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

1

ANCO ASH Highlights 2007:Multiple Myeloma

Joseph M. Tuscano, MD

University of California, Davis

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Abstracts

► [73] Bortezomib (Velcade )-Thalidomide-Dexamethasone (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-Containing 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

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[73] Bortezomib (Velcade )-Thalidomide-Dexamethasone (VTD) vs Thalidomide-Dexamethasone (TD) in Preparation for Autologous Stem-Cell (SC) Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (MM). Session Type:

Oral Session

Michele 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

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VTD vs TD for SCT Induction

► Endpoints: Primary include CR+nCR post-induction: Secondary include:CR+nCR post-consolidation, TTP, EFS, OS, Stem cell yield, and Safety

► Patients: 450 planned patients: 256 enrolled (Arm A n=129, Arm B n=127)

► Dose: Three 21-day cycles

Newly Diagnosed

Cavo M, et al. ASH 2007, abstract #73

Phase III study: Planned interim analysis

Arm A– VTD: Bortezomib 1.3mg/m2 days 1, 4,

8, 11; Dex 40mg day of and day after bortezomib; Thal 200mg daily

MaintenanceDexArm B

– TD: Thal 200mg daily; Dex 40mg/d days 1-4, 9-12

SC collection +

MEL 200 MEL 200

Consolidation VTD

Consolidation TD

RANDOMIZE

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

INDEX

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Newly Diagnosed


► Base-Line Patient Characteristics

VTD(n=129)

TD(n=127)

Median age yrs (range) 58 (34-66) 57 (29-65)

ISS (%) I II III

473419

473419

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(4;14) pos (%) Del17 pos (%)

492310

44198

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Newly Diagnosed


►Response* Induction Post-SCT

VTD(n=129)

TD(n=127) P value VTD

(n=74)TD

(n=79)

CR+nCR 36% 9% <0.001 57% 28%

VGPR 60% 27% <0.001 77% 54%

< PR 7% 20% 0.003 - -*Modified EBMT criteria

►PBSC Harvest VTD(n=112)

TD(n=108) 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

– Cytogenetic abnormalities [Del 13q and t(4;14)] had no adverse impact on CR+nCR post-induction; a significantly improved CR+nCR rate with VTD was seen in these patients (Del 13q [P<0.001] and t(4;14) [P=0.002]) vs with TD

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Newly Diagnosed


►Safety: Grade 3-4 AE (%)VTD

(n=129)TD

(n=127) 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 >90% of planned bortezomib administrations

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Newly Diagnosed


► 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(4;14) or chromosome 13 deletion

– Significant response benefit by VTD induction translated into a significantly higher probability of CR+nCR 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 >90% planned dose, and absence of early deaths

– Primary therapy with VTD did not adversely impair the efficiency of PBSC harvest

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[76] MMY-3002: A Phase 3 Study Comparing Bortezomib Melphalan Prednisone (VMP) with Melphalan Prednisone (MP) in Newly Diagnosed

Multiple Myeloma. Session Type: Oral Session

J.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

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VMP vs MP VISTA: Phase III

► Endpoints: Primary: TTP; Secondary: CR rate, ORR, TTR, DOR, PFS, TNT, OS, QoL

Newly Diagnosed

San Miguel J, et al. ASH 2007, abstract #76

ARM A (VMP)VMP: Four 6-week cycles: Cycles 1-4Bortezomib 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 1–4

ARM B (MP)MP: Nine 6-week cycles: Cycles 1-9Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4

Max of 9 cycles (total 54 weeks) in both Arms

RANDOMIZE

– 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

Randomized, international phase 3 study: Planned interim analysis of VMP vs MP in previously untreated MM patients, not candidates for SCT

Assessment of Efficacy and Safety

1. Bladé et al. Br J Haematol 1998;102:1115-23.

► Study Schema:

INDEX

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VMP vs MP

► 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: β2microglobulin, 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

Newly Diagnosed

Statistical Methods


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

INDEX

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►CharacteristicsVMP

n=344MP,

n=338

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 <2.5/2.5 - 5.5/>5.5 mg/L, % 12 / 55 / 33 12 / 55 / 33

