Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center

Current Approaches to Managing Multiple Myeloma

Shaji Kumar, M.D. Associate Professor of Medicine

Mayo Clinic

Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Mul$ple  Myeloma  

•  Malignancy  of  terminally  differen$ated  plasma  cells  

•  Age  standardized  incidence  rate  of  0.7-­‐2.2  per  100,000  worldwide  and  death  rate  of  0.6-­‐1.3  per  100,000  

•  Second  most  common  hematological  malignancy;  2%  of  all  cancers  

•  Median  Age  at  diagnosis  67  years,  male  predominance  

•  Twice  as  common  among  African  Americans,  less  common  in  Asians  

Plasma  cells  

•  Plasma  cells  are  terminally  differen$ated,  non-­‐dividing,  effector  cells  of  B-­‐cell  lineage  

•  They  synthesize  an$gen  specific  immunoglobulins  

•  Abnormali$es  of  plasma  cells  are  responsible  for    –  autoimmune  diseases  

–  Plasma  cell  neoplasms  

•  The  development  and  func$on  are  $ghtly  regulated  

The  immune  response  and  plasma  cell  forma$on  

Monoclonal  Gammopathies  

MGUS 58% (23,179)

Multiple myeloma

17.5% (6,974)

Amyloidosis 9.5% (3,781)

Lymphoproliferative 3% (1,298)

SMM 4% (1,494)

Solitary or extramedullary 2% (774) Macro 2% (940)

Other 4% (1,489)

n=39,929

Mayo Clinic 1960-2008

Natural  History  

Kyle et al, NEJM, Volume 356:2582-2590, June 21, 2007

Preceding  MGUS  

•  MM  is  always  preceded  by  MGUS  stage  

•  Among  77  469  healthy  adults  from  PLCO  Cancer  Screening  Trial:  71  subjects  developed  MM  

•  Serially  collected  pre-­‐diagnos$c  serum  samples  studied  

•  MGUS  was  present  in  100.0%,  98.3%,  97.9%,  94.6%,  100.0%,  93.3%,  and  82.4%  at  2,  3,  4,  5,  6,  7,  and  8+  years  prior  to  MM  diagnosis  

Landgren O, Blood. 2009 :5412-7.

Progression  to  Symptoma$c  MM  •  MGUS:  up  to  2  percent  of  persons  50  years  of  age  or  older  and  about  3  

percent  of  those  older  than  70  years  •  For  SMM,  maximum  risk  in  the  first  5  years  

•  Risk  factors:  Higher  M  spike,  higher  plasma  cell  burden,  type  of  M  protein,  Abnormal  free  light  chain  ra$o,  circula$ng  plasma  cells  

Kyle et al, NEJM, Volume 356:2582-2590, June 21, 2007

Risk  factors  for  monoclonal  gammopathies  

•  Race:  Higher  risk  in  African  Americans  –  Similar  risk  in  a  popula$on  from  Ghana  

•  Chemical  and  radia$on  exposure  –  Increased  risk  among  those  with  pes$cide  exposure  

•  Familial  risk  –  Increased  risk  among  first  degree  rela$ves    

Stages  of  myeloma  treatment  

1.  Diagnose  and  determine  need  for  treatment  

2.  Risk  stra$fy  

3.  Control  disease  and  treat/  reverse  complica$ons  

4.  Consolidate  ini$al  response  

5.  Maintain  response  

6.  Iden$fy  disease  relapse  and  treat  

7.  Suppor$ve  care  at  all  stages!  

Diagnosis  of  Mul$ple  Myeloma  

•  Clonal  bone  marrow  plasma  cells  ≥  10%  •  Serum  and/or  urinary  monoclonal  protein  and  •  “End-­‐organ  Damage”  or  CRAB  features  

–  HyperCalcemia  –  Renal  Insufficiency  –  Anemia  –  Bone  Disease  

Detec$on  of  Clonal  Plasma  Cells  

         Bone  marrow                    Plasmacytoma                  Peripheral  blood  

Demonstra$ng  Monoclonal  Protein  

0.1

1

10

100

1000

10000

100000

0.1 1 10 100 1000 10000 100000

Serum Kappa (mg/L)

Seru

m L

ambd

a (m

g/L)

