Upload
tobit
View
44
Download
0
Tags:
Embed Size (px)
DESCRIPTION
Changing Landscape of Treatment for Multiple Myeloma. Ravi Vij MD Associate Professor Section of BMT and Leukemia Washington University School of Medicine, . 1989–1994. 1995–2000. 2001–2006. M. Trends in Overall Survival of MM. 1.0. Diagnosis period Median OS 1996–200645 months - PowerPoint PPT Presentation
Citation preview
Changing Landscape of Treatment for Multiple Myeloma
Ravi Vij MDAssociate Professor
Section of BMT and LeukemiaWashington University School of Medicine,
Trends in Overall Survival of MM
Overall survival 1971–2006 Diagnosis period Median OS1996–2006 45 months1971–1996 30 months
(P<0.001)
Kumar SK, et al. Blood. 2008;111:2516-2520. Time from diagnosis (Months)
Surv
ival
0
0.2
0.4
0.6
0.8
1.0
0 20 40 60 80 100 120 140
2001–2006
1995–2000
2001–2006
1989–1994
1983–1988
1977–1982
1971–1976
OS, overall survival.
3
M
Trends in 10-Year Relative Survival of MM
4
Period estimates of 10-year relative survival of patients with MM by major age groups in defined calendar periods from 1984-1986 to 2002-2004
*Relative survival reflects survival of patients with cancer compared with survival of the general population.
Brenner H, et al. Blood. 2008;111:2521-2526.
Calendar period
1984-1986
1987-1989
1990-1992
1993-1995
1996-1998
1999-2001
2002-2004
10-y
ear r
elati
ve su
rviv
al (%
)*
05
101520253035404550
15-49
50-59
60-69
70-79
80+
Age range
Survival Outcomes from Time Zero
0%
20%
40%
60%
80%
100%
0 12 24 36 48 60Months from Time Zero
Overall SurvivalEvent-Free Survival
Events / N173 / 291222 / 291
Medianin Months9 (7,11)5 (4,6)
Kumar S. EHA 2010
Overall and Event-Free Survival in Patients Relapsing and Refractory to Bortezomib and Thalidomide/Lenalidomide
Proteasome Inhibitors in MM
R/R: relapsed/refractoryNIH clinical trials. Available at: www.clinicaltrials.gov. Accessed February 2012.
Bortezomib
Carfilzomib
MLN9708 (oral)
CEP-18770
Marizomib
ONX 0912 (oral)
Phase I Phase II/IIb Phase Ib/II Ph IIIHeme Malig. R/R R/Rw/ Rd Newly
Diagnosed
Phase I/II
Phase I/II
Phase I
Phase I/II
Accelerated FDA approval R/R
Full FDA approval
R/R
FDA approval 1st-line
Optimization in combination with
other agents
2001 2003 2005 2007 2009 2011 2012
Differentiation of Proteasome Inhibitors
Compound Phase Compound Type
Main Enzymatic Site Specificity
Dissociation Kineticst ½ (min)
Route of admin.
Bortezomib Approved Peptide boronate
b5 110 IV
Carfilzomib III Peptide epoxyketone
b5 Irreversible IV
CEP-18770 I Peptide boronate
b5 Slowly reversible IV
MLN9708 I Peptide boronate
b5 18 IVOral
ONX 0912 I Peptide epoxyketone
b5 Irreversible Oral
NPI-0052 I b-lactone inhibitor
b1, b2, b5 Irreversible IV
Dick LR and Fleming PE. Drug Discov Today. 2010;15(5/6):243-249. Demo SD, et al. Cancer Res. 2007;67:6383-6391. Parlati F, et al. Blood. 2009;114(16):3439-3447. Miller CP, et al. Blood. 2007;110(1):267-277. Piva R, et al. Blood. 2008;111(5):2765-2775. Kupperman E, et al. Cancer Res. 2010;70(5):1970-1980. Chauhan D, et al. Blood. 2010;116(23):4906-4915.
b1: Caspase-like site; b2: Trypsin-like site; b5: Chymotrypsin-like site. NR, not reported.