Median ß2M, mg/L 4.2 4.3

CrCl ≤30/>30 - 60/>60 (ml/min), % 6 / 48 / 46 5 / 50 / 46

Median serum Cr, mg/dL 1.1 1.1

Albumin <3.5 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

VMP vs MP

Newly Diagnosed

Patient Demographics and Disease Characteristics


INDEX

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VMP vs MP

Newly Diagnosed


►ResponseVMP

(n=336)MP

(n=331) P-valueM-Protein* EBMT1 M-Protein* EBMT1

CRIF- 35% 30% 5% 4% <0.000001

PR 46% 40% 45% 31%

VGPR 10% N/A 5% N/A

ORR (CR+PR) 82% 71% 50% 35% <0.000001

Time to Response1

All Responders 1.4 mos 4.2 mos <10-10

Time to CR 4.2 mos 5.3 mos <10-10

Duration of Response1

All Responders 20 mos 13 mos

CR 24 mos 13 mos

•*Measured in serum or urine by central laboratory1. Bladé et al. Br J Haematol 1998;102:1115-23.

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

INDEX

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VMP vs MP

Newly Diagnosed


►Overall survival ~ 40% reduced risk of death on VMP

VMP MP

OS @ 2-years 83% 70%

<75 year 84% 74%

≥75 years 79% 60%

Treatment related deaths 1% 2%

Median follow-up 16.3 mosVMP: not reached (45 deaths)MP: not reached (76 deaths)HR = 0.607, p = 0.0078

–VMP– MP

MP: 338 320 301 280 220 157 116 69 29 7VMP:344 315 300 290 235 168 115 72 36 4 Number of patients at risk

►Time to progression~52% reduced risk of progression on VMP

–VMP shows benefit in TTP across sub-groups analyzed Time to Next Therapy (TTNT): not reached

for VMP vs 21 mos for MP (p=0.000009); 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 (p=0.0001)

VMP: 24.0 months (83 events)MP: 16.6 months (146 events)HR = 0.483, p < 0.000001

MP: 338 296 241 206 152 86 53 22 5VMP:344 295 272 245 185 111 65 31 17Number of patients at risk

VMPMP

INDEX

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VMP vs MP

Newly Diagnosed


► Grade 3/4 AE (%)VMP (n=340) MP (n=337)

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 <1

Peripheral Sensory Neuropathy 13 <1 0 0

Fatigue 7 1 2 0

Asthenia 6 <1 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

INDEX

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VMP vs MP

Newly Diagnosed


► 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

INDEX

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[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 Session

S. 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

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Lenalidomide Plus Standard- or Low-Dose Lenalidomide Plus Standard- or Low-Dose Dexamethasone in Newly Diagnosed MMDexamethasone in Newly Diagnosed MM

ECOG-E4A03: Phase III, Randomized StudyECOG-E4A03: Phase III, Randomized Study

Newly diagnosed,

untreated MM

(N=445)

Arm I. Lenalidomide 25 mg/day po, 25 mg/day po, days 1–21days 1–21

Standard-dose dexamethasone 40 mg/day40 mg/day po, days 1–4, 9–12, 17–20po, days 1–4, 9–12, 17–20

(n=223)(n=223)

Arm II. Lenalidomide 25 mg/day po, po, days 1–21days 1–21

Lower-dose dexamethasone 40 mg/day po, days 1, 8, 15, 22po, days 1, 8, 15, 22

(n=222)(n=222)

Arm III. Salvage therapy

Thalidomide 200 mg/day po,200 mg/day po, days 1–28 days 1–28

Standard-dose dexamethasone 40 mg/day po, days 1–4, 9–12, 17–20 po, days 1–4, 9–12, 17–20

Arm IV. Salvage therapy

Thalidomide 200 mg/day po, po, days 1–28days 1–28

Lower-dose dexamethasone 40 mg/day po, days 1, 8, 15, 22po, days 1, 8, 15, 22

If PD within 4 moIf PD within 4 moCourses repeat q 28 days ≤1 yr in absence of PD or unacceptable toxicity

1o Endpoint: RR at 4 mo; 2o Endpoints: Safety in arms I, II; RR in arms III, IV

Rajkumar SV et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

Induction trial: Not intended to test efficacy of long-term lenalidomide/dex

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E4A03: Selected Patient CharacteristicsE4A03: Selected Patient Characteristics

Characteristic LD (n=223) Ld (n=222)

ISS, %ISS, %

Stage IStage I

Stage IIStage II

Stage IIIStage III

33.033.0

41.341.3

25.725.7

33.333.3

41.441.4

25.325.3

Male, %Male, % 58.3 54.1

Age, yr (range)Age, yr (range) 66 (3666 (36––87)87) 65 (3565 (35––85)85)

