, 8, 15, 22 (n222)
1o Endpoint RR at 4 mo 2o Endpoints Safety in
arms I, II RR in arms III, IV
Induction trial Not intended to test efficacy of
long-term lenalidomide/dex
Rajkumar SV et al. Presented at 49th ASH Annual
Meeting December 811, 2007 Atlanta, GA
19
E4A03 Selected Patient Characteristics
Characteristic LD (n223) Ld (n222)
ISS, Stage I Stage II Stage III 33.0 41.3 25.7 33.3 41.4 25.3
Male, 58.3 54.1
Age, yr (range) 66 (3687) 65 (3585)
ECOG PS 1, 91.0 90.5
Serum M protein (g/dL) 3.2 3.1
Durie-Salmon stage III, 79.3 75.2
MM bone disease, 65.3 56.8
Patients eligible, n 195 188
LLenalidomide DStandard-dose dexamethasone
dLow-dose dexamethasone
Rajkumar SV et al. Presented at 49th ASH Annual
Meeting December 811, 2007 Atlanta, GA
20
E4A03 Serious AEs (3)
Toxicity (Gr 3) LD, (n222) Ld, (n219) P Value
Hemoglobin 8.1 6.8 0.718
Neutrophils 5.4 5.5 1.000
Platelets 11.7 18.7 0.047
DVT/PE 25 9 lt0.001
Infection/Pneumonia 14 7 0.030
Fatigue 13 10 0.294
Hyperglycemia 11 6 0.126
Nonneuropathic weakness 10 4 0.008
Cardiac ischemia 3 0.5 0.068
Atrial fib/flutter 3 0.5 0.122
Any non hem toxicity (4 mo) 50 30 lt0.001
Any non hem toxicity 65 45 lt0.001
Any toxicity (Gr 4) 19 8 0.001
Early Deaths (4 mo) 5 0.5 0.01
LLenalidomide DStandard-dose dexamethasone
dLow-dose dexamethasone Fishers exact
Rajkumar SV et al. Presented at 49th ASH Annual
Meeting December 811, 2007 Atlanta, GA
21
E4A03 Causes of Death
Median Follow up 21 mos
LD (N46), n Ld (N25), n
Progressive Disease 26 17
Thromboembolic 5 1
Infection 4 3
Cardiac 6 2
Stroke 1 1
Respiratory Failure 1 0
Second Cancer 1 0
Unknown 2 1
LLenalidomide DStandard-dose dexamethasone
dLow-dose dexamethasone
Rajkumar SV et al. Presented at 49th ASH Annual
Meeting December 811, 2007 Atlanta, GA
22
E4A03 Response Data
100
82
82
P0.007
P0.01
71
70
80
30
38
PR
60
29
VGPR
44
40
Response,
CR
48
42
40
20
2
1
2
4
25
0
LD (n190)
Ld (n196)
LD (n190)
Ld (n196)
Response 4 cycles
Best Overall Response
LLenalidomide DStandard-dose dexamethasone
dLow-dose dexamethasone Fishers exact
Rajkumar SV et al. Presented at 49th ASH Annual
Meeting December 811, 2007 Atlanta, GA
23
E4A03 Interim Analysis PFS, TTP and OS
LD Ld P value
Median PFS, mo 19.3 21.9 0.0637
Median, TTP, mo 21.8 22.6 0.2117
1
0.8
0.6
LD
Probability
Ld
0.4
0.2
P0.0060
0
0
5
10
15
20
25
Time in Months
No. of Subjects
Event
Censored
Median (95 CL)
LD
223
22 (46)
79 (177)
NA ( NA NA )
Ld
222
11 (25)
89 (197)
NA ( 30.55 NA )
LLenalidomide DStandard-dose dexamethasone
dLow-dose dexamethasone Log rank
Rajkumar SV et al. Presented at 49th ASH Annual
Meeting December 811, 2007 Atlanta, GA
24
E4A03 Interim Analysis Conclusions