Normal sera Kappa LCMM Lambda LCMM Renal impairment

Serum or Urine Protein Electrophoresis Serum or Urine

Immunofixation

Serum Free Light Chain Assay

Intact Immunoglobulin

Exposed surface

Hidden surface

Kappa Free Light Chain Binding Site®, free light chain assay

Previously hidden surface

FLC reference range: κ 3.3 – 19.4 mg/L λ 5.7 – 26.3 mg/L κ/λ ratio 0.26 - 1.65

Prognos$c  Factors  

•  Interna'onal  Staging  System  Stage  •  Cytogene'c  Abnormali'es  

–  Dele'on  13,  hypodiploidy  –  (FISH)  t(4;14),  t(14;16),  or  del(17p)  

•  Poor  performance  status  •  Plasma  cell  labeling  index  (>1%)  •  Abnormal  free  light  chain  ra$o  •  Circula$ng  myeloma  cells    •  Plasmablas$c  morphology  •  High  LDH,  CRP  levels  

Stage Criteria Median Survival (months) I Serum ß2-microglobulin < 3.5 mg/L 62

Serum albumin > 3.5 g/dL II Not stage I or III* 44 III Serum ß2-microglobulin > 5.5 mg/L 29

Greipp, P. R. et al. J Clin Oncol; 23:3412-3420 2005

Interna$onal  Staging  System  (ISS)  

Cytogene$c  Abnormali$es  

Hyperdiploid Non-hyperdiploid

IgH (chr 14) translocations

1.  11q13 (CCN D1):16%

2.  6p21 (CCN D3):3%

3.  16q23 (MAF): 5%

4.  20q12 (MAFB): 2%

5.  4p16 (FGFR3 and MMSET): 15%

Multiple trisomies Chromosomes 3, 5, 7, 9, 11, 15, 19, and 21

Chromosome 13 abnormalities P53 mutations Ras mutations

High  Risk  Myeloma  

High-risk abnormality % of patients with newly

diagnosed MM Conventional cytogenetics

  Deletion of chromosome 13 (monosomy) 14   Hypodiploidy 9

  Either hypodiploidy or deletion of chromosome 13 17

Fluorescence in situ hybridization (FISH)   t(4;14) 15   t(14;16) 5   17p– 10

Plasma cell labeling index ≥3% 6

Any 1 of the high-risk abnormalities 25-30

General  approach  to  treatment  

Not a transplant candidate Transplant candidate

Melphalan-based regimens

Observation

Induction therapy

Auto transplant

Newly diagnosed MM

Continue induction and

delayed transplant at relapse Maintenance

options?

Ini$al  Therapy  

The  ideal  ini$al  therapy  should:  

•  Rapidly  and  effec$vely  control  disease    

•  Reverse  disease  related  complica$ons  

•  Decrease  the  risk  of  early  death  

•  Be  easily  tolerated  with  minimal/manageable  toxicity  

•  Not  interfere  with  the  ability  to  collect  stem  cells  for  transplanta$on  

Recent  advances  

The  old  

•  Dexamethasone  •  VAD    

–  Vincris$ne  –  Adriamycin  –  dexamethasone  

The  New  

•  Thalidomide  •  Lenalidomide  •  Bortezomib  

Response  criteria  in  myeloma  

PR VGPR nCR CR sCR

Serum Protein electrophoresis > 50% > 90% 0 0 0

Serum Protein electrophoresis >90% < 100

mg/24 hrs

0 0 0

Serum/Urine Immunofixation Positive Negative Negative

Bone marrow PC <5% <5% <5%

Bone marrow immunoflourescence Negative

Serum Free light chain ratio Normal

Durie et al, Leukemia. 2006 Sep;20(9):1467-73

Thalidomide  (Thalomid®)  

•  Mul$ple  mechanisms,  Response  rates  of  25-­‐35%  when  used  alone  in  relapsed  MM  

•  Seda$on,  Fa$gue    •  Cons$pa$on    •  Peripheral  neuropathy    •  Rash    •  DVT  in  combina$on  with  steroids  or  chemotherapy  

•  Teratogenicity  –  contracep$on  required    

Rajkumar SV, et al. J Clin Oncol. 2008;26:2171-7.

