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Multiple Myeloma: Treatment Updates Andy Kurtzweil, PharmD, BCOP Pharmacy Clinical Team Leader, Hem/Onc/BMT University of Minnesota Medical Center, Fairview Los Angeles, CA/ March 23, 2013 Heimberg J, et al. N Engl J Med. 1999;102:365-78
Treatment Evolution
Objectives
Cure?? Treatment Options
• Choose appropriate initial and salvage therapies for multiple myeloma (MM) based on patient characteristics. • Examine the role of transplantation in the treatment of patients with MM. • Analyze the use of maintenance therapy posttransplant in MM. • Describe the pharmacology, efficacy (place in therapy), and safety of newer agents used to treat MM.
Improved OS
Palliation Auto SCT Chemo VAD
Steroids Radiation Melphalan 1950s1960s 5-year Survival
1970s1980s 1975-77: 25%
Thalidomide Tandem SCT AlloSCT
Lenalidomide Bortezomib Combo Txs Thal Maint
Combos & Sequencing Risk Stratify Maintenance Carfilzomib
PI: Proteosome Inhibitors IMiDs: Immunomodulatory Drugs SCT: Stem Cell Transplant, Thal: Thalidomide VAD: Vincristine, Doxorubicin, Dexamethasone
1990s
2000s
1987-89: 28%
2010s 2001-07: 41%*
2010+ 2010+: ??%
Laubach JP, et al. Med Oncol. 2010; 27:S1-S6 Siegel R, et al. CA Cancer J Clin. 2012;62:10-29.
Initial Treatment
New IMiDs New PIs Elotuzumab New Combos & Sequencing Role of Transplant New Targets?
*P<0.05 vs 1975-77.
Identifying Risk • Staging
• Goals of treatment
Durie-Salmon (DS)
– Control disease & related complications – Minimize side effects – Minimize early mortality rate – Allow for collection of stem cells
• Cure versus Control • Considerations – Eligible for transplant – Stage of disease – Genetic risk factors Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Rajkumar SV, et al. Am J Hematol. 2012; 87:79-88
International Staging System (ISS)
Stage I
Hgb > 10 g/dL Normal serum calcium Normal bone x-ray or solitary bone plasmacytoma only Low M-protein production
B2M <3.5 mg/L Albumin ≥ 3.5 g/dL -Median OS: 62 months
Stage II
Not stage I or III
Not stage I or III -Median OS: 45 months
Stage III Hgb <8.5 g/dL
B2M ≥ 5.5 mg/L -Median OS: 29 months
Serum calcium > 12 mg/dL Bone lesions present High M-protein production
• Genetics & cell proliferation Risk Stratification
B2M = Beta-2 Microglobin
– Hyper- or Hypodiploid – Chromosome abnormalities Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Durie BGM, et al. Cancer. 1975;36:842-54.
Greipp P, et al. J Clin Oncol; 2005;23:3412-20.
Chromosomal Abnormalities
Risk Stratification
• Patients enrolled in ECOG E9486 & E9487 • Treatment with conventional chemo • Outcomes vs cytogenetic abnormalities Genetic Abnormality
Median OS (Months) With
Without
Pvalue
12.7%
26
45
<0.001
4.6%
16
41
0.003
336
15.8%
50
39
Del 17p
345
10.7%
23
Δ13
325
54.2%
35
N
% with
t(4;14)
332
t(14;16)
323
t(11;14)
Median PFS (Months) Without
Pvalue
17
31
<0.001
9
30
0.003
0.332
33
27
0.590
44
0.005
17
30
0.051
51
0.028
25
33
0.030
With
Risk Group
Comments
High Risk -Deletion 17p (p53) -t(14;16) -t(14;20) -GEP High Risk signature
GEP not yet standardized
Intermediate Risk -Chromosome 13 or 13q deletion -t(4;14)* -PCLI > 3%
*Worse prognosis with high B2M & anemia
Standard Risk -t(11;14) -t(6;14) -Hyperdiploid -All Others
Prognosis worsens if LDH >ULN & β-2 >5.5 for all standard risk patients Hyperdiploid = trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19, or 21 GEP = gene expression profiling PCLI = plasma cell labeling index
Fonseca R, et al. Blood. 2003;101:4569-75.
ECOG=Eastern Cooperative Oncology Group
ULN = upper limit of normal Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Munshi NC, et al. Blood. 2011;117:4696-4700. Adopted from: mSMART 2.0: Classification of Active MM. Retreived 9/30/12 from www.msmart.org.