• Lenalidomide plus standard-dose deaxamethasone
  (LD) and lenalidomide plus low-dose dexamethasone
  (Ld) are highly active in newly diagnosed MM
• Ld had lower response rates than LD, but within
  the 15 limit that was defined in study design as
  clinically equivalent
• Ld is associated with superior OS compared to LD
• Response duration, TTP or PFS with Ld not
  inferior to LD
• The excess mortality with LD was due to both
  disease progression as well as increased toxicity
• This study has major implications for the use of
  high-dose dexamethasone in the treatment of newly
  diagnosed MM

Rajkumar SV et al. Presented at 49th ASH Annual
Meeting December 811, 2007 Atlanta, GA
25
2716 The Efficacy and Toxicity of the RAD
Regimen (Revlimid , Adriamycin , Dexamethasone)
in Relapsed and Refractory Multiple Myeloma A
Phase I/II Trial of Deutsche Studiengruppe
Multiples Myelom . Session Type Poster Session,
Board 906-IIStefan Knop, Christian Gerecke,
Peter Liebisch, Max S. Topp, Georg Hess, Uwe
Platzbecker, Sandra Frohnert, Hermann Einsele,
Ralf Bargou W rzburg University Hospital, W
rzburg, Germany Charit Campus Buch, Berlin,
Germany University Hospital, Ulm, Germany
University Hospital, Mainz, Germany University
Hospital, Dresden, Germany
26
Lenalidomide, Doxorubicin, and Dexamethasone in
Relapsed MM Results of Phase I/II Trial
Lenalidomide po
max 6
Doxorubicin 24-h cont IV
Tag
Dexamethasone 40 mg po
q d29
1
2
3
4
5
6
7
8
9
10
11
12
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Dose Level Pt (n) Lenalidomide Doxorubicin Dexamethasone Pegfilgrastim
1 3 10 mg d121 4 mg/m2 d14 40 mg d14, d1720
2 3 10 mg d121 6 mg/m2 d14 40 mg d14, d1720
3 3 10 mg d121 9 mg/m2 d14 40 mg d14, d1720
4 6 15 mg d121 9 mg/m2 d14 40 mg d14, d1720
4-G 3 15 mg d121 9 mg/m2 d14 40 mg d14, d1720 6 mg d6
5-G 6 25 mg d121 9 mg/m2 d14 40 mg d14, d1720 6 mg d6
Knop S. Presented at 49th ASH Annual Meeting
December 811, 2007 Atlanta, GA
27
RAD Trial in Relapsed MM Patient Characteristics
Characteristic N 69
Median age, yr (range) 63 (4677)
Median no. of previous therapies (range) 2 (13)
Autologous transplantation, 72
Allogeneic transplantation, 12
Conventional therapy, 16
Bortezomib, 57
Thalidomide, 20
Cytogenetic analysis del(13) t(414) del(17p), 46 16 19
Knop S. Presented at 49th ASH Annual Meeting
December 811, 2007 Atlanta, GA
28
RAD Trial for Relapsed MM
AE, n n63 n63 n63 n63
AE, n Gr 1 Gr 2 Gr 3 Gr 4
Neutropenia 3 12 16 14
Thrombocytopenia 12 10 13 9
Constipation 2 2 0 0
Fatigue 22 9 0 0
PN 24 2 0 0
Infection/fever 22 8 6 0
VTE 1 3 0 0
Response Rate (n 38 EBMT criteria)
Patients ()
Grades according to NCI CTC
Knop S. Presented at 49th ASH Annual Meeting
December 811, 2007 Atlanta, GA
29
310 A Prospective, Randomized, Phase III Study
of Enoxaparin Versus Aspirin Versus
Low-Fixed-Dose of Warfarin in Newly Diagnosed
Myeloma Patients Treated with Thalidomide-Containi
ng Regimens. Session Type Oral SessionAntonio
Palumbo, Michele Cavo, Sara Bringhen, Giulia
Perrone, Valeria Magarotto, Francesca Patriarca,
Maria Teresa Petrucci, Monica Galli, Francesco Di
Raimondo, Davide Rossi, Roberto Marasca, Massimo
Offidani, Maria Goldaniga, Paolo Corradini,
Claudia Crippa, Lucio Catalano, Vincenzo Callea,
Antonella Gozzini, Patrizia Tosi, Mario Boccadoro
Divisione di Ematologia dell Universit di
Torino, Az. Osp. San Giovanni Battista, Torino,
Italy Istituto di Ematologia e Oncologia Medica
Ser gnoli , Universit di Bologna, Bologna,
Italy Italian Multiple Myeloma Network, GIMEMA,
Italy First Authorship Equally Shared
30
LMWH vs Warfarin vs ASA in Newly Diagnosed MM
Treated with Thalidomide-Containing Regimens
Thalidomide regimens VTD TD
VMPT Randomize ASA WAR
LMWH Aspirin
Warfarin Enoxaparin 100 mg/day
1.25 mg/day 40 mg/day
VMP No prophylaxis