Thal  +  Dex  vs.  Dex  in  newly  diagnosed  MM  (MM-­‐003):  response  rates  

Patie

nts

(%)

p = 0.001

0

20

40

60

63

Thal + Dex

46

Dex

19.2

7.7

30.2

2.6

PR

CR 80 VGPR

36.1 13.2

CR + VGPR

p < 0.001

Patie

nts

(%)

Time (weeks)

Thal + Dex Placebo + Dex Censored

MM-­‐003:  $me  to  progression  and  overall  survival  

Time to progression Overall survival HR (95% CI): 0.43 (0.32–0.58)

Thal + Dex: median time to progression 22.6 months Placebo + Dex: median time to progression 6.5 months

Thal + Dex: median overall survival not reached Placebo + Dex: median overall survival 32 months

HR (95% CI): 0.82 (0.57–1.16)

p < 0.0001

Prog

ress

ion-

free

pat

ient

s (%

)

Time (weeks)

Thal + Dex Placebo + Dex Censored

Rajkumar SV, et al. J Clin Oncol. 2008;26:2171-7.

Thalidomide  combina$ons  vs  VAD  

TD vs VAD1 TD vs VAD2 TAD vs VAD3 CTD vs CVAD4

4 months 4 months 3 cycles NA

Patients, n 200 204 402 251

Response before ASCT, %

CR 10 vs 8 12.5 4 vs 2 20 vs 12

> VGPR 19 vs 14 35 vs 13 33 vs 15 38 vs 26

> PR 76 vs 52 – 72 vs 54 96 vs 83

Response after ASCT, %

CR – – 16 vs 11 58 vs 41

> VGPR – 44 vs 42 49 vs 32 67 vs 43

> PR – – 79 vs 76 99 vs 96

Deep-vein thrombosis 15 vs 2 23 vs 7.5 8 vs 4 NA

1. Cavo M, et al. Blood. 2005;106:35-39. 2. Macro M, et al. Blood. 2006;108:[abstract 57]. 3. Lokhorst HM, et al. Haematologica. 2008;93:124-7. 4. Morgan GJ, et al. Blood. 2007;110:[abstract 3593].

ASCT = autologous SCT; CTD = cyclophosphamide + thalidomide + dexamethasone; CVAD = cyclophosphamide + VAD; TAD = thalidomide + doxorubicin + dexamethasone; TD = thalidomide + dexamethasone.

Bortezomib  (PS  341;  Velcade®)  

•  Proteasome  inhibitor  

•  Intravenous  administra$on  

•  Common  side  effects  

–  Neuropathy  –  Thrombocytopenia  

–  Flu  like  syndrome  

–  Fever  –  Increased  risk  of  infec$on,    zoster  reac$va$on  

IFM  2005-­‐01:    bortezomib  +  dexamethasone  vs  VAD  

Response VAD Bortezomib + Dex

Post induction, % Final, %* Post induction, % Final, %*

CR 1 NR 6 NR

CR + nCR 7 32 15 39

≥ VGPR 16 47 39 68

≥ PR 65 NR 82 NR

* Best response, including second ASCT.

Harousseau JL, et al. Presented at ASH/ASCO symposium, ASH 2008. NR = not reported.

IFM  2005-­‐01:  progression-­‐free  survival  

Harousseau JL, et al. JCO October 20, 2010; 28 (30) 4621-4629

VAD: 101 events Median PFS 28 months;

2-year PFS 60%

Bortezomib + Dex (B1 + B2) VAD (A1 + A2)

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Time (months)

Patie

nts

(%)

Bortezomib + Dex: 71 events Median PFS not reached; 2-year PFS 69%

Log-rank p = 0.0115

80

60

40

20

0

Lenalidomide  (CC-­‐5013;  Revlimid®)  

•  More  “potent”  immunomodulator  than  thalidomide  

•  Fewer  side  effects:  no  significant  cons$pa$on,  neuropathy,  or  seda$on  

•  Common  side  effects:  anemia,  leukopenia,  thrombocytenia,  skin  rash,  thrombosis  

•  Not  teratogenic  in  animal  studies  

N N H O

O

N H

SWOG  S0232:  phase  III  trial  of  Len  +  Dex    vs  Dex  in  transplant-­‐eligible  pa$ents  

CR VGPR PR

Zonder J, et al. Blood December 23, 2010, p 5838.