Transplant Eligible - Induction
Transplant Eligible - Induction
Regimen
Treatment Schedule
Cycle Length
Regimen
Treatment Schedule
Cycle Length
Rd
R= Lenalidomide 25 mg PO days 1-21 d= Dexamethasone 40 mg PO days 1, 8, 15, 22
28 days
VTD
21 days
RD
R= Lenalidomide 25 mg PO days 1-21 D= Dexamethasone 40 mg PO days 1-4, 9-12, 17-20
28 days
V= Bortezomib 1.3 mg/m2 IV days 1, 4, 8, & 11 T = Thalidomide 50-200mg PO days 1-21 D= Dexamethasone 40 mg PO days 1, 2, 4, 5, 8, 9, 11, & 12 or days 1-4 and 9-12
TD
T = Thalidomide 50-200 mg PO days 1-28 D= Dexamethasone 40 mg PO days 1-4, 9-12, 17-20
28 days
VRd
21 days
BD
B= Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11 D= Dexamethasone 40 mg PO days 1-4 (all cycles) & 9-12 (cycles 1 & 2 only)
21 days
V= Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11 R= Lenalidomide 25 mg PO days 1-14 d= Dexamethasone 20 mg PO days 1, 2, 4, 5, 8, 9, 11, & 12 or 40 mg PO days 1, 8, & 15
VDC (CyBorD)
V= Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11 D= Dexamethasone 40 mg PO days 1-4, 9-12, & 17-20 or 40 mg PO days 1, 8, & 15 (every 21 days) C= Cyclophosphamide 300 mg/m2 PO days 1, 8, 15, & 22 or 500 mg/m2 PO days 1, 8, & 15 (every 21 days)
21-28 days
DVd
D= Liposomal Doxorubicin 40 mg/m2 IV day 1 V= Vincristine 1.4 mg/m2 IV day 1 d= Dexamethasone 40 mg PO days 1-4
28 days
mg/m2
PAD
P= Bortezomib 1.3 IV days 1, 4, 8, & 11 A= Doxorubicin 9 mg/m2 IV days 1-4 D= Dexamethasone 40 mg PO days 1-4, 9-12, & 17-20
28 days
VAD
V= Vincristine 0.4 mg IV days 1-4 A= Doxorubicin 9 mg/m2 IV days 1-4 D= Dexamethasone 40 mg PO days 1-4, 9-12, & 17-20
28 days
Rajkumar SV, et al. Am J Hematol. 2012;87:79-88.
Rajkumar SV, et al. Am J Hematol. 2012;87:79-88.
IMiDs Front Line
Thalidomide vs Lenalidomide
• TD or RD vs Dex Alone – Addition of IMiDs improve RRs – Dex alone is only a short-term treatment option
• RD vs Rd – Open label randomized trial, newly diagnosed (n=445) – Results • CR or PR: 79% vs 68% (p=0.008) • OS at 1-year: 87% vs 96% (p=0.0002) • OS at 1-year (age ≥65): 83% vs 94% (p=0.004)
– TD (n=183) vs RD (n=223) • PR or better: 61.2% vs 80.3% (p<0.001) • TTP: 17.2 mo vs 27.4 mo (p=0.019) • OS: 57.2 mo vs not reached (P=0.018)
– Toxicity (grade ≥3) • Lenalidomide – neutropenia • Thalidomide – VTE & peripheral neuropathy
– Toxicity • Grade ≥3 DVT: 26% vs 12% (p=0.0003) • Infection & fatigue increased in HD group • Risk of serious AEs greatest in patient > 65 years in HD group
– Rd is an effective option, especially elderly patients Zonder JA, et al. Blood. 2007;110:Abstract77. Rajkumar S, et a. J Clin Oncol. 2006;24:431-436 Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.
• Mayo Clinic retrospective analysis:
Dex =Dexamethasone HD=High dose
• Lenalidomide & stem cell collection – Increased risk of inadequate stem cell collection – Highest risk if given >3-6 cycles or age >65 years Gay F, et al. Blood. 2010;115:1343-50. Kumar S, et al. Blood. 2009;114:1729-35.
JB is a 60 yo male with MM that will be starting treatment with lenalidomide + dexamethasone. His physician asks you what should JB expect from treatment with Rd as compared to treatment with RD?
A. Higher response rate B. Improved survival C. Increase risk of thromboembolism D. More toxicity in patients >65 yo E. No difference in survival for patient >65 yo
IFM 2005-01: BD vs VAD Randomization
Arm A1
Induction
Arm B1
Arm B2
VAD x 4 cycles (n=121)
VAD x 4 cycles (n=121)
BD x 4 cycles (n=121)
BD x 4 cycles (n=119)
None
DCEP x 2 cycles (n=108)
None
DCEP x 2 cycles (n=111)
Consolidation
Autologous Stem Cell Transplant (ASCT)
Arm A2
Total A1+A2 (n=218) Received ASCT (n=184) Did not receive ASCT (n=34)
Total B1+B2 (n=223) Received ASCT (n=197) Did not receive ASCT (n=26)
DCEP = Dexamethasone, Cyclophosphamide, Etoposide, & Cisplatin
Harousseau JL, et al. J Clin Oncol. 2010;28:4621-29.
IFM 2005-01 Results
HOVON-65/GMMG-HD4
Response to Induction Therapy 90%
• Randomized, open-label phase III trial • Newly diagnosed, DS stage II-III myeloma • Median PFS
80% 70% 60% 50% 40%
VAD
30%
BD
20% 10% 0% ORR
≥VGPR
≥VGPR [del (13)]
– VAD: 28 mo – PAD: 35 mo
≥VGPR ≥VGPR [t(4;14) or del(17p)] [B2M >3 mg/L and del(13)]
• Median follow-up: 32.2 months • PFS (VAD vs BD): 29.7 months vs 36 months (p=0.064) • Toxicity – VAD: Hematologic toxicity & deaths – BD: Peripheral neuropathy
Arm B
Induction: VAD x3 cycles n=414
Induction: PAD x3 cycles n=413
Melphalan 200 mg/m2 + ASCT x 1 or 2 P=0.002
• OS at 5-years – VAD: 55% – PAD: 61%
Arm A
P=0.07
Maintenance: Thal 50 mg PO Daily x 2 years
Maintenance: Bortezomib 1.3 mg/m2 IV Q2 wks x 2 yrs
• BD should be considered a standard induction regimen NS=not significant VGPR=very good partial response
Harousseau JL, et al. J Clin Oncol. 2010;28:4621-29.