Carfilzomib Monotherapy in Heavily Pre-Treated MM Patients, Phase IIb
Carfilzomib20 mg/m2 days 1, 2, 8, 9, 15,
16 every 28 daysN = 46
MM: Progressive disease> 2 prior therapy lines for relapsed
disease including bortezomib, thalidomide
or lenalidomide, an alkylating agent, or an anthracycline alone or
in combination
CarfilzomibDose escalation to 27 mg/m2
after cycle 1 up to 12 cyclesN = 266
003-A0003-A1
Siegel DS, et al. Blood. 2012;120(14):2817-25
Primary Endpoints: overall response rate (ORR; ≥ partial response)
Secondary Endpoints: clinical benefit response rate (≥ minimal response), duration of response (DOR), progression-free survival, overall survival (OS), and safety
Carfilzomib Monotherapy in Heavily Pre-Treated MM Patients, Phase IIb
Patient Baseline Characteristics N = 266
Median age 63 years (range, 37-87)
Median time since diagnosis 5.4 years (range, 0.5-22.3)
ECOG < 1 87%
Baseline grade 1/2 neuropathy 77%
Unfavorable Cytogenetic/FISH Prognostic Markers 28%
Median prior lines of therapy > 4 prior lines Median # anti-MM agents PD at study entry Refractory to last therapy Refractory or intolerant to bortezomib & lenalidomide
5 (range, 1-20)82%
13 (range, 3-45)100%95%80%
Siegel DS, et al. Blood. 2012;120(14):2817-25
*** 266 patients evaluable for safety & 257 evaluable for efficacy (9 patients excluded because of missing baseline and/or post-baseline disease assessment)
Carfilzomib Monotherapy in Heavily Pre-Treated MM, 003 Trial
N ORR % Median DOR
(month)
Median OS
(month)
Median PFS
(month)Response-Evaluable Patients 257 23.7% 7.8* 15.6 3.7
Bz + len-refractory 169 15.4% 7.8 11.9 NR
Bz + len refractory/intolerant 214 20.1 % 7.4 13.2 NR
ORR ≥ partial response * Calculated from 61 patients with partial response or betterBz, bortezomib; len, lenalidomide; imid, lenalidomide or thalidomide; mo, month; NR, not reported.
Siegel DS, et al. Blood. 2012 ;120(14):2817-25.
Unfavorable cytogenetics did not significantly impact response rates or DOR
Selected Adverse Events With Carfilzomib in Heavily Pre-Treated MM Patients
Adverse Event > Grade 3 N = 266
Hematologic: Anemia Thrombocytopenia Lymphopenia Neutropenia
24%29%20%11%
Non-hematologic: Fatigue Dyspnea Upper respiratory tract infection Headache
7.5%3.4%4.5%1.9%
Other: Febrile neutropenia Peripheral neuropathy*
0.8%1.1%
Siegel DS, et al. Blood. 2012 ;120(14):2817-25.
* Grouped PN all events of neuropathy, peripheral neuropathy, peripheral sensory neuropathy, & peripheral motor neuropathy
Carfilzomib in MM Patients Following 1-3 Prior Therapies
004, Phase II
1:1Carfilzomib
Cohort 120 mg/m2
(all treatment cycles)Relapsed / Refractory Multiple Myeloma1-3 Prior Therapies
N = 164 CarfilzomibCohort 2
20 mg/m2 (cycle 1)→27 mg/m2
Bortezomib-treated (n=35)
Bortezomib-naïve (n=59)
Bortezomib-naïve (n=70)
Bortezomib-naïve Bortezomib-treated
N 129 35Median age 65 years 63 yearsMedian # prior therapies 2 3
Carfilzomib: IV, days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles
Vij R, et al. Blood. 2012; 119(24):5661-70. Vij R, et al. Br J Haematol. 2012 Sep;158(6):739-48.
Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies
Bortezomib-Treated Cohort 1 (20 mg/m2 Carfilzomib)n = 35
ORR 17.1%CBR (> MR) 31.4%Median TTP 4.6 monthsMedian DOR † >10.6 monthsMedian PFS 4.6 months
Vij R, et al. Blood. 2012; 119(24):5661-70. Vij R, et al. Br J Haematol. 2012 Sep;158(6):739-48.
Bortezomib-naïve Cohort 1 (20 mg/m2)n = 59
Cohort 2 (20→27 mg/m2)n = 67
ORR (CR + VGPR + PR) 42.4% 52.2%CBR 59.3% 64.2%CR 3.4% 1.5%VGPR 13.6% 26.9%Median TTP 8.3 mo Not reachedMedian DOR* 13.1 mo Not reachedMedian PFS 8.2 mo Not reached†Precise estimate not determined since 4/6 patients with responses had DOR censored at study close* Calculated for ORR patients
Dose Escalation of Carfilzomib• CFZ 30-minute IV infusion on days 1, 2, 8, 9, 15, and 16 + DEX 8 mg
premedication (28-day cycle) – Cycle 1, day 1 and 2 20 mg/m2 followed by escalation to 56 mg/m2
• 78% BTZ-refractory; 21% prior alloHSCT• Results (N=34)
– ORR (completed 4 cycles or PD prior to 4 cycles): 58% (1 CR, 7 VGPR, 6 PR)– ORR (after 4 cycles): 57% (BTZ-refractory)– ORR (ITT): 50%– Median PFS: 4.6 months– Median OS: not reached (median follow-up 9.6 months)
• 35% patients required a dose reduction
Lendvai N, et al. Blood. 2012;120. Abstract 947.
Dose Escalation of Carfilzomib is Feasible
• CFZ 30-minute IV infusion on days 1, 2, 8, 9, 15, and 16 – Cycle 1 (Day 1/2) 20 mg/m2 → escalation to 45 or 56 mg/m2
• DEX 20 mg prior to CFZ on Days 1, 2, 8, 9, 15, and 16– DEX 40 mg administered on Day 22
• Median 4 lines treatment; 96% patients prior BTZ• Results (in patients completing at least 2 cycles); n=20
– ORR: 55% (VGPR: n=2; PR: n=9); SD: n=6; PD: n=3– Discontinued due to PD: N=7 (45 mg/m2)– Discontinued due to SAE: N=1 (56 mg/m2)
Badros AZ, et al. Blood. 2012;120. Abstract 4036.
MLN9708 and MarizomibAgent MTD N Response Toxicity Notes
MLN9708(2x weekly)
2.0 mg/m2 orally 46 13% ≥ PR2% CR2% MR61% SD
DLT: rash, nausea, vomitingCommon: thrombocytopenia, GI, rash, fatigue≥ Gr 3: vomiting, DVT, anemia, rash, thrombocytopeniaPN: 11% gr 1/2; 0% gr 3
MLN9708(1x weekly)
2.97 mg/m2 orally 32 6 % ≥ PR25% SD
Marizomib(NPI-0052)
0.4 mg/m2 IV over 60 min 0.5 mg/m2 IV over 120 min
21 15% ≥ MR55% SD
DLT: transient hallucinations, cognitive changes, loss of balance (all reversible)Common: headache, GI, insomnia, dizziness, dyspneaNo PN or myelosuppression
Richardson PG, et al. ASH Annual Meeting Abstracts. 2011;118(21):301. Berdeja JG, et al. ASH Annual Meeting Abstracts. 2011;118(21):479. Richardson PG, et al. ASH Annual Meeting Abstracts. 2011;118(21):302.
MTD, maximum tolerated dose; PR, partial response; CR, complete response; MR, marginal response; SD, stable disease; GI, gastrointestinal; Gr, grade; DVT, deep vein thrombosis; DLT, dose limiting toxicity; PN, peripheral neuropathy; min, minute.