Outcome Len + Dex, % Dex, % p value

1-Year PFS 77 55 0.002

1-Year OS 93 91 NS

Len + Dex Dex 0

20

40

60

80

100 Pa

tient

s (%

)

14

47

15

29

17 2

75

48

p = 0.001

Zonder J, et al. Blood December 23, 2010, p 5838.

SWOG  S0232:  prolonged  progression-­‐free  survival  with  Len  +  Dex  

0

20

40

60

80

100

0 6 12 18 24 30 36

Prog

ress

ion-

free

pat

ient

s (%

)

Time since registration (months)

Len + Dex Dex alone

p = 0.002

1-year PFS Len + Dex: 77% Dex: 55%

ECOG-­‐E4A03:  phase  III  trial  of  Len  +    high-­‐dose  Dex  vs  Len  +  low-­‐dose  Dex  

RD, % Rd, % p value Response (≥ PR) in 4 cycles 79 68 0.008

≥ VGPR within 4 cycles 42 24 < 0.008

Best overall response (≥ PR) 81 70 0.009

≥ VGPR 51 40 0.040

CR (IF−) 17 14 0.428

Any non-haematological adverse event (grade ≥ 3)

66 8 < 0.001

Adverse event of any type (grade ≥ 4) 21 14 < 0.001

Rajkumar SV, et al, Lancet Oncology; 11 (1), 29-37

ECOG-­‐E4A03:  overall  survival  

RD 223 208 195 184 173 123 78 Rd 222 217 212 201 192 146 83

3-year OS rate 75%

Numbers at risk

0

Patie

nts

(%)

Time (months)

20

40

60

80

100

0 6 12 18 24 30 36

Log-rank p = 0.46 Pepe-Fleming p = 0.01

RD

Rd

Rajkumar SV, et al, Lancet Oncology; 11 (1), 29-37

VTD (n = 226)

TD (n = 234) p value

Induction

CR + nCR, % 32 12 < 0.001

VGPR, % 62 29 < 0.001

PR, % 94 79 < 0.001

Post-SCT

CR + nCR, % 55 32 < 0.001

CR, % 43 23 < 0.001

VGPR, % 76 58 < 0.001

Cavo M, et al, Lancet 2010; 376 (9758), 2075–2085

Neuropathy and skin rash were more common with VTD

Phase  III  trial  of  VTD  vs  TD  in    transplant-­‐eligible  pa$ents:  response  rates  

Cavo M, et al. Blood. 2008;112:[abstract 158]; updated data presented at ASH 2008.

VTD  versus  TD:    progression-­‐free  survival  and  overall  survival  

Progression-free survival

0 5 10 15 30 20 25

p = 0.009

2-Year rates VTD (n = 226) 90% TD (n = 234) 80%

0

40

60

80

100

20

Time (months)

Prog

ress

ion-

free

pat

ient

s (%

)

Overall survival

p = 0.2

2-Year rates VTD (n = 226) 96% TD (n = 234) 91%

0 5 10 15 30 20 25 0

40

60

80

100

20

Time (months)

Patie

nts

(%)

Phase  I/II:  New  Combina$ons  

Efficacy Len/Cyc/

Dex1

N = 53

Len/Bort/aDex2

N = 65

Bort/Dex/Cyc/Len3

N = 25

Bort/Cyc/Dex → Bort/Thal/Dex4

N = 44 Best response ORR ≥ nCR ≥ VGPR

45 (85%)

NR 17 (32%)

65 (100%)b

29 (44%) 49 (74%)b

25 (100%) 9 (36%)c

17 (68%)

41 (90%) 15 (35%) 24 (60%)

aDexamethasone, 20 mg Days 1–2, 4–5, 8–9, 11–12. bIndependent of ISS and high-risk cytogenetics. c≥ CR. Len = lenolidomide; ORR = overall response rate; NR = not reached; ISS = International Staging System. 1Kumar, Hayman, et al, 2008; 2Richardson, Lonial, et al, 2008; 3Kumar, Flinn, et al, 2008; 4Bensinger, 2008.

aDexamethasone, 20 mg Days 1–2, 4–5, 8–9, 11–12. bIndependent of ISS and high-risk cytogenetics. c≥ CR. Len = lenolidomide; ORR = overall response rate; NR = not reached; ISS = International Staging System. 1Kumar, Hayman, et al, 2008; 2Richardson, Lonial, et al, 2008; 3Kumar, Flinn, et al, 2008; 4Bensinger, 2008.

