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Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Current Approaches to Managing
Multiple Myeloma
Sh...
Mul$ple	
  Myeloma	
  
•  Malignancy	
  of	
  terminally	
  differen$ated	
  plasma	
  cells	
  
•  Age	
  standardized	
  ...
Plasma	
  cells	
  
•  Plasma	
  cells	
  are	
  terminally	
  differen$ated,	
  
non-­‐dividing,	
  effector	
  cells	
  of...
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)
Lymphoproliferati...
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	
  adu...
Progression	
  to	
  Symptoma$c	
  MM	
  
•  MGUS:	
  up	
  to	
  2	
  percent	
  of	
  persons	
  50	
  years	
  of	
  ag...
Risk	
  factors	
  for	
  monoclonal	
  gammopathies	
  
•  Race:	
  Higher	
  risk	
  in	
  African	
  Americans	
  
–  S...
Stages	
  of	
  myeloma	
  treatment	
  
1.  Diagnose	
  and	
  determine	
  need	
  for	
  treatment	
  
2.  Risk	
  stra...
Diagnosis	
  of	
  Mul$ple	
  Myeloma	
  
•  Clonal	
  bone	
  marrow	
  plasma	
  cells	
  ≥	
  10%	
  
•  Serum	
  and/o...
Detec$on	
  of	
  Clonal	
  Plasma	
  Cells	
  
	
  	
  	
  	
  	
  Bone	
  marrow	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  ...
Demonstra$ng	
  Monoclonal	
  Protein	
  
0.1
1
10
100
1000
10000
100000
0.1 1 10 100 1000 10000 100000
Serum Kappa (mg/L)...
Intact Immunoglobulin
Exposed surface
Hidden surface
Kappa
Free Light Chain
Binding Site®, free light chain assay
Previous...
Prognos$c	
  Factors	
  
•  Interna'onal	
  Staging	
  System	
  Stage	
  
•  Cytogene'c	
  Abnormali'es	
  
–  Dele'on	
 ...
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 ...
Cytogene$c	
  Abnormali$es	
  
Hyperdiploid Non-hyperdiploid
IgH (chr 14) translocations
1.  11q13 (CCN D1):16%
2.  6p21 (...
High	
  Risk	
  Myeloma	
  
High-risk abnormality
% of patients with newly
diagnosed MM
Conventional cytogenetics
  Deleti...
General	
  approach	
  to	
  treatment	
  
Not a transplant candidate Transplant candidate
Melphalan-based regimens
Observ...
Ini$al	
  Therapy	
  
The	
  ideal	
  ini$al	
  therapy	
  should:	
  
•  Rapidly	
  and	
  effec$vely	
  control	
  diseas...
Recent	
  advances	
  
The	
  old	
  
•  Dexamethasone	
  
•  VAD	
  	
  
–  Vincris$ne	
  
–  Adriamycin	
  
–  dexametha...
Response	
  criteria	
  in	
  myeloma	
  
PR VGPR nCR CR sCR
Serum Protein
electrophoresis
> 50% > 90% 0 0 0
Serum Protein...
Thalidomide	
  (Thalomid®)	
  
•  Mul$ple	
  mechanisms,	
  Response	
  rates	
  of	
  25-­‐35%	
  when	
  used	
  
alone	...
Rajkumar SV, et al. J Clin Oncol. 2008;26:2171-7.
Thal	
  +	
  Dex	
  vs.	
  Dex	
  in	
  newly	
  diagnosed	
  MM	
  
(MM...
Patients(%)
Time (weeks)
Thal + Dex
Placebo + Dex
Censored
MM-­‐003:	
  $me	
  to	
  progression	
  and	
  
overall	
  sur...
Thalidomide	
  combina$ons	
  vs	
  VAD	
  
TD vs VAD1 TD vs VAD2 TAD vs VAD3 CTD vs CVAD4
4 months 4 months 3 cycles NA
P...
Bortezomib	
  (PS	
  341;	
  Velcade®)	
  