Oprozomib (ONX 0912) Phase 1b Study Design
Phase 1b open-label dose escalation study
Oprozomib BID Days 1 – 5 of a 14 day cycle
Starting dose 60 mg BID (doses administered at least 4-6 hours apart)
Escalation in 30 mg increments
Hematologic malignancies3 + 3 dose-escalation schema
• Primary endpoint:• Safety and tolerability and to determine the maximum
tolerated dose• Secondary endpoints
• Pharmacokinetic and pharmacodynamic analyses
Savona MR, et al. Blood. 2012;120. Abstract 203. Confidential: For Internal Use Only
Lenalidomide15-25 mg/d
MyelosuppressionSkin rash
DVT
NNHO O
O
NH2
Structurally similar, but functionally different both qualitatively and quantitatively
NN
O
O
O
O
Thalidomide100-200 mg/d
NeuropathyConstipation
SedationDVT
Pomalidomide 1-4 mg/d
N
O
O
NH
O
O
N H 2
Pomalidomide
19
MM-002: Phase 2 Study Design• Primary endpoint: PFS• Secondary endpoints: ORR,1,2 safety, DOR, OS• Stratification factors: Age (≤75 vs >75 yrs), prior THAL, and 2 vs >2 prior treatments
Aspirin (80–100 mg) or equivalent was mandated for all patients* Patients aged > 75 years had a starting DEX dose of 20 mg/week.
Rand
omiza
tion
Option to add LoDEX*
(40 mg/week)Discontinue and
follow up for survival and subsequent treatment
Progressive disease
Progressive diseasePOM (4 mg days 1–21 of
28-day cycles) + LoDEX* (40 mg/week)
POM (4 mg days 1–21 of 28-day cycles)
DOR, duration of response; G-CSF, granulocyte colony-stimulating factor; LoDEX, low-dose dexamethasone; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; POM, pomalidomide; RBC, red blood cell; yrs, years.1. Bladé J, et al. Br J Haematol. 1998;102:1115-23; 2. Richardson PG, et al. N Engl J Med. 2003;348:2609-17.
Progressive disease
• Patients in both arms were heavily pretreated with a median of 5 prior therapies• Median number of cycles received was 5 (range 1-17)• Disease control (≥SD) was observed in 76% of overall patients
VariablePom Alone(n = 108)
Pom + LoDex(n = 113) Hazard Ratio
ORR (≥PR) (%) 9 30 -Median DOR (≥PR) , months Not reached 7.4 -≥MR 25 45 -
CR 0 1 -PR 9 29 -MR 16 15 -
SD 46 35 -PD 16 6 -Median time to ORR (≥PR), months 2.0 1.9 -Median PFS, months 2.5 3.8 HR=0.73 (P=0.037)Median OS, months 13.6 14.4 HR=0.85 (P=0.449)
Pomalidomide Alone or With Low-Dose Dexamethasone in RRMM
Efficacy
Responses assessed by IRAC review using EBMT criteria. ITT Population. Vij R, et al. ASCO 2012. Abstract 8016.
Discrepancies in totals are due to rounding.
Len refractory
(n = 87)BTZ refractory
(n = 82)
Len-BTZ refractory
(n=69)
Len-BTZ refractory +
prior transplant
(n=47)ORR (≥PR), % 25 29 28 34
≥MR 41 46 46 53CR 0 0 0 0PR 25 29 28 34MR 16 17 19 19
SD, % 40 33 35 28PD, % 7 7 7 6Time to ≥PR, mo 1.9 1.9 1.8 1.6Median DOR (≥PR), mo 7.0 5.8 6.2 5.7Median duration of MR only, mo 3.4 3.2 3.0 5.7OS 14.4 13.4 13.5 Not reached
Pomalidomide Alone or With Low-Dose Dexamethasone in RRMM
Efficacy in Refractory Patients
Vij R, et al. ASCO 2012. Abstract 8016.