Efficacy  improvements  with  novel  induc$on  regimens  

Regimen

Patie

nts

with

≥ V

GPR

(%)

Cavo M, et al. Blood. 2008;112:[abstract 158]. Harousseau J-L, et al. ASH/ASCO symposium at ASH, 2008. Lokhorst HM, et al. Haematologica. 2008;93:124-7. Macro M, et al. Blood. 2006;108:[abstract 57]; updated data from ASH 2006. Morgan G, et al. Blood. 2007;110:[abstract 3593]; updated data from ASH 2007. Rajkumar SV, et al. ASH/

ASCO symposium at ASH 2008. Richardson P, et al. Blood. 2008;112:[abstract 92]. Sonneveld P, et al. Blood. 2008;112:[abstract 653].

Ini$al  treatment  and  early  deaths  

Regimen* Response, % Early deaths, %

Dex (ECOG-E1A00) 41 11

Dex ± IFN (IFM 95-01) 41 10.5

MP (IFM 99-06) 35 8

Thal + Dex (ECOG-E1A00) 63 7

MPT (IFM 99-06) 76 3

Len + high-dose Dex (ECOG-E4A03) 81 4.5

Len + low-dose Dex (ECOG-E4A03) 70 0.5

* Recent phase III trials that did not restrict entry to transplant candidates.

Facon T, et al. Blood. 2006;107:1292-8. Facon T, et al. Lancet. 2007;370:1209-18. Rajkumar SV, et al. J Clin Oncol. 2006;24:431-6. Rajkumar SV, et al. ASH/ASCO symposium at ASH 2008.

Stages  of  myeloma  treatment  

1.  Diagnose  and  determine  need  for  treatment  

2.  Risk  stra$fy  

3.  Control  disease  and  treat/  reverse  complica$ons  

4.  Consolidate  ini$al  response  

5.  Maintain  response  

6.  Iden$fy  disease  relapse  and  treat  

7.  Suppor$ve  care  at  all  stages!  

Attal M. N Engl J Med. 1996;335:91-7.

Transplant  vs.  Conven$onal  chemotherapy  

Patients (95% CI), % Conventional dose 63 (53–73) 35 (22–50) 12 (1–40) High dose 69 (58–78) 61 (50–71) 52 (36–67)

Time (months)

0

25

50

75

100 O

vera

ll su

rviv

al (%

)

0 15 30 45 60

High dose Conventional dose

What  does  transplant  add?  

Regimen

Patie

nts

with

≥ V

GPR

(%)

Cavo M, et al. Blood. 2008;112:[abstract 158]; updated data presented at ASH 2008. Harousseau J-L, et al. ASH/ASCO symposium at ASH 2008. Lokhorst HM,et al. Haematologica 2008;93:124-7. Macro M, et al. Blood. 2006;108:[abstract 57]; updated data from ASH 2006. Morgan G, et al. Blood.

2007;110:[abstract 3593]; updated data from ASH 2007. Sonneveld P, et al. Blood. 2008;112:[abstract 653]; updated data from ASH 2008.

Depth  of  response  improves  over    $me  with  lenalidomide  

Lacy MQ, et al. Mayo Clin Proc. 2007;82:1179-84.

Mayo clinic phase II

CR VGPR PR

Patie

nts

resp

ondi

ng to

tr

eatm

ent (

%)

4 cycles (n = 34)

19 cycles (n = 21)

0

20

40

60

80

100

43

19

24

53

6

32

HDT  and  ASCT  in  MM  pa$ents  <  55  years  old:    up-­‐front  or  rescue  treatment  

   

Fermand J-P, et al. Blood. 1998;92:3131-6.