Sonneveld P, et al. J Clin Oncol. 2012;30:2946-55.
Results
TD vs VTD
Response Rates
100%
• Phase III, randomized, open-label study – Induction: TD (n=239) vs VTD (n=241) – Plus double ASCT & consolidation x2 cycles
80% 60% VAD
40%
PAD
• Results after induction (TD vs VTD) – Response ≥nCR: 11% vs 31% (p<0.0001) – Response ≥PR: 79% vs 93% (p<0.0001)
20% 0% ≥VGPR After induction
≥VGPR Overall
≥VGPR ISS stage III
≥VGPR [β2-M >3]
≥VGPR [del (13)]
≥VGPR [t(4;14)]
≥VGPR [del(17p)]
• PAD improved PFS (p=0.004) & OS (p<0.001) when SCr > 2 mg/dL • VAD vs PAD – PN ≥ grade 2: 18% vs 40% (p<0.001) – GI symptoms ≥ grade 3: 7% vs 11% (p<0.05) – Thrombocytopenia ≥ grade 3: 5% vs 10% (p<0.01)
• Bortezomib improves RR, PFS, & OS during induction therapy (including high risk patients)
• Toxicity – Grade 3/4 AEs: 33% vs 56% (p<0.0001) – Grade 3/4 PN: 2% vs 10% (p<0.0001) – Discontinuation due to toxic effects: 4% vs 3%
• VTD should be considered a standard induction regimen Cavo M, et al. Lancet. 2010;376:2075-85.
Sonneveld P, et al. J Clin Oncol. 2012;30:2946-55.
PN=Peripheral neuropathy
nCR=near CR; AE=adverse events
Bortezomib/Lenalidomide/Dex
EVOLUTION
• Phase 1/2 study VRd, newly diagnosed • Treatment – Eight 3 week cycles – ASCT after 4 cycles if ≥PR
• Results – – – –
Best Response to Treatment 100% 80%
Medium follow-up: 21 mo PFS (18 mo): 75% Gr 3 PN: 2% Gr 3/4 neutropenia: 9%
• VRd is highly effective with tolerable side effect profile
60% 40% 20% 0% ORR
≥VGPR
≥VGPR [del (13)]
Richardson PG, et al. Blood. 2010;116:679-86.
≥VGPR [t(4;14) or del(17p)]
Gr = grade
• Phase II trial in untreated MM • Primary endpoint: rate of CR+PR • Treatment arms (eight 3 week cycles) – VDCR (R=15 mg), n=48 V=Bortezomib 1.3 mg/m2, days 1,4,8,11 D or d =Dexamethasone 40mg, days 1,8,15 – VRd (R=25 mg), n=42 C=Cyclophosphamide 500mg/m2, days 1,8 – VDC, n=33 -mod= additional day 15 cyclophosphamide R=Lenalidomide day 1-14 – VDC-mod, n=17 • Maintenance (four 6 week cycles) – Bortezomib 1.3 mg/m2 day 1,8,15,22 Kumar S, et al. Blood. 2012;119:4375-82.
EVOLUTION Results Treatment Response VDCR
VRd
VDC
Weekly Bortezomib with VDC (CyBorD)
Toxicity (≥ grade 3) VDCmod
ORR at cycle 4
80%
73%
63%
82%
ORR (overall)
88%
85%
75%
100%
≥VGPR at cycle 4
33%
32%
13%
41%
≥VGPR (overall)
58%
51%
41%
53%
Phase II study, newly diagnosed MM
VDCR
VRd
VDC
VDCmod
Neutropenia
44%
10%
30%
24%
Cyclophosphamide
300 mg/m2 PO Days 1, 8, 15, 22
Same as cohort 1
Thrombocytopenia
15%
12%
12%
0%
Dexamethasone
40 mg PO Days 1-4, 9-12, & 17-20
Cycle 1 & 2: same as cohort 1 Cycles 3+: 40mg PO Days 1, 8, 15, 22
Bortezomib
1.3 mg/m2 IV Days 1, 4, 8, 11
1.5 mg/m2 IV Days 1, 8, 15, 22
Anemia
8%
Neuropathy
13%
17%
9%
Fatigue
17%
7%
3%
0%
At least 1 AE
83%
76%
79%
88%
7%
0%
12%
Cohort 1
Administered every 28 days x 4 cycles, followed by transplant or continuation of treatment.
18%
• High rates of neuropathy in all arms • No efficacy advantage for 4 drug regimen • VRd & VDC-mod have good activity, tolerable side effect profile, & both would be good treatment options Kumar S, et al. Blood. 2012;119:4375-82.
AE=adverse event.
Response Rates ORR: 88% vs 93% CR/nCR: 39% vs 43% ≥VGPR: 61% vs 60% (no statistical analysis reported)
• Non-inferiority trial comparing DVd to VAd • Goal: compare pegylated liposomal doxorubicin to conventional doxorubicin • Patients: previously untreated age 37-84 years (n=192) • Results PFS & OS: no significant difference Neutropenia (Gr ≥3): 10.3% vs 24.2% (p=0.02) Alopecia: 20% vs 44% (p<0.0001) Hand-foot syndrome (Gr ≥3): 4.1% vs 0%
• DVd vs VAd – similar efficacy, less toxic, more convenient dosing Rifkin RM, et al. Cancer. 2006;106:848-58.
