Multiple Myeloma: Treatment Updates


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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??