•  Proteasome	
  inhibitor	
  
•  Intravenous	
  administra$on	
  
•  Common	
 ...
IFM	
  2005-­‐01:	
  	
  
bortezomib	
  +	
  dexamethasone	
  vs	
  VAD	
  
Response
VAD Bortezomib + Dex
Post induction, ...
IFM	
  2005-­‐01:	
  progression-­‐free	
  survival	
  
Harousseau JL, et al. JCO October 20, 2010; 28 (30) 4621-4629
VAD:...
Lenalidomide	
  (CC-­‐5013;	
  Revlimid®)	
  
•  More	
  “potent”	
  immunomodulator	
  than	
  thalidomide	
  
•  Fewer	
...
SWOG	
  S0232:	
  phase	
  III	
  trial	
  of	
  Len	
  +	
  Dex	
  	
  
vs	
  Dex	
  in	
  transplant-­‐eligible	
  pa$en...
Zonder J, et al. Blood December 23, 2010, p 5838.
SWOG	
  S0232:	
  prolonged	
  progression-­‐free	
  
survival	
  with	
...
ECOG-­‐E4A03:	
  phase	
  III	
  trial	
  of	
  Len	
  +	
  	
  
high-­‐dose	
  Dex	
  vs	
  Len	
  +	
  low-­‐dose	
  Dex...
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%
Nu...
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
...
Cavo M, et al. Blood. 2008;112:[abstract 158];
updated data presented at ASH 2008.
VTD	
  versus	
  TD:	
  	
  
progressio...
Phase	
  I/II:	
  New	
  Combina$ons	
  
Efficacy
Len/Cyc/
Dex1
N = 53
Len/Bort/aDex2
N = 65
Bort/Dex/Cyc/
Len3
N = 25
Bor...
Efficacy	
  improvements	
  with	
  novel	
  
induc$on	
  regimens	
  
Regimen
Patientswith≥VGPR(%)
Cavo M, et al. Blood. 20...
Ini$al	
  treatment	
  and	
  early	
  deaths	
  
Regimen* Response, % Early deaths, %
Dex (ECOG-E1A00) 41 11
Dex ± IFN (I...
Stages	
  of	
  myeloma	
  treatment	
  
1.  Diagnose	
  and	
  determine	
  need	
  for	
  treatment	
  
2.  Risk	
  stra...
Attal M. N Engl J Med. 1996;335:91-7.
Transplant	
  vs.	
  Conven$onal	
  chemotherapy	
  
Patients (95% CI), %
Convention...
What	
  does	
  transplant	
  add?	
  
Regimen
Patientswith≥VGPR(%)
Cavo M, et al. Blood. 2008;112:[abstract 158]; updated...
Depth	
  of	
  response	
  improves	
  over	
  	
  
$me	
  with	
  lenalidomide	
  
Lacy MQ, et al. Mayo Clin Proc. 2007;8...
HDT	
  and	
  ASCT	
  in	
  MM	
  pa$ents	
  <	
  55	
  years	
  old:	
  	
  
up-­‐front	
  or	
  rescue	
  treatment	
  
...
Single	
  vs	
  double	
  ASCT	
  for	
  	
  
newly	
  diagnosed	
  MM	
  
Study ASCT n CR, %
Median EFS,
months
Median OS...
Thalidomide	
  maintenance:	
  IFM	
  99-­‐02	
  
Attal M, et al. Blood. 2006;108:3289-94.
Event-free survival
4-Year EFS ...
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+
Estimatedpercentagestillalive
24.4
%
23.0...
MPT Arm
Melphalan, 4 mg/m2 (7 days per month)
Prednisone, 40 mg/m2 (7 days per month)
Thalidomide, 100 mg/d (continuously)...
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 de...
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/m...
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, continu...
1117273140658096105116
1626364557708096101113
0,00
0,20
0,40
0,60
0,80
1,00
0 6 12 18 24 30 36 42 48 54
Months
Proportiono...
MP	
  vs	
  MPT:	
  progression-­‐free	
  survival	
  	
  
and	
  overall	
  survival	
  
GIMEMA1,2 IFM 99-063 IFM 01-014 ...
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
Cycle...
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 ov...
mSMART – Off-Study
Transplant Eligible
* Bortezomib containing regimens preferred in
renal failure or if rapid response ne...
mSMART – Off-Study
Transplant Ineligible
** In patients in whom administration of
thalidomide or bortezomib is of concern,...
Suppor$ve	
  care	
  