VAd= VAD with dexamethasone on days 1-4 only.
Toxicity Gr ≥ 3 PN: 6% vs 0% Any Grade PN: 64% vs 57% Gr ≥ 3 Thrombocytopenia: 21% vs 0% Bortezomib dose reduced: 21% vs 13%
-Weekly Bortezomib maintains efficacy while reducing Gr ≥ 3 PN Reeder CB, et al. Leukemia. 2009;23:1337-41. Reeder CB, et al. Blood. 2010;22:3416-17
Liposomal Doxorubicin
– – – –
Cohort 2
Transplant Ineligible - Induction Regimen
Treatment Schedule
Cycle Length
MPT
M= Melphalan 0.2-0.25 mg/kg PO x 4-5 days OR 4 mg/m2 PO x 7 days P= Prednisone 1-2 mg/kg PO x 4-5 days OR 40 mg/m2 x 7 days T= Thalidomide 100-400 mg PO daily
28-42 days
MPR
M= Melphalan 0.18 mg/kg PO days 1-4 P= Prednisone 2 mg/kg PO days 1-4 R= Lenalidomide 10 mg PO days 1-21
28 days
MPB
M= Melphalan 9 mg/m2 PO days 1-4 P= Prednisone 60 mg/m2 PO days 1-4 B= Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11, 22, 25, 29, & 32 (cycles 1-4) & days 1, 8, 22, & 29 (cycles 5-9)
42 days
Rd
See transplant eligible induction regimen table
VD
See transplant eligible induction regimen table
DVD
See transplant eligible induction regimen table
VAD
See transplant eligible induction regimen table
Rajkumar SV, et al. Am J Hematol. 2012;87:79-88.
MP vs MPT
Results
• No clear survival advantage in individual studies of MPT • Meta-analysis of 5 RCTs – MP (n=819) vs MPT (n=752) – Accrual periods: 5/2000 – 7/2007 – Patients
• Efficacy – HR for OS: 0.8 (P=0.07; 95% CI: 0.63-1.02) – HR for PFS: 0.68 (P<0.001; 95% CI: 0.55-0.82) – OR of ≥PR: 3.39 (P<0.001; 95% CI: 2.24-5.12)
In favor of MPT
• Toxicity – OR of ≥ grade 3 PN: 6.61 (P<0.001) – OR of ≥ grade 3 DVT: 2.43 (P=0.02)
• Age >60-75 years or • Transplant ineligible
– Thalidomide maintenance in 3 of the studies
In favor of MP
• MPT can be considered a treatment option for elderly or transplant ineligible patients – Must take toxicity into consideration
Kapoor P, et al. Leukemia. 2011;25:689-96.
RCTs=Randomized controlled clinical trials.
VISTA Trial
MP + Lenalidomide: MM-015 Trial
• Randomized phase III trial of MP vs MPB • Median follow-up: 60.1 months (final analysis) • Results MP (n=338)
MPB (n=344)
P-value
43.1 mo
56.4 mo
0.0004
34.4%
46%
--
Median TNT
19.2 mo
27 mo
<0.0001
Median TFI
8.3 mo
16.6 mo
<0.0001
OS 5-year OS
– – – –
OS benefit retained after subsequent therapies High risk cytogenetics no difference in OS benefit Novel agents could be used successfully at relapse No increased risk of 2nd primary malignancies
San Miguel JF, et al. Blood. 2011;118:Abstract 476. San Miguel, et al. J Clin Oncol. 2013; 31(4):448-55.
Kapoor P, et al. Leukemia. 2011;25:689-96.
TNT=time to next therapy TFI=treatment-free interval
HS is a 70 yo male with newly diagnosed myeloma, ineligible for transplant. Which of the following induction regimens would be the most effective and appropriate?
• Randomized, double-blind, phase III study – Newly diagnosed, transplant ineligible – Age: ≥ 65 yo – MP (n= 154) vs MPR (n=153) vs MPR+R (n=152) ORR
VGPR
CR
PFS
PFS (65-75 yo)
3-year OS
MP
50%
9.1%
3.2%
13 mo
12 mo
66%
MPR
68%
29.4%
3.3%
14 mo
15 mo
62%
P-value
0.002
--
--
NS
<0.001
NS
MPR is an active regimen for patients 65-75 years old, but benefits are less evident if >75 years Palumbo A, et al. N Engl J Med. 2012;366:1759-69.