Patients could be classified under more than one category. Discrepancies in totals are due to rounding.
Response to Pomalidomide + Low Dose Dexamethasone According to Age
≤ 65 yearsN=62
>65 yearsN=51
OverallN=113
≥PR, % 31 37 34≥MR, % 47 43 45Median duration of response, mo*
10.1 7.7 8.3
Median PFS, mo 4.7 3.7 4.6Median OS, mo 19.7 11.8 16.5
*For patients who achieved ≥PR.MR, minimal response; PR, partial response.
Jagannath S, et al. Blood. 2012; 120. Abstract 450 (oral presentation).
Confidential: For Internal Use Only
Mayo Clinic StudiesPomalidomide / Dexamethasone by Previous Therapy
Cohort N Pom (mg/day)
Prior therapies
ORR(%)
≥ MR(%)
DOR(mo)
PFS(mo)
OS(mo)
1: 1-3 prior therapies 60 2 2 (1-3) 65 67 21 13.0 40 mo
2: Len refractory 34 2 4 (1-14) 32 44 9 5.0 27 mo
3: Bor/len refractory 35 2 6 (3-9) 26 49 16 6.5 17 mo
4: Bor/len refractory 35 4 6 (2-11) 29 43 3 3.3 9 mo
5: Len refractory 1-3 prior therapies
60 4 2 (1-5) 38 57 N/A 7.9 N/A
Lacy MQ, et al. ASH Annual Meeting Abstracts. 2011;118(21):3963.
ORR, overall response rate; MR, marginal response; DOR, duration of response; PFS, progression-free survival; OS, overall survival; len, lenalidomide; bor, bortezomib; Pom, pomalidomide; mo, month; N/A, not applicable.
Pomalidomide / Dexamethasone: Administration Schedule
21 / 28n = 43
28 / 28n = 41
TotalN = 84
ORR 35% 34% 34.5%Stable Disease 44% 51% 48%Median time to 1st response 2.7 mo 1.1 mo 1.8 moMedian DOR 10.5 mo 7.2 mo 8.1 mo≥ 1 yr in responders 47.5% 36% 37.5%
Leleu X. et al. ASH Annual Meeting Abstracts. 2011;118(21):812.
MM, multiple myeloma; 21/28, 21 days of 4 mg pomalidomide on a 28-day cycle; 28/28, 28 days of 4 mg pomalidomide on a 28-day cycle; ORR, overall response rate; DOR, duration of response.
Pomalidomide plus Low Dose Dex vs. High Dose Dex
• Primary endpoint: PFS• Secondary endpoints: safety, OS, ORR (≥PR), DoR, TTP, QoL
Continue treatment until PD or unacceptable toxicity
Arm B: High dose DEX (n=153)Dexamethasone: 40 mg, D 1-4, 9-12,
and 17-2028-day cycles
Arm A: POM – loDEX (n=302)Pomalidomide 4mg/day D1-21
Dexamethasone: 40 mg, D1, 8,15,2228-day cycles
Randomization (N=455) 2:1
Primary refractory or relapsed and refractory MMPD during treatment or within 60 days of last MM treatment
(including ≥ cycles LEN or BTZ)
Dimopoulos M, et al. Blood. 2012;120. Abstract LBA-6.
Patients were stratified by age (≤ 75 vs > 75 years), disease population (refractory vs refractory and relapsed vs refractory and intolerant [intolerant to BTZ only]), and number of prior therapies (2 vs > 2).
Pomalidomide + Low Dose Dex vs. High Dose Dex
• Patient population– Median number of prior therapies: 5 (range, 1-17)– Refractory to both LEN and BTZ: 72%
• Treatment results
Characteristic Arm APOM+loDEX
Arm BHigh DEX
Treatment duration (median), wks 12.4 8
Remain on study, % 45 25
Deceased, % 25 38
Dimopoulos M, et al. Blood. 2012;120. Abstract LBA-6.
