1 anco ash highlights 2007: multiple myeloma joseph m. tuscano, md university of california, davis
TRANSCRIPT
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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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VTD vs TD for SCT Induction
Newly Diagnosed
Cavo M, et al. ASH 2007, abstract #73
► 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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VTD vs TD for SCT Induction
Newly Diagnosed
Cavo M, et al. ASH 2007, abstract #73
►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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VTD vs TD for SCT Induction
Newly Diagnosed
Cavo M, et al. ASH 2007, abstract #73
►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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VTD vs TD for SCT Induction
Newly Diagnosed
Cavo M, et al. ASH 2007, abstract #73
► 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
San Miguel J, et al. ASH 2007, abstract #76
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
San Miguel J, et al. ASH 2007, abstract #76
INDEX
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VMP vs MP
Newly Diagnosed
San Miguel J, et al. ASH 2007, abstract #76
►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
San Miguel J, et al. ASH 2007, abstract #76
►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
San Miguel J, et al. ASH 2007, abstract #76
► 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
San Miguel J, et al. ASH 2007, abstract #76
► 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
Rajkumar SV et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
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
Rajkumar SV et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
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
Rajkumar SV et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
L=Lenalidomide; D=Standard-dose dexamethasone; d=Low-dose dexamethasone
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Response ≤4 cycles Best Overall Response
2 1Res
po
nse
, %
24
8270 71
E4A03: E4A03: Response Data
Rajkumar SV et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
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
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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
Rajkumar SV et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
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
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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
Rajkumar SV et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
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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
26
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
Knop S. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
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
Knop S. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
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
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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
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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
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[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
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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
Richardson PG et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
36
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
Richardson PG et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
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)
Richardson PG et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
38
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
Richardson PG et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
39
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)
Richardson PG et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA
► 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