NS=not significant, yo= years old +R=lenalidomide maintenance treatment
Recommendation & Risk • Transplant Eligible (TE)
A. VAD (Vincristine + Doxorubicin + Dexamethasone) B. MP (Melphalan + Prednisone) plus Lenalidomide or Thalidomide or Bortezomib C. Melphalan + Prednisone D. Lenalidomide + HD Dexamethasone E. Liposomal Doxorubicin + Dexamethasone
– Standard risk: lenalidomide or bortezomib based • High response rates & low mortality • Manageable adverse effects
– High risk: bortezomib (preferred) or lenalidomide • Bortezomib may overcome adverse prognostic factors including high risk cytogenetics • High risk disease benefits most from CR
• Transplant Ineligible (TI) – Standard risk: MPT or Rd • Oral administration & convenience
– High risk: similar to TE +/- melphalan Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Rajkumar SV, et al. Am J Hematol. 2012; 87:79-88
Stem Cell Transplantation • Integral part of myeloma treatment • Autologous, Tandem, & Allogeneic vs Eligibility • Transplant vs standard treatment – Conflicting results – TBI inferior to HD Melphalan conditioning – Longer symptom free interval
• Results after ASCT in IFM 2005/01 (VAD vs BD) – Median PFS if ≥VGPR vs
• BDT vs TD before ASCT – ≥VGPR: 62% vs 31% – Similar responses after ASCT
Suggest improved responses before ASCT result in improved responses after ASCT • Kumar, et al
• Early vs Delayed ASCT – Similar OS – Improved QoL with early ASCT
• IMiDs/Bortezomib & past transplant results Giralt S. Hematology Am Soc Hematol Educ Program. 2011;2011:191-6. Attal M, et al. N Engl J Med. 1996;335:91-97. Fermand JP, et al. Blood. 1998;92:3131-36
Induction Response & ASCT Results
TBI=Total body irradiation
Tandem ASCT Updates • Updated results of 8 trials – French: IFM90, IFM94, IFM9902, IFM9904, – US: TT1, TT2, TT3, & SWOG S9321
• Results – Tandem transplants associated with better survival, HR 0.61 (P<0.001; 95% CI: 0.55,0.68) – If EFS > 3.5 years, then PRS was increased – Ten year OS estimates approaching >50%
• Tandem ASCTs should be considered in all patients – Benefit most evident if achieve
Barlogie B, et al. J Clin Oncol. 2010;26:1209-1214. NCCN Guidelines & Clinical Practice. Multiple Myeloma. Accessed Oct 1st, 2012. www.NCCN.org.
Results
– Patients with refractory myeloma can still respond to ASCT – ASCT is still an option in patient with refractory disease Harousseau JL, et al. J Clin Oncol. 2010;28:4621-29. Harousseau JL, et al. Blood. 2009;114:Abstract 353.
Kumar S, et al. Bone Marrow Transplant. 2004;34:161-67.
Role of Allogeneic Transplant • Prospective analysis of allogeneic transplant based on availability of donor • Patients HOVON-50 Trial (n=536) – DS stage II-III – Age 18-65 yo
• Allo-RIC – TBI 2 Gy – Cyclosporine & mycophenolate
Lokhorst HM, et al. Blood. 2012;119:6219-6225.
Induction: VAD vs TAD ASCT: HD Melphalan (n=439) Included in DvND analysis (n=260)
No Match Sib (N=138) Further Treatments: -Maintenance: n=97 -2nd ASCT: n=3
Match Sib (N=122) Further Treatments: -Maintenance: n=15 -Allo RIC: n=99
T-Thalidomide, A: doxorubicin, D:dexamethasone, V: vincristine; DvND: Donor versus no donor RIC: reduced intensity conditioning regimen
Progression Free Survival
No Donor
Donor
PFS at 6 years
22%
28%
Significance P=0.17 (HR 0.82, 95% CI: 0.62-1.09)
OS at 6 years
55%
55%
P=0.72 (HR 1.07, 95% CI: 0.75-1.52)
Cumulative Incidence of Relapse at 6 years
77%
55%
P=0.005
Cumulative Incidence of NRM at 6 years
3%
16%
P<0.001
• No differences for high risk patients • Rates of aGVHD: 50% (9% grade ≥3) • Conclusions – No benefit to allo-SCT – Benefits may require longer follow-up – Only conduct as part of clinical trial Lokhorst HM, et al. Blood. 2012;119:6219-6225.
NRM = non-relapse mortality aGVHD = actue graft versus host disease
Republished with permission of the American Society of Hematology, from Donor Versus No-Donor Comparison of Newly Diagnosed Myeloma Patients Included in the HOVON-50 Multiple Myeloma Study, Lokhorst, H. M., et al., 119, 2012; permission conveyed through Copyright Clearance Center, Inc.
Post ASCT Thalidomide Studies
Maintenance Treatments
Author
Maintenance Treatment
N
Results
Barlogie
T vs none
668
No difference in EFS or OS overall. Thal improved RR, EFS, & OS for high-risk cytogenetics
Attal
T+Pam vs Pam vs None
597
EFS: 52% vs 37% vs 36% @ 3yr (P<0.01) OS: 87% vs 74% vs 77% @ 4yr (P=0.04)
Spencer
T+Pred vs Pred
243
PFS: 42% vs 23% @ 3yr (P<0.001) OS: 86% vs 75% @ 3yr (P=0.004)
Lokhorst T vs IFN
556
Median PFS: 34 mo vs 25 mo (P<0.001) Median OS: 73 mo vs 60 mo (P=0.77)
Stewart
332
Median PFS: 28 mo vs 17 mo (p<0.0001) Median OS: Not reached vs 5 yrs (P=0.18)
T+Pred vs none
Pam = pamidronate, Pred = prednisone, IFN = interferon Barlogie B, et al. J Clin Oncol. 2010;28:3023-3027. Attal M, et al. Blood. 2006;108:3289-3294. Spencer A, et al. J Clin Oncol. 2009;27:1788-1793
Post ASCT Thalidomide
Post ASCT Lenalidomide CALGB 100104 (McCarthy)
• Efficacy – Most benefit if
• Toxicities – – – – –
Neuropathy: 52-69% (grade ≥3: 6-10%) Fatigue up to 78% Infection 6-28% Constipation 18-44% Thrombosis 6-8%
– Overall: 23-80% – Mainly related to neuropathy Lokhorst HM, et al. Blood. 2010;115:1113-1120. Stewart AK, et al. Blood. 2010;116:Abstract 39.