•  Bisphosphonates	
  
•  An$bio$cs	
  
•  Renal	
  failure	
  management	
  
•  Erythropoie$c	
  ag...
Bisphosphonate	
  Guidelines	
  
•  In	
  general	
  18	
  months	
  to	
  24	
  months	
  
•  Beyond	
  18-­‐24	
  months...
Pamidronate	
  
•  90	
  mg	
  IV	
  given	
  over	
  2-­‐4	
  hours	
  every	
  month	
  
•  Renal	
  abnormali$es	
  (Al...
Zoledronic	
  acid	
  	
  
•  Zoledronic	
  acid	
  is	
  a	
  highly	
  potent	
  bisphosphonate	
  
•  4	
  mg	
  IV	
  ...
Infec$ous	
  disease	
  prophylaxis	
  
•  No	
  randomized	
  data	
  on	
  outcome	
  
•  Infec$ons	
  common	
  in	
  t...
Management	
  of	
  anemia	
  
•  Anemia	
  common	
  
•  Mul$factorial,	
  several	
  mechanisms	
  
•  Usually	
  improv...
Renal	
  Failure	
  
•  Nearly	
  a	
  third	
  of	
  pa$ents	
  with	
  MM	
  have	
  some	
  
degree	
  of	
  renal	
  i...
Thromboprophylaxis	
  
•  Risk	
  of	
  thrombosis	
  about	
  5%	
  among	
  pa$ents	
  with	
  
MM	
  
•  Increased	
  r...
What	
  about	
  when	
  these	
  fail?	
  
Relapsed	
  disease:	
  factors	
  to	
  consider	
  
•  Risk	
  factors,	
  including	
  cytogene$cs	
  
•  Dura$on	
  of...
Have	
  we	
  made	
  progress?	
  
Kumar SK, et al. Blood. 2008;111:2516-20.
Overall survival in 6-year intervals from ti...
Thank	
  You!	
  
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Management of Multiple myeloma

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Transcript of "Management of Multiple myeloma"