ECOG PS ECOG PS ≤1, %≤1, % 91.0 90.5

Serum M protein (g/dL)Serum M protein (g/dL) 3.23.2 3.13.1

Durie-Salmon stage III, %Durie-Salmon stage III, % 79.379.3 75.275.2

MM bone disease, %MM bone disease, % 65.365.3 56.856.8

Patients eligible, nPatients eligible, n 195 188


L=Lenalidomide; D=Standard-dose dexamethasone; d=Low-dose dexamethasone

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E4A03: Serious AEs (E4A03: Serious AEs (≥3%)≥3%)Toxicity (≥Gr 3) LD, % (n=222) Ld, % (n=219) P Value*

HemoglobinHemoglobin 8.1 6.8 0.718

NeutrophilsNeutrophils 5.4 5.5 1.000

PlateletsPlatelets 11.7 18.7 0.047

DVT/PE 25% 9% <0.001

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% <0.001

Any non hem toxicity 65% 45% <0.001

Any toxicity (≥Gr 4) 19% 8% 0.001

Early Deaths (≤4 mo) 5% 0.5% 0.01


L=Lenalidomide; D=Standard-dose dexamethasone; d=Low-dose dexamethasone; *Fishers exact

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E4A03: E4A03: Causes of Death

LD (N=46), n Ld (N=25), 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

Median Follow up 21 mos


L=Lenalidomide; D=Standard-dose dexamethasone; d=Low-dose dexamethasone

22

Response ≤4 cycles Best Overall Response

2 1Res

po

nse

, %

24

8270 71

E4A03: E4A03: Response Data


L=Lenalidomide; D=Standard-dose dexamethasone; d=Low-dose dexamethasone; *Fishers exact

P=0.007 82 P=0.01

4225

4840

38

44

3029

0

20

40

60

80

100

LD (n=190) Ld (n=196) LD (n=190) Ld (n=196)

PR

VGPR

CR

23

E4A03 Interim Analysis: 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


No. of Subjects Event Censored Median (95% CL)

LDLd

223

222

22% (46)

11% (25)

79% (177)

89% (197)NA ( NA NA )NA ( 30.55 NA )

Time in Months

1

0.8

0.6

0.4

0.2

0

0 5 10 15 20 25

Pro

bab

ilit

y

P=0.0060*

LDLd

L=Lenalidomide; D=Standard-dose dexamethasone; d=Low-dose dexamethasone; *Log rank

24

E4A03 Interim Analysis: ConclusionsE4A03 Interim Analysis: Conclusions

► Lenalidomide plus standard-dose deaxamethasone (LD) Lenalidomide plus standard-dose deaxamethasone (LD) and lenalidomide plus low-dose dexamethasone (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


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[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-II

Stefan 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

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Tag

1 2 3 4 5 6 7 8 9 10 11 122 3 4 5 6 7 8 9 10 11 12

Lenalidomide, Doxorubicin, and Dexamethasone in Relapsed MM: Results of Phase I/II Trial

Dexamethasone 40 mg poDexamethasone 40 mg po

Lenalidomide poLenalidomide po

Doxorubicin 24-h cont IVDoxorubicin 24-h cont IV

q d2913 14 15 16 17 18 19 20 21

max

× 6

Dose Level Pt (n) Lenalidomide Doxorubicin Dexamethasone Pegfilgrastim

1 3 10 mg d1–21 4 mg/m2 d1–4 40 mg d1–4, d17–20

2 3 10 mg d1–21 6 mg/m2 d1–4 40 mg d1–4, d17–20

3 3 10 mg d1–21 9 mg/m2 d1–4 40 mg d1–4, d17–20

4 6 15 mg d1–21 9 mg/m2 d1–4 40 mg d1–4, d17–20

4-G 3 15 mg d1–21 9 mg/m2 d1–4 40 mg d1–4, d17–20 6 mg; d6

5-G 6 25 mg d1–21 9 mg/m2 d1–4 40 mg d1–4, d17–20 6 mg; d6

Knop S. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

27

Characteristic N = 69

Median age, yr (range) 63 (46–77)

Median no. of previous therapies (range) 2 (1–3)

Autologous transplantation, % 72

Allogeneic transplantation, % 12

Conventional therapy, % 16

Bortezomib, % 57

Thalidomide, % 20

Cytogenetic analysis: del(13); t(4;14); del(17p), %

46; 16; 19

RAD Trial in Relapsed MM: RAD Trial in Relapsed MM: Patient CharacteristicsPatient Characteristics