Age <71 years, post ASCT (n=460)
Age <65 years, post ASCT (n=614)
Treatment
Len 10mg/day until disease progression vs placebo
Len 10mg/day x 3 mo, then 15mg/day until relapse vs placebo
Median followup
34 months
45 months
Results
PFS: 46 mo vs 27 mo (P<0.001) OS: 88% vs 80% @ 3yr (P=0.03) PD or death: 37% vs 58% @ 34 mo (HR 0.48; 95% CI, 0.36 to 0.63)
PFS: 41 mo vs 23 mo (P<0.001) -Observed in high risk also OS: 70% in both groups @ 45 months
Side Effects (Grade≥3)
Hematologic: 48% vs 17% (p<0.001) Infection: 6% vs 3% (p=0.108) Febrile Neutropenia: 5% vs 1% (p=0.019) Fatigue: 6% vs 3% (p=0.253) Thrombotic events: 1.3% vs 0.4% Second primary cancers: 7.8% vs 2.6%
Hematologic: 58% vs 23% (p<0.001) Infections: 13% vs 5% Fatigue: 5% vs 2% Thrombotic events: 6% vs 2% (p=0.01) Second primary cancers: 7.5% vs 2.9%
Discontinuation
10% vs 3.1%
27.1% vs 14.6%
McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781. Attal M, et al. N Engl J Med. 2012;366:1782-1791.
Lenalidomide Maintenance • MM-015 Trial (MP vs MPR vs MPR-R) • Results – Median PFS: 13 mo vs 14 mo vs 31 mo (P<0.001) – OS at 3-yrs: 66% vs 62% vs 70% (P=NS) – Toxicities • Hematologic, infection, fatigue, GI, & rash • Maintenance Discontinuation: 8% (at 65-75 yo) & 17% (>75 yo) • Risk of second primary malignancies (SPMs)
Lenalidomide prolongs response, but OS benefit is less obvious & it has toxicity. Need to inform patients before starting. Palumbo A, et al. N Engl J Med. 2012;366:1759-69.
MPR-R= MPR with Lenalidomide Maintenance
PD = progressive disease
Lenalidomide & SPMs Study
– Transplant ineligible, age ≥65 years – Maintenance: Lenalidomide 10mg days 1-21 of 28
IFM 2005-02 (Attal)
Patients
• Discontinuation of drug due to toxicity
Barlogie B, et al. J Clin Oncol. 2010;28:3023-3027. Attal M, et al. Blood. 2006;108:3289-3294. Spencer A, et al. J Clin Oncol. 2009;27:1788-1793
Lokhorst HM, et al. Blood. 2010;115:1113-1120. Stewart AK, et al. Blood. 2010;116:Abstract 39.
Hematologic Malignancies
Solid Tumors
Totals (excluding non-melanoma skin cancer)
Lenalidomide
Placebo
Lenalidomide
Placebo
Lenalidomide
Placebo
P-value
CALGB 100104 (McCarthy)
3.5%
0.4%
4.3%
2.2%
7.8%
2.6%
0.008
IFM 2005-002 (Attal)
4.2%
1.7%
3.3%
1.3%
7.5%
2.9%
0.002
--
--
--
--
7%
3%
not reported
MM-015 (Palumbo)
• Median time to diagnosis of SPM (CALGB 100104) – Hematologic: 28 mo (12-46) vs 30 mo – Solid Tumor: 15 mo (3-51) vs 21 mo (6-34)
• Incidence of SPM (IFM 2005-002): – Lenalidomide vs placebo: 3.1/100 pt-yrs vs 1.2/100 pt-yrs (P=0.002) – Risk factors identified: age 55-67, male gender, & ISS stage III McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781. Attal M, et al. N Engl J Med. 2012;366:1782-1791.
Palumbo A, et al. N Engl J Med. 2012;366:1759-69.
NB is a 62 yo female post Autologous HSCT. She is starting treatment with Lenalidomide maintenance and heard about the risk of SPMs. What should you tell her?
Outcomes & Risk SPMs MM-015:
CALGB 100104: A. B.
C.
D. E. From N Engl J Med, Palumbo, A., et al., Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma, 366, 1759–1769. Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. From N Engl J Med, McCarthy, P. L., Owzar, K., Hofmeister, C. C., et al. Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma, 366, 1770–1781. Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Bortezomib Maintenance
Relapsed/Refractory Myeloma
Maintenance Post ASCT Study
N & age
Treatment
HOVON-65 (Sonneveld)
800 ≤65 yo
Bor 1.3 mg/m2 q2wk vs Thal 50mg daily x 2yr
48% vs 42% 78% vs 71% (@ 3 yrs)* (@ 3 yrs)*
Bor 1.3 mg/m2 d1,4,8,11 q3mo + Thal 100mg daily vs Thal 100mg daily vs IFN-α2b x 3yr
78% vs 63% vs 49% (@ 2 yrs)*
PETHEMA/ 266 GEM (Rosinol) ≤65 yo
EFS/PFS
OS
• Combination or single agent? • Available agents – Bortezomib, thalidomide, lenalidomide – Cyclophosphamide, doxorubicin (liposomal), cisplatin, etoposide, & dexamethasone – Carfilzomib – Bendamustine & vorinostat
Not Significant
Maintenance Post Induction (Transplant Ineligible) Study
N & age
Treatment
GIMEMA (Palumbo)
511 ≥65 yo
Bor 1.3 mg/m2 d1&15 q4wk + Thal 50mg daily vs Observation
EFS/PFS
OS
NR vs 27mo*
89% vs 87% (@ 3 years)
• Around the corner – Pomalidomide – Elotuzumab – New proteosome inhibitors
Bortezomib is an effective maintenance treatment. Must consider neuropathy as a long term toxicity. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-55. Rosinol, et al. Blood. 2012;120:1589-96. Palumbo A, et al. J Clin Oncol. 2010;28:5101-09.