  1. 1. 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
  2. 2. 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  
  3. 3. 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  $ghtly   regulated  
  4. 4. The  immune  response  and  plasma  cell  forma$on  
  5. 5. 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
  6. 6. Natural  History   Kyle et al, NEJM, Volume 356:2582-2590, June 21, 2007
  7. 7. 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$c  serum  samples   studied   •  MGUS  was  present  in  100.0%,  98.3%,  97.9%,  94.6%,   100.0%,  93.3%,  and  82.4%  at  2,  3,  4,  5,  6,  7,  and  8+   years  prior  to  MM  diagnosis   Landgren O, Blood. 2009 :5412-7.
  8. 8. Progression  to  Symptoma$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
  9. 9. 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    
  10. 10. 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$ve  care  at  all  stages!  
  11. 11. Diagnosis  of  Mul$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  
  12. 12. Detec$on  of  Clonal  Plasma  Cells            Bone  marrow                    Plasmacytoma                  Peripheral  blood  
  13. 13. Demonstra$ng  Monoclonal  Protein   0.1 1 10 100 1000 10000 100000 0.1 1 10 100 1000 10000 100000 Serum Kappa (mg/L) SerumLambda(mg/L) Normal sera Kappa LCMM Lambda LCMM Renal impairment Serum or Urine Protein Electrophoresis Serum or Urine Immunofixation Serum Free Light Chain Assay
  14. 14. 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
  15. 15. 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  
  16. 16. 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$onal  Staging  System  (ISS)  
  17. 17. Cytogene$c  Abnormali$es   Hyperdiploid Non-hyperdiploid IgH (chr 14) translocations 1.  11q13 (CCN D1):16% 2.  6p21 (CCN D3):3% 3.  16q23 (MAF): 5% 4.  20q12 (MAFB): 2% 5.  4p16 (FGFR3 and MMSET): 15% Multiple trisomies Chromosomes 3, 5, 7, 9, 11, 15, 19, and 21 Chromosome 13 abnormalities P53 mutations Ras mutations
  18. 18. High  Risk  Myeloma   High-risk abnormality % of patients with newly diagnosed MM Conventional cytogenetics   Deletion of chromosome 13 (monosomy) 14   Hypodiploidy 9   Either hypodiploidy or deletion of chromosome 13 17 Fluorescence in situ hybridization (FISH)   t(4;14) 15   t(14;16) 5   17p– 10 Plasma cell labeling index ≥3% 6 Any 1 of the high-risk abnormalities 25-30
  19. 19. General  approach  to  treatment   Not a transplant candidate Transplant candidate Melphalan-based regimens Observation Induction therapy Auto transplant Newly diagnosed MM Continue induction and delayed transplant at relapseMaintenance options?
  20. 20. Ini$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  
  21. 21. Recent  advances   The  old   •  Dexamethasone   •  VAD     –  Vincris$ne   –  Adriamycin   –  dexamethasone   The  New   •  Thalidomide   •  Lenalidomide   •  Bortezomib  
  22. 22. Response  criteria  in  myeloma   PR VGPR nCR CR sCR Serum Protein electrophoresis > 50% > 90% 0 0 0 Serum Protein electrophoresis >90% < 100 mg/24 hrs 0 0 0 Serum/Urine Immunofixation Positive Negative Negative Bone marrow PC <5% <5% <5% Bone marrow immunoflourescence Negative Serum Free light chain ratio Normal Durie et al, Leukemia. 2006 Sep;20(9):1467-73
  23. 23. Thalidomide  (Thalomid®)   •  Mul$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    
  24. 24. Rajkumar SV, et al. J Clin Oncol. 2008;26:2171-7. Thal  +  Dex  vs.  Dex  in  newly  diagnosed  MM   (MM-­‐003):  response  rates   Patients(%) 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
  25. 25. Patients(%) Time (weeks) Thal + Dex Placebo + Dex Censored MM-­‐003:  $me  to  progression  and   overall  survival   Time to progression Overall survival HR (95% CI): 0.43 (0.32–0.58) Thal + Dex: median time to progression 22.6 months Placebo + Dex: median time to progression 6.5 months Thal + Dex: median overall survival not reached Placebo + Dex: median overall survival 32 months HR (95% CI): 0.82 (0.57–1.16) p < 0.0001 Progression-freepatients(%) Time (weeks) Thal + Dex Placebo + Dex Censored Rajkumar SV, et al. J Clin Oncol. 2008;26:2171-7.
  26. 26. Thalidomide  combina$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.
  27. 27. 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  
  28. 28. 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.
  29. 29. 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) Patients(%) Bortezomib + Dex: 71 events Median PFS not reached; 2-year PFS 69% Log-rank p = 0.0115 80 60 40 20 0
  30. 30. Lenalidomide  (CC-­‐5013;  Revlimid®)   •  More  “potent”  immunomodulator  than  thalidomide   •  Fewer  side  effects:  no  significant  cons$pa$on,  neuropathy,  or   seda$on   •  Common  side  effects:  anemia,  leukopenia,  thrombocytenia,   skin  rash,  thrombosis   •  Not  teratogenic  in  animal  studies   N N H O O NH