Pomalidomide + Low Dose Dex vs. High Dose Dex
• EfficacyCharacteristic Arm A
POM+loDEXArm B
High DEXProgression-free survival, wks 15.7 8*
Overall survival, wks Not reached 34*
*P<.001 SafetyCharacteristic, % Arm A
POM+loDEXArm B
High DEXNeutropenia 42 15Thrombocytopenia 21 24Febrile neutropenia 7 0Infection 24 231% of patients in each group developed neuropathy (Grade 3/4); 1% Arm A developed VTE.
Dimopoulos M, et al. Blood. 2012;120. Abstract LBA-6.
Immunomodulatory AgentsImmunomodulatory
Tumor micro-environment
CEREBLON BINDING
↓IRF-4
Direct anti-tumor effects
T cell co-stimulation
Treg suppression
Th1 cytokine NK and NKT cell
activation
ADCC
Induce p21, p27, & p15
cell cycle arrest
Alterations in (ERG)-1,2 3 and SPARC
↓ NFkB
Inhibit caspase 3,8,9
Anti-angiogenesis
Anti-inflammatory
↓ adhesion molecules
Anti-osteoclastogenic
Tai YT, et al. Cancer Res. 2005;65(13):5898-5906. Hideshima T, et al. Clin Cancer Res. 2005;11(24 Pt 1):8530-8533. Catley L, et al. Blood. 2006;108(10):3441-3449.
Blockade of Ubiquitinated Protein Catabolism with HDAC inhibitors
HDAC6
HDAC6
HDAC6
Protein
Protein aggregates(toxic)
Ub
26S Proteasome
Ub Ub
Ub
Aggresome
TubacinLBH, vorinostat
Dynein
Dynein
MicrotubuleAutophagy
Bortezomib
Ub Ub
Ub
Lysosome
Ub
Ub
Ub
Ub
UbUb
Ub
Ub Ub
Vorinostat / BortezomibVANTAGE 088, Phase III
Bortezomib + Placebo
Bortezomib + VorinostatMultiple Myeloma
1-3 Prior TherapiesN = 637
R
Bortezomib + Vorinostat
Bortezomib + Placebo
P
ORR 56% 41% < 0.0001CBR 71% 54% < 0.0001Median PFS 7.63 mo 6.83 mo < 0.01Median OS NR 28.1 mo 0.35
Dimopoulos MA, et al. ASH Annual Meeting Abstracts. 2011;118(21):811.
ORR, overall response rate; CBR, clinical benefit rate; PFS, progression-free survival; OS, overall survival.
PANORAMA 2 Study DesignPhase II, Simon 2-stage study in BTZ-refractory MM
a Response measured according to modified European Group for Blood and Marrow Transplantation 1998 criteria.CR, complete response; nCR, near CR; DOR, duration of response; OS, overall survival; PD, disease progression; PFS, progression-free survival; PR, partial response; TTP, time to progression; TTR, time to response.
• Adult pts• Relapsed and
BTZ-refractory MM• ≥ 2 prior lines of
therapy• Exposed to IMiDs
Panobinostat
BTZ
Dexamethasone
Panobinostat
BTZ
Dexamethasone
ScreeningTreatment Phase 1
Eight 3-wk cyclesTreatment Phase 26-wk cycles until PD
After 8 cycles, continuation into treatment phase 2 in pts with clinical benefit
Primary endpoint: overall response rate (CR + nCR + PR)a
Key secondary endpoints: PFS, TTP, OS, MR, TTR, DOR
Alsina et al. ASCO 2012. ABSTRACT 8012.