0

0.2

0.4

0.6

0.8

1.0

0 20 40 100

Surv

ival

pro

babi

lity

60 80 Time (months)

Early HDT Late HDT

0

0.2

0.4

0.6

0.8

1.0

0 20 40 50 70 90 100

EFS

prob

abili

ty

10 30 60 80 Time (months)

TWiSTT

TWiSTT OS

Post-HDT EFS Post-CCT EFS

Late HDT

Early HDT

0

0.2

0.4

0.6

0.8

1.0

0 20 40 50 70 90 100

EFS

prob

abili

ty

10 30 60 80 Time (months)

TWiSTT OS EFS

HDT = high-dose therapy; TWiSTT = time without symptoms, treatment, or treatment toxicity.

Single  vs  double  ASCT  for    newly  diagnosed  MM  

Study ASCT n CR, % Median EFS, months

Median OS, months

IFM941 Single

Double

199

200

42*

50*

25

30

48

58

MAG952 Single 94 42‡ No difference No difference

Double 99 37‡

HOVON 243 Single 148 13 20 55 Double 155 28 22 50

Bologna 964 Single

Double

115

113

33§

47§

Significant prolongation of EFS with double SCT

46% at 7 years

43% at 7 years

1. Attal M, et al. N Engl J Med. 2003;349:2495-502. 2. Fermand JP, et al. Blood. 2001;98:815a:[abstract 3387]. 3. Sonneveld P, et al. Blood. 2005;106:715a:[abstract 2545]. 4. Cavo M, et al. J Clin Oncol. 2007;25:2434-41.

* CR + VGPR; p = NS by ITT. ‡ CR + minimum residual disease; p = NS. § CR + nCR; ITT analysis.

NS

NS

p = 0.002

p = 0.008

p = 0.03

p = 0.02

p = 0.01

NS

NS

Thalidomide  maintenance:  IFM  99-­‐02  

Attal M, et al. Blood. 2006;108:3289-94.

Event-free survival

4-Year EFS 36% vs 26%

+ Thal

Time since randomization (months)

0

10

20

30

40

50 60

70

80

90

100

1 13 25 37 49

Even

t-fre

e pa

tient

s (%

)

− Thal

Overall survival

4-Year OS 87% vs 75%

+ Thal

0

10

20

30

40

50 60

70

80

90

100

1 13 25 37 49

Time since enrolment (months)

Patie

nts

(%)

− Thal

What  about  the  transplant  ‘ineligible’  popula$on?  

Melphalan  +  Prednisone  

0 10 20 30 40 50 60 70 80 90

100 0 1 2 3 4 5 6+ Es

timat

ed p

erce

ntag

e st

ill a

live

24.4%

23.0 19.4%

18.0 1.4% SD 1.4

(log-rank 2P > .1; NS) – Allocated CCT (% ± SD)

– Allocated MP (% ± SD)

Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16;12:3832

Years

27 randomized trials

MPT Arm

Melphalan, 4 mg/m2 (7 days per month)

Prednisone, 40 mg/m2 (7 days per month)

Thalidomide, 100 mg/d (continuously)*

(n=129)

MP Arm

Melphalan, 4 mg/m2 (7 days per month)

Prednisone, 40 mg/m2 (7 days per month)

(n=126)

→ ×6 courses

Newly diagnosed MM patients,

Age >65 years

(median age: 72 years) n=255

*Thalidomide dose reduced to 50% if grade 2 toxicity. Enoxaparin prophylaxis added to protocol in December 2003.

GIMEMA Phase III Randomized

Controlled Trial

Palumbo et al. Lancet 2006;367:825-831

MP  vs  MP-­‐thalidomide  (MPT)  in  Elderly  Pa$ents  

Palumbo et al. Lancet 2006;367:825-831

MPT vs MP: Survival Rates

EFS

49% ↓ in risk of event for MPT OS

65% ↓ in risk of death at >9 mo for MPT

0 6 12 18 24

HR 0.51 (95% CI 0.35–0.75) P=0.0006

Pro

porti

on o

f Pat

ient

s

0

01

02

03

04

05

06

07

08

09

1.0

Months

0

01

02

03

04

05

06

07

08

09

1.0

0 6 12 18 24 30

HR 0.68 (95% CI 0.38–1.22) P=0.19

Pro

porti

on o

f Pat

ient

s

Months

MP MPT

Arm A

MP X 12 cycles

Arm C

VAD X 2

Cyclophosphamide 3g/m2 + G-CSF

+ PBSC harvest

MEL 100 mg/m2

+ PBSC + G-CSF

MEL 100 mg/m2 + PBSC + G-CSF

Arm B

MP X 12 cycles

+ Thal

≤ 400 mg/d

Facon T et al. The Lancet 2007; 370:1209-1218

IFM  99-­‐06:  Newly  Diagnosed    MM  65-­‐75  years  

IFM  99-­‐06:  Overall  Survival  

Facon T et al. The Lancet 2007; 370:1209-1218

MP (12 cycles q 6 weeks) •  Melphalan: 0.2 mg/kg/d Day 1-4 •  Prednisone:2 mg/kg/d Day 1-4