28

AE*, n

n=63

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

RAD Trial for Relapsed MM

Response Rate (n = 38; EBMT criteria)Response Rate (n = 38; EBMT criteria)

ORR = 89%ORR = 89%

Pat

ien

ts (

%)

*Grades according to NCI CTC


24

63

3 5 5

010203040506070

IF-CR nCR PR SD PD

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[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-Containing Regimens. Session Type: Oral Session

Antonio 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*

*A prospective randomized GIMENA phase III trial Palumbo A et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

Thalidomide regimens

VTD – TD – VMPT

Randomize

ASA WAR LMWH

Aspirin Warfarin Enoxaparin 100 mg/day 1.25 mg/day 40 mg/day

VMPVMP

No No prophylaxisprophylaxis

• VTD-TD (<65 yr): 9 wk before ASCTVTD-TD (<65 yr): 9 wk before ASCT

• VMPT (>65 yr): 6 moVMPT (>65 yr): 6 mo

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LMWH vs Warfarin vs ASA Prophylaxis For Thalidomide-Containing Regimens: Patient Characteristics

CharacteristicASA

(n=112)WAR

(n=120)LMWH(n=115)

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 8–11, 2007; Atlanta, GA

32

LMWH vs Warfarin vs ASA Prophylaxis For Thalidomide-Containing Regimens: VTE According to Risk Factors

Patients (%)Patients (%)

Palumbo A et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

0 1 2 3 4 5 6

ASA

WAR

LMWH

>2 risk factors 1 risk factor 0 risk factor

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-II

Paul 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

• 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

*Dex, 40 mg/day d1, 2, 4, 5, 8, 9, 11 and 12; 20 mg/day, cycles 5–8; Amended to 20mg/10mg cycles 1-4/5-8 based on safety data

Up to 8 21-D cycles*

1 2 4 5 8 9 11 12 14 21

Lenalidomide

Bz Bz Bz Bz

Dex Dex Dex Dex

Richardson PG et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

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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 5–8

► Phase I (Successive cohorts of 3–6 pts per dose level)– Dose escalation proceeded depending on occurrence of DLTs:

Gr ≥3 non-hematologic toxicity; Gr 4 thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; Gr 4 neutropenia for >5 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)

Bortezomib, Lenalidomide and Dexamethasone in Newly Diagnosed MM: Dose Escalation


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Phase l enrollment (N=33*) n

Dose level 1 3

Dose level 2 3

Dose level 3 4†

Dose level 4 6

Dose level 4M¶ 17†

Phase ll enrollment (N=20*¥)

*as of 12/1/07*as of 12/1/07

†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


Bortezomib, Lenalidomide and Dexamethasone in Newly Diagnosed MM:

Patient Disposition

► 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)

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Bortezomib, Lenalidomide and Dexamethasone in Newly Diagnosed MM: Patient Characteristics

Characteristic (N=53) Value

Median age, years (range) 58 (22-86)

Male, n (%) 27 (51)

Myeloma type, n (%)

IgG 36 (68)

IgA 14 (26)

light-chain 2 (4)

light-chain 1 (2)

ISS stage II/III at diagnosis, n (%) 26 (49)

Durie-Salmon stage III at diagnosis, n (%) 16 (30)


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Bortezomib, Lenalidomide and Dexamethasone in Newly Diagnosed MM: Most Common Grade 3/4 AEs

• Toxicities have been manageable– No unexpected toxicities have been seen; no Gr 3

PN– No treatment-related mortality

0 2 4 6 8

Anemia

Leukopenia

Lymphopenia

Neutropenia

Thrombocytopenia

Cardiac

Insomnia

Infection

Liver

Renal

Metabolic

Dizziness

Mental status

Neuropathic pain

Chest pain

Pneumonia

DVT G3

G4

Patient, n


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Bortezomib, Lenalidomide and Dexamethasone in Newly Diagnosed MM:

Response Data

EBMT/UC Response (N=42 evaluable as of 12/1/2007) n(%)

CR 9(21)

nCR 3(7)

VGPR 10(24)

PR 29(69)

≥PR 41(98)


► 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

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

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Transcript of 1 ANCO ASH Highlights 2007: Multiple Myeloma Joseph M. Tuscano, MD University of California, Davis.