• VTD-TD (lt65 yr) 9 wk before ASCT
• VMPT (gt65 yr) 6 mo

A prospective randomized GIMENA phase III trial
Palumbo A et al. Presented at 49th ASH Annual
Meeting December 811, 2007 Atlanta, GA
31
LMWH vs Warfarin vs ASA Prophylaxis For
Thalidomide-Containing Regimens Patient
Characteristics
Characteristic ASA (n112) WAR(n120) LMWH(n115)
Age (median) 60 59 59
65 years 17 20 16
MBI 30 kg/m2 13 18 13
Central venous catheter 31 37 22
Immobilization 15 16 21
Cardiac disease/diabetes 20 34 26
Surgery 10 11 7
Inherited conditions N/A N/A N/A
2 above risk factors 24 34 22
Palumbo A et al. Presented at 49th ASH Annual
Meeting December 811, 2007 Atlanta, GA
32
LMWH vs Warfarin vs ASA Prophylaxis For
Thalidomide-Containing Regimens VTE According to
Risk Factors
Patients ()
Palumbo A et al. Presented at 49th ASH Annual
Meeting December 811, 2007 Atlanta, GA
33
2714 Lenalidomide, Bortezomib, and
Dexamethasone (Rev/Vel/Dex) in Patients with
Relapsed or Relapsed/Refractory Multiple Myeloma
(MM) Preliminary Results of a Phase II Study.
Session Type Poster Session, Board 904-IIPaul
Richardson, Sundar Jagannath, Noopur Raje,
Andrzej Jakubowiak, Sagar Lonial, Irene Ghobrial,
Robert Schlossman, Amitabha Mazumder, Nikhil
Munshi, Kathleen Colson, Mary McKenney, Melissa
Farrell, Laura Lunde, Lawrence Giove, Sarah
Kaster, Constantine Mitsiades, Teru Hideshima,
Robert Knight, Dixie-Lee Esseltine, Kenneth
Anderson Dana-Farber Cancer Institute, Boston,
MA, USA St. Vincent s Comprehensive Cancer
Center, New York, NY, USA Massachusetts General
Hospital Cancer Center, Boston, MA, USA
University of Michigan, Ann Arbor, MI, USA
Winship Cancer Institute, Emory University,
Atlanta, GA, USA Celgene Corporation, Summit,
NJ, USA Millennium Pharmaceuticals, Inc.,
Cambridge, MA, USA
34
Phase I/II Study of Bortezomib, Lenalidomide and
Dexamethasone in Newly Diagnosed MM
Dex, 40 mg/day d1, 2, 4, 5, 8, 9, 11 and 12 20
mg/day, cycles 58 Amended to 20mg/10mg cycles
1-4/5-8 based on safety data

• Patients achieving PR may proceed to ASCT after
  ?4 cycles
• Maintenance therapy permitted in patients
  achieving SD using weekly (d1 and d8) schedule
  of Bz, and Dex on d1, 2, 8, and 9
• Antithrombotic therapy with daily aspirin (81 or
  325 mg)
• Antiviral therapy as prophylaxis against Herpes
  Zoster