The incidence was not different than placebo Lenalidomide increases the risk of developing solid tumors only The decreased risk of death and disease progression with lenalidomide outweigh the risks of second malignancies Female gender & ISS stage I may be risk factors Lenalidomide should not be used in the maintenance setting due to the risk of 2nd malignancies
NR= not reached, Bor=bortezomib, Thal=thalidomide. *Denotes statistically significant difference.
Moreau P, et al. Sem Hematol. 2012;49:S33-S46. Lonial S, et al. Clin cancer Res. 2011;17:1264-1277.
Subcutaneous Bortezomib • Randomized, phase III, non-inferiority study • Patients – Age ≥18 years old – Disease progression after 1-3 prior lines of treatment – No prior bortezomib
• Treatment (Assigned 2:1) – Bortezomib 1.3 mg/m2 SQ or IV days 1, 4, 8, & 11 – Up to 8 cycles – SQ injection: 2.5 mg/mL Moreau P, et al. Lancet Oncol. 2011;12:431-40.
SQ = subcutaneous
Results – SQ vs IV Subcutaneous (n=147)
Intravenous (n=74)
ORR
61 (42%)
31 (42%)
≥VGPR
Significance P=0.002 for noninferiority
24 (17%)
12 (16%)
n/a
PN any grade
38%
53%
P=0.044
PN ≥ grade 2
24%
41%
P=0.012
PN ≥ grade 3
6%
16%
P=0.026
Cmax (ng/mL)
20.4 (8.87)
223 (101)
n/a
AUClast (ngxh/mL)
155 (56.8)
151 (42.9)
n/a
63.7% (10.6)
69.3% (13.2)
n/a
Emax (%)
• Injection site reaction: 9 of 147 (6%) • No differences in PK or PD based on site of SQ inj Republished with the permission of the American Society of Hematology, from Potent Activity of Carfilzomib, a Novel, Irreversible Inhibitor of the Ubiquitin-Proteasome Pathway, Against Preclinical Models of Multiple Myeloma, Kuhn, D. J., et al., 110, 2007; permission conveyed through Copyright Clearance Center, Inc.
PD: progressive disease, Cmax: max plasma conc AUClast: AUC from time 0-last timepoint Emax: max % inhibition of 20S proteasome activity
Carfilzomib Carfilzomib
Phase II PX-171-003
Bortezomib
• Patients – Relapsed from ≥2 prior therapies including bortezomib & an IMiD – Refractory to last therapy
• Novel epoxyketone proteasome inhibitor • Irreversible binding • More selective for chymotrypsin-like active site of the proteasome • Fewer off-target effects than bortezomib • Active against bortezomib resistant cell lines Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; 2012. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc: 2012. Kuhn, et al. Blood. 2007;110:3281-3290.
• Carfilzomib dose – Given IV on days 1, 2, 8, 9, 15, & 16 q28 days – Pilot Study (A0): 20 mg/m2 all 12 cycles – Amended (A1): 20 mg/m2 cycle 1, then 27 mg/m2 cycles 2-12 Jagannath S, et al. Clin Lymphoma Myeloma Leuk. 2012;12:310-8. Siegel DS, et al. Blood. 2012;120:2817-2825.
PX-171-003 Results
Carfilzomib Adverse Effects Toxicity (PX-171-003-A1)
PX-171-003-A0 (95% CI) Number of patients
PX-171-003-A1 (95% CI)
n = 46
n = 266
5 (range of 2-15)
5 (range 1-20)
ORR
16.7% (7-31.4)
23.7% (18.7-29.4)
CBR
23.8% (12.1-39.5)
37% (31.1-43.2)
Median number of prior therapies
Median DOR (mo)
7.2 (1.9-NR)
7.8 (5.6-9.2)
Median PFS (mo)
3.5 (2.4-6.7)
3.7 (2.8-4.6)
Median OS (mo)
--
15.6 (13-19.2)
Jagannath S, et al. Clin Lymphoma Myeloma Leuk. 2012;12:310-8. Siegel DS, et al. Blood. 2012;120:2817-2825.
DOR = duration of response CBR=clinical benefit response (≥ minimal response)
Use in Special Populations • Patients with renal insufficiency – Studied in a phase II study – Patients divided into cohorts based on creatinine clearance (>80, 50-80, 30-49, <30, & dialysis)* – No effect on peak exposure, AUC, or clearance
• Specific Warnings (use with caution): – Cardiac arrest, CHF, MI – Pulmonary complications – Hepatic toxicity – Thrombocytopenia – treatment related Niesvizky R, et al. Haematologica. 2011;96(suppl2):370-1. *Displayed in mL/min. Siegel DS, et al. Blood. 2012;120:2817-2825. Vij R, et al. Blood. 2012;119:5661-5670. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; 2012.