MP + Placebo 18 months, continuos

MP + Thalidomide (100 mg/d) 18 months, continuos

Clodronate  was  given  to  all  pts.  No  an3-­‐coagulant  prophylaxis  was  planned.  

Hulin C, et al. Blood. 2007;108:78a, abstract 75

IFM  01/01:  Pa$ents  Over  75  Years  

1117273140658096105116

1626364557708096101113

0,00

0,20

0,40

0,60

0,80

1,00

0 6 12 18 24 30 36 42 48 54Months

Prop

ortio

n of

sur

vivi

ng p

atie

nts

MP

MP+Thalidomide

IFM 01-01: Overall survival

44 vs 29.1 months, p = 0.001

Hulin C, et al, J Clin Oncol. 2009; article in press.

MP  vs  MPT:  progression-­‐free  survival    and  overall  survival  

GIMEMA1,2 IFM 99-063 IFM 01-014 Nordic5 HOVON6 Median PFS, months

MP MPT

15 22

18 28

19 24

14 16

10* 13

p value 0.0004 < 0.0001 0.001 TTP‡ < 0.001 Median OS, months

MP MPT

48 45

33 52

29 44

39 29

30 37

p value NS 0.0006 0.028 NS NS

1. Palumbo A, et al. Lancet. 2006;111:825-31. 2. Palumbo A, et al. Blood. 2008;112:3107-14. 3. Facon T, et al. Lancet. 2007;370:1209-18. 4. Hulin C, et al. J Clin Oncol. 2009; in press. 5. Waage A, et al. Blood. 2007;110:[abstract 78].

6. Wijermans P, et al. Blood. 2008;112:[abstract 241]; updated data presented at ASH, 2008.

* Event-free survival. ‡ Significant.

In 5 of 5 studies, MPT was superior to MP in terms of PFS or TTP (or both) In 2 of 5 studies, MPT was superior to MP in terms of OS

VMP Cycles 1-4 Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32 Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

Cycles 5-9 Bortezomib 1.3 mg/m2 IV: days 1,8,22,29 Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

MP Cycles 1-9 Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

R A N D O M I Z E

9 x 6-week cycles (54 weeks) in both arms

•  Previously untreated MM patients who were not candidates for HDT-ASCT •  682 patients randomized from December 2004 to September 2006

VISTA:  Randomized,  Phase  III  Trial  of  VMP  vs  MP  

San Miguel et al. NEJM. 359 (9): 906

VISTA:  Survival  

San Miguel et al. NEJM. 359 (9): 906

24.0 months for bortezomib vs. 16.6 months in the control group

Melphalan/  Prednisone/  Lenalidomide  

MPR

any dose (n=53)

MTD (n=21)

1-Year event-free survival, % 92 95

1-Year overall survival, % 100 100

MTD = maximum tolerated dose (melphalan 0.18 mg/kg + lenalidomide 10 mg/day + prednisone 2 mg/kg/day)

Palumbo et al. J Clin Oncol 2007;25:4459-65

mSMART – Off-Study Transplant Eligible

* Bortezomib containing regimens preferred in renal failure or if rapid response needed

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Jan 2009

Collect Stem Cells

High Risk Standard Risk

If not in CR, consider autologous stem cell transplant (ASCT)

All patients receive Rd† until progression

Autologous stem cell transplant (ASCT)

If not in CR/VGPR after 1st ASCT, consider consolidation (eg.,

second ASCT or IMiD)

4-6 cycles of bortezomib containing regimen (CBD, VRd, VTD etc)

4 cycles of Rd*

Collect Stem Cells**

† Continuing Rd is an option for patients responding well to induction with low toxicities; Dex is usually discontinued after first year