Preliminary Response Data Activity in BTZ-refractory MM patients
Best confirmed response (confirmed at 6 wks) N = 55Overall response (CR + nCR + PR), n (%) 17 (31)
Complete response –
Near complete response 1 (2)
Partial response 16 (29)
Clinical benefit (CR + nCR + PR + MR), n (%)1-3 28 (51)
Minimal response 11 (20)
• VGPR observed in 3 pts• Responses were typically observed after 1 to 2 cycles• Stable disease observed in 3 pts, progressive disease in 18 pts;
3 pts not evaluable, 3 pts with unconfirmed response 1. Anderson KC, et al. Leukemia. 2008;22:231-239. 2. Richardson PG, et al. Br J Haematol. 2009;144:895-903. 3. Niesvizky R, et al. Br J Haematol. 2009;143:46-53.
Alsina et al. ASCO 2012. ABSTRACT 8012.
Current Phase III PANORAMA I
Placebo Bortezomib
Dexamethasone
PanobinostatBortezomib
Dexamethasone
Relapsed or Refractory MM
R
National Institutes of Health. Available at: www.clinicaltrials.gov. Accessed March 2011.
Clinical trial ID: NCT01023308
Trial has met accrual goals
Perifosine / Bortezomib / DexN = 73
CR 4%PR 13%MR 19%SD 41%Median PFS 6.4 monthsMedian OS 25 months
MM, multiple myeloma; CR, complete response; PR, partial response; MR, marginal response; SD, stable disease; PFS, progression-free survival; OS, overall survival; dex, dexamethasone.
AKT InhibitorsPerifosine, Bortezomib, and Dexamethasone
Richardson PG, et al. ASH Annual Meeting Abstracts. 2011;118(21):815.
Common grade 1/2 AE• Nausea, diarrhea, fatigue and musculoskeletal pain, upper respiratory infection, anorexia,
constipationGrade 3/4 AE• Thrombocytopenia (23%), neutropenia (15%), anemia (14%), pneumonia (12%), musculoskeletal pain
(11%), bleeding (10%)
MONOCLONAL ANTIBODIES
• CS1 is highly and uniformly expressed on MM cells– Restricted expression on NK cells– Little to no expression on normal tissues
• In an MM xenograft mouse model lenalidomide enhanced the anti-tumor effect of elotuzumab
Elotuzumab: Anti-CS1
Hsi ED, et al. Clin Cancer Res. 2008;14(9):2775-2784. Tai YT, et al. Blood. 2008;112(4):1329-1337. van Rhee F, et al. Mol Cancer Ther. 2009;8(9):2616-2624. Lonial S, et al. Blood. 2009;114. Abstract 432.
MM, multiple myeloma; NK, natural killer.
Elotuzumab, Lenalidomide, and Dexamethasone in RR Lenalidomide-naïve MM
RRMMPhase 2
(1 – 3 prior therapies)
Elotuzumab (10 mg)Lenalidomide
Dexamethasone
Elotuzumab (20 mg)Lenalidomide
Dexamethasone
Elotuzumab:10 or 20 mg/kg IV, d1, 8, 15, 22 cycles 1-2; d1, 15 for subsequent cyclesLenalidomide: 25 mg, daily, days 1-21Dexamethasone: 40 mg, weekly.Premedication Regimen: 30-60 minutes prior to each elotuzumab infusionMethylprednisolone 50 mg IV or dexamethasone 8 mg IV, diphenhydramine 25-50 mg PO or IV (or equivalent), ranitidine 50 mg IV (or equivalent), acetaminophen 650-1000 mg PO
Richardson P, et al. Blood. 2012;120. Abstract 202.Moreau P, et al. J Clin Oncol. 2012;30. Abstract 8020.
Best Response (IMWG Criteria)
Elotuzumab 10 mg/kg
n = 36
Elotuzumab 20 mg/kg
n = 37
TotalN = 73
ORR (≥ PR)1 92% 76% 84%
CR / stringent CR2 14% 11% 12%
VGPR2 47% 35% 41%
Median PFS1 26.9 mo 18.6 mo 25 mo
CR, complete response; IMWG, International Myeloma Working Group; ORR, objective response rate; PFS, progression-free survival; PR, partial response; VGPR, very good partial response; len / dex, lenalidomide and dexamethasone.