All grades
Grade 3 or 4
Neutropenia 18% 11% Thrombocytopenia 39% 29% Anemia 46% 24% Upper respiratory tract infection 27% 4.5% Pneumonia 12% 9.4% Dyspnea 34% 3.4% Febrile Neutropenia 0.8% 0.8% Nausea 45% 1.9% Vomiting 22.2% 0.8% Diarrhea 32% 0.8% Fatigue 46% 7.5% Pyrexia 31% 1.5% Headache 28% 1.9% Increased serum creatinine 25% 2.6% Acute renal failure 4.9% 3.4% Tumor lysis syndrome 0.4% 0% -Cardiac adverse effects – CHF: 10 pts (3.8%), cardiac arrest: 4 pts (1.5%), MI: 2 pts (0.8%) -Peripheral neuropathy – All grades: 33 pts (12.4%), grade 3/4: 3 pts (1.1%) Siegel DS, et al. Blood. 2012;120:2817-2825. Singhal S, et al. Blood. 2011;118:(abstract 1876).
MI = myocardial infarction, pts = patients
Carfilzomib Approval • Indication – Received at least 2 prior therapies, including bortezomib and an IMiD, & progressed within 60 days of last therapy
• FDA approved dosing (BSA capped at 2.2 m2): – Cycle 1: 20 mg/m2/dose – Cycle ≥2: 27 mg/m2/dose (if tolerated) • Increased RRs at 27 mg/m2/dose
• Administration – IV over 2-10 minutes – Hydration (250-500 mL) before & after (cycle 1) • To prevent TLS & associated nephrotoxicity
• Infusion reaction prevention – Premed: dexamethasone 4 mg IV/PO (cycles 1&2) Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; 2012. Vij R, et al. Blood. 2012;119:5661-5670. TLS = tumor lysis syndrome
Carfilzomib – Combination Studies
UR is starting his 2nd cycle of carfilzomib for relapsed multiple myeloma. He tolerated his 1st cycle very well. What concominant treatment should he receive with his carfilzomib infusion?
• Carfilzomib/lenalidomide/dexamethasone, phase 1/2 – Dosing schemes: 20/27 mg/m2 and 20/36 mg/m2 – Response: ≥PR 98%, CR 42% (n=53)
• Carfilzomib/melphalan/prednisone, phase 1/2 – Dosing: up to 45 mg/m2 – Overall response rate: 92% (n=40)
• ENDEAVOR, phase III study – Carfilzomib/Dex vs Bortezomib/Dex – Dose: 20 mg/m2 days 1 & 2, then 56 mg/m2/dose thereafter – Planned enrollment of 888 patients
A.
Ondansetron 8 mg IV before each dose B. Normal saline 250 mL IV before and after each dose C. Acetaminophen 500 mg PO before each dose D. Dexamethasone 4 mg PO before each dose E. Loperamide 2 mg PO before each dose
• ASPIRE, phase III study – Lenalidomide/Dexamethasone ± Carfilzomib – Enrolled 792 patients (accrual complete) www.clinicaltrials.gov, accessed January 28th, 2013. Thompson JL. Annals Pharmacother. 2013; 47:56-62
Pomalidomide
Pomalidomide MM-002 Trial • Phase II trial
Thalidomide
Lenalidomide
Pomalidomide
• Immunomodulatory drug (IMiD) • Structurally similar to lenalidomide & thalidomide • Greater activity than thalidomide (in vitro) • Possible better safety profile than other IMiDs Moreau, et al. Sem Hematol. 2012;49:S33-S46. Quach H, et al. Leukemia. 2010;24:22-32.
– POM 4mg PO days 1-21 q28, ±Dex 40mg/wk – Refractory to lenalidomide and/or bortezomib
• Results (POM vs POM+Dex) – Overall ≥PR: 13% vs 34% – Median DOR: 8.5 mo vs 7.9 mo – Median PFS: 2.7 mo vs 4.7 mo – Median OS: 14 mo vs 16.9 mo
Richardson PG, et al. Proc ASH. 2011: Abstract 634.
Pomalidomide Toxicity POM (n = 107)
Elotuzumab
POM + DEX (n = 112)
Neutropenia
45%
38%
Thrombocytopenia
21%
19%
Anemia
17%
21%
Pneumonia
8%
19%
Fatigue
8%
10%
Thrombotic events, grade 3/4
3%
4%
Discontinue due to AE
8%
10%
-No grade 3/4 peripheral neuropathy
Pomalidomide with or without dexamethasone shows good activity in patient refractory to lenalidomide and/or bortezomib. **FDA to make decision on application for pomalidomide by Feb 10th, 2013** Richardson PG, et al. Proc ASH. 2011;118: Abstract 634.
POM = pomalidomide
• Humanized Mab against cell surface adhesion molecule CS1 • Phase II trial with lenalidomide & dex (n=73) – ORR 84% (48% ≥VGPR) – Median PFS: 26.9 mo (10 mg/kg) & 18.6 mo (20 mg/kg) – Toxicities: hematologic, hyperglycemia, pneumonia, diarrhea, fatigue, & hypokalemia
• ELOQUENT-1 & ELOQUENT-2 Phase III Trials – Len/Dex ± Elotuzumab in previously untreated or relapsed/refractory myeloma – Elotuzumab 10 mg/kg weekly – Results not yet available Richardson PG, et al. Blood. 2012;120:abstr202.
Mab = Monoclonal Antibody
Conclusions • Expanding arsenal • Newer combinations & sequences • New agents • Potential for cure??