OR Continue Rd†

(**If age >65 or > 4 cycles of Rd Consider G-CSF plus cytoxan or plerixafor )

mSMART – Off-Study Transplant Ineligible

** In patients in whom administration of thalidomide or bortezomib is of concern, consider MP or Rd

Observation

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Jan 2009

High Risk Standard Risk*

MP + Bortezomib**

Observation

MP + Thalidomide** or Rd†

† Continuing Rd is an option for patients responding well to induction with low toxicities; Dex is usually discontinued after first year

*Bortezomib containing regimens preferred in renal failure or if rapid response needed

Suppor$ve  care  

•  Bisphosphonates  

•  An$bio$cs  

•  Renal  failure  management  

•  Erythropoie$c  agents/  Anemia  management  

•  Preven$on  of  thrombo$c  events  

Bisphosphonate  Guidelines  

•  In  general  18  months  to  24  months  

•  Beyond  18-­‐24  months,  individualized  decision  based  on  disease  status  

•  Beneficial  in  all  pa$ents,  irrespec$ve  of  ly$c  disease  

•  Calcium  and  vitamin  D  supplementa$on  

•  Baseline  dental  evalua$on  

•  Careful  monitoring  for  ONJ  

Pamidronate  

•  90  mg  IV  given  over  2-­‐4  hours  every  month  

•  Renal  abnormali$es  (Albuminuria,  azotemia)  infrequently  reported  with:  –  Long  term  use  with  

•  Higher  doses  (>  90  mg  q3-­‐4  wks)  •  Faster  infusion  $mes  (<  1  hour)  

•  Reversible  –  Hold  dose  un$l  albuminuria/Cr  improves  –  Then  try  slower  infusion  $me  (>  2  hours)  

Zoledronic  acid    

•  Zoledronic  acid  is  a  highly  potent  bisphosphonate  •  4  mg  IV  over  at  least  15  minutes  

•  Monitor  renal  func$on-­‐  risk  of  acute  renal  failure  

•  Not  recommended  in  pa$ents  with  severe  renal  impairment  

Infec$ous  disease  prophylaxis  

•  No  randomized  data  on  outcome  

•  Infec$ons  common  in  the  ini$al  phase  of  disease  

•  Bactrim/  quinolone  prophylaxis  can  be  considered  on  an  individual  basis  

•  Zoster  prophylaxis  in  pa$ents  on  bortezomib  

•  PJP  prophylaxis  for  those  on  steroids  •  Role  of  IVIG  not  clear,  may  reduce  infec$ons  in  those  severely  hypogammoglobulinemic  

Management  of  anemia  

•  Anemia  common  

•  Mul$factorial,  several  mechanisms  

•  Usually  improve  with  effec$ve  therapy  

•  Persistent  anemia  may  reflect  treatment  agent  

•  Erythropoie$n  use  may  increase  risk  of  thrombosis  

Renal  Failure  

•  Nearly  a  third  of  pa$ents  with  MM  have  some  degree  of  renal  insufficiency  

•  5-­‐10%  have  severe  renal  insufficiency  

•  Mul$factorial:  cast  nephropathy,  hypercalcemia,  hyperuricemia,  amyloidosis  

•  Effec$ve  therapy  cri$cal,  bortezomib  based  

•  PLEX  may  benefit  selected  pa$ents  

•  Suppor$ve  renal  management  

Thromboprophylaxis  

•  Risk  of  thrombosis  about  5%  among  pa$ents  with  MM  

•  Increased  risk  associated  with  IMiDs,  high  dose  steroids  and  cytotoxic  drugs  

•  Aspirin  decreases  risk  among  pa$ents  receiving  IMiDs  

•  Selected  pa$ents  may  benefit  from  coumadin/  heparin  

What  about  when  these  fail?  

Relapsed  disease:  factors  to  consider  

•  Risk  factors,  including  cytogene$cs  

•  Dura$on  of  first  response  

•  Previous  therapies  and  response  

•  Toxicity  from  previous  therapies  

•  Residual  hematological  func$on  

•  Performance  status  

Have  we  made  progress?  

Kumar SK, et al. Blood. 2008;111:2516-20.

Overall survival in 6-year intervals from time of diagnosis

Time (months)

Prop

ortio

n of

pat

ient

s

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

Thank  You!