Richardson PG et al. Presented at 49th ASH
Annual Meeting December 811, 2007 Atlanta, GA
35
Bortezomib, Lenalidomide and Dexamethasone in
Newly Diagnosed MM Dose Escalation

• Phase I (Successive cohorts of 36 pts per dose
  level)
• Dose escalation proceeded depending on occurrence
  of DLTs
• Gr 3 non-hematologic toxicity Gr 4
  thrombocytopenia with platelets lt10,000/mm3 on
  gt1 occasion despite transfusion support Gr 4
  neutropenia for gt5 d and/or resulting in
  neutropenic fever
• Inability to receive cycle 2/d1 dose due to
  drug-related toxicity
• MTD dose level prior to that resulting in 2
  DLTs
• 10 additional pts to be enrolled at the MTD
• Phase II (35 pts to be enrolled at MTD or maximum
  planned dose)

Dose level Lenalidomide (mg/day) Bortzomib (mg/m2) Dex (mg)
1 15 1.0 40
2 15 1.3 40
3 20 1.3 40
4 25 1.3 40
4M 25 1.3 20
An additional dose level, 4M, was introduced
based on safety data 20 mg, cycles 58
Richardson PG et al. Presented at 49th ASH
Annual Meeting December 811, 2007 Atlanta, GA
36
Bortezomib, Lenalidomide and Dexamethasone in
Newly Diagnosed MM Patient Disposition
as of 12/1/07
Phase l enrollment (N33) n
Dose level 1 3
Dose level 2 3
Dose level 3 4
Dose level 4 6
Dose level 4M 17
Phase ll enrollment (N20)
1 patient in each never received treatment not
included in MTD determination Starting Dex dose
changed to 20 mg/day as safety data beyond cycle
1 indicated Dex at 40mg/day was not well
tolerated 11 pts continue on treatment but have
yet to complete 2 cycles as of 12/1/07

• Two DLTs seen at dose level 4 Gr 3 hyperglycemia
  due to high-dose Dex (40 mg)
• Maximum planned dose level has been reached (4M)
  Len 25 mg Bz 1.3 mg/m2 Dex 20 mg
• Ph I enrollment complete Ph II enrollment
  ongoing (at dose level 4M)

Richardson PG et al. Presented at 49th ASH
Annual Meeting December 811, 2007 Atlanta, GA
37
Bortezomib, Lenalidomide and Dexamethasone in
Newly Diagnosed MM Patient Characteristics
Characteristic (N53) Value
Median age, years (range) 58 (22-86)
Male, n () 27 (51)
Myeloma type, n ()
IgG 36 (68)
IgA 14 (26)
k light-chain 2 (4)
l light-chain 1 (2)
ISS stage II/III at diagnosis, n () 26 (49)
Durie-Salmon stage III at diagnosis, n () 16 (30)
Richardson PG et al. Presented at 49th ASH
Annual Meeting December 811, 2007 Atlanta, GA
38
Bortezomib, Lenalidomide and Dexamethasone in
Newly Diagnosed MM Most Common Grade 3/4 AEs
Patient, n

• Toxicities have been manageable
• No unexpected toxicities have been seen no Gr ?3
  PN
• No treatment-related mortality

Richardson PG et al. Presented at 49th ASH
Annual Meeting December 811, 2007 Atlanta, GA
39
Bortezomib, Lenalidomide and Dexamethasone in
Newly Diagnosed MM Response Data

• Responses assessed by EBMT1 criteria and Uniform
  Criteria (UC)2 (modified to include nCR)3
• After cycle 2, then after every cycle
• Responses for evaluable patients were confirmed
  by 2 assessments, 6 wks apart

EBMT/UC Response (N42 evaluable as of 12/1/2007) n()
CR 9(21)
nCR 3(7)
VGPR 10(24)
PR 29(69)
PR 41(98)
Richardson PG et al. Presented at 49th ASH
Annual Meeting December 811, 2007 Atlanta, GA