Historical Controls N ORR to len / dex* CR to len / dex
MM009, Weber et al.3 177 61% 14%
MM010, Dimopoulos et al.4 106 60% 16%*High-dose dex.
1. Richardson P, et al. Blood. 2012;120. Abstract 202 (oral presentation). 2. Moreau P, et al. J Clin Oncol. 2012;30 (15 suppl):8020. 3. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 4. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132.
Elotuzumab, Lenalidomide, Dex in RR Lenalidomide-naïve MM
Confidential: For Internal Use Only
Siltuximab + BTZ vs BTZ Alone in Relapsed/Refractory MM
• Siltuximab: chimeric IgG1k anti–human IL-6 antibody– High affinity, half-life ≈ 3 wks– Tolerability: no DLT up to ≥ 15 mg/kg• Study design: phase II, randomized, double-blind, placebo-controlled– Patients:1-3 previous lines of therapy; no previous BTZ– Treatment
– BTZ 1.3 mg/m2, 8 x 42-day cycles on Days 1, 4, 8, 11, 22, 25, 29, 32 followed by maintenance, 4 x 35-day cycles on Days 1, 8, 15, 22
– Placebo or siltuximab 6 mg/kg every 2 wks– Patients progressing had option to end BTZ and start DEX 40 mg on Days 1-4, 9-
12, 17-20 and maintenance therapy at 40 mg on Days 1-4
Orlowski R, et al. ASCO 2012. Abstract 8018.
Siltuximab + BTZ Efficacy
• Nonsignificant trend toward improved ORR with siltuximab
• Nonsignificant, marginal effect on overall PFS• Regional differences in PFS noted
– Significant increase in NA and WE (P = .01) vs no effect for rest of world
– Patients outside of NA and WE less often pretreated, which was thought to obviate benefit of adding siltuximab
• Siltuximab continues to be developed for frontline therapy
Orlowski R, et al. ASCO 2012. Abstract 8018.
Daratumumab: Phase I/II Study in Relapsed/Refractory MM
• Daratumumab: anti-CD38 antibody; kills MM cells via ADCC, CDC, and induction of apoptosis
• Patients: relapsed/refractory MM (≥ 2 different therapies), not eligible for ASCT; 3 patients/dosing group
• Efficacy based on serum and/or urine M-component analyses
• At the highest dose (4 mg/kg), patients had a 49%, 55%, and 64% reduction in serum M-component and a 80%, 89%, and 97% reduction in plasma cells
• Adverse events were manageable
Plesner T, et al. ASCO 2012. Abstract 8019.
Targeting Myeloma Cells in the Bone Marrow Microenvironment
Bone marrow
Targeting MM cell
stromal cells
Targeting bone marrow milieu
Proteosome Inhibitors (CEP 18770, NPI 0052, MLN 2238)
Other targetsFGFR3IGF-1Hsp-90DACPI-3-Akt-Mtor,bcl-2CDKIKK /p38MAPKAurora kinasesMetHGF
Monoclonal antibodies( CD 138,CD40, CD56,1L-6, TRAIL-R)
•Massively parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs.
•Mutation of :
• genes involved in protein translation (seen in nearly half of the patients), • genes involved in histone methylation, • genes involved in blood coagulation.• in 11 members of the NF-kB pathway• kinase BRAF in 4%of patients,
4 M A R C H 2 0 1 1 | VO L 4 7 1 | N AT U R E | 4 6 7
Key Genetic Changes
Whole-genome sequencing of multiple myeloma from diagnosis to plasma cellleukemia reveals genomic initiating events, evolution, and clonal tides
Egan et al Blood. 2012;120(5):1060-1066)
Clonal competition with alternating dominance in multiple myeloma
( Keats et al. Blood. 2012;120(5):1067-1076)
47
The Goal: CureTu
mor
Vol
ume
→
Time →
Ineffective treatment
High-Dose Therapy
Alkylators
Dexamethasone
Goal of newertherapy options
Limit ofdetection