  31. 31. SWOG  S0232:  phase  III  trial  of  Len  +  Dex     vs  Dex  in  transplant-­‐eligible  pa$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 Patients(%) 14 47 15 29 17 2 75 48 p = 0.001
  32. 32. 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 Progression-freepatients(%) Time since registration (months) Len + Dex Dex alone p = 0.002 1-year PFS Len + Dex: 77% Dex: 55%
  33. 33. 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
  34. 34. 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 Patients(%) 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
  35. 35. 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$ents:  response  rates  
  36. 36. Cavo M, et al. Blood. 2008;112:[abstract 158]; updated data presented at ASH 2008. VTD  versus  TD:     progression-­‐free  survival  and  overall  survival   Progression-free survival 0 5 10 15 3020 25 p = 0.009 2-Year rates VTD (n = 226) 90% TD (n = 234) 80% 0 40 60 80 100 20 Time (months) Progression-freepatients(%) Overall survival p = 0.2 2-Year rates VTD (n = 226) 96% TD (n = 234) 91% 0 5 10 15 3020 25 0 40 60 80 100 20 Time (months) Patients(%)
  37. 37. Phase  I/II:  New  Combina$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.
  38. 38. Efficacy  improvements  with  novel   induc$on  regimens   Regimen Patientswith≥VGPR(%) Cavo M, et al. Blood. 2008;112:[abstract 158]. Harousseau J-L, et al. ASH/ASCO symposium at ASH, 2008. Lokhorst HM, et al. Haematologica. 2008;93:124-7. Macro M, et al. Blood. 2006;108:[abstract 57]; updated data from ASH 2006. Morgan G, et al. Blood. 2007;110:[abstract 3593]; updated data from ASH 2007. Rajkumar SV, et al. ASH/ ASCO symposium at ASH 2008. Richardson P, et al. Blood. 2008;112:[abstract 92]. Sonneveld P, et al. Blood. 2008;112:[abstract 653].
  39. 39. Ini$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.
  40. 40. 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$ve  care  at  all  stages!  
  41. 41. Attal M. N Engl J Med. 1996;335:91-7. Transplant  vs.  Conven$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 Overallsurvival(%) 0 15 30 45 60 High dose Conventional dose
  42. 42. What  does  transplant  add?   Regimen Patientswith≥VGPR(%) 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.
  43. 43. Depth  of  response  improves  over     $me  with  lenalidomide   Lacy MQ, et al. Mayo Clin Proc. 2007;82:1179-84. Mayo clinic phase II CR VGPR PR Patientsrespondingto treatment(%) 4 cycles (n = 34) 19 cycles (n = 21) 0 20 40 60 80 100 43 19 24 53 6 32
  44. 44. HDT  and  ASCT  in  MM  pa$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 Survivalprobability 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 EFSprobability 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 EFSprobability 10 30 60 80 Time (months) TWiSTT OS EFS HDT = high-dose therapy; TWiSTT = time without symptoms, treatment, or treatment toxicity.
  45. 45. 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
  46. 46. 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 Event-freepatients(%) − 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) Patients(%) − Thal
  47. 47. What  about  the  transplant  ‘ineligible’   popula$on?  
  48. 48. Melphalan  +  Prednisone   0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6+ Estimatedpercentagestillalive 24.4 % 23.0 19.4 % 18.0 1.4% SD 1.4 (log-rank 2P > .1; NS)– Allocated CCT (% ± SD) – Allocated MP (% ± SD) Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16;12:3832 Years 27 randomized trials
  49. 49. MPT Arm Melphalan, 4 mg/m2 (7 days per month) Prednisone, 40 mg/m2 (7 days per month) Thalidomide, 100 mg/d (continuously)* (n=129) MP Arm Melphalan, 4 mg/m2 (7 days per month) Prednisone, 40 mg/m2 (7 days per month) (n=126) → ×6 courses Newly diagnosed MM patients, Age >65 years (median age: 72 years) n=255 *Thalidomide dose reduced to 50% if grade 2 toxicity. Enoxaparin prophylaxis added to protocol in December 2003. GIMEMA Phase III Randomized Controlled Trial Palumbo et al. Lancet 2006;367:825-831 MP  vs  MP-­‐thalidomide  (MPT)  in  Elderly  Pa$ents  
  50. 50. 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 ProportionofPatients 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 ProportionofPatients Months MP MPT
  51. 51. 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  
  52. 52. IFM  99-­‐06:  Overall  Survival   Facon T et al. The Lancet 2007; 370:1209-1218
  53. 53. 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  
  54. 54. 1117273140658096105116 1626364557708096101113 0,00 0,20 0,40 0,60 0,80 1,00 0 6 12 18 24 30 36 42 48 54 Months Proportionofsurvivingpatients 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.
  55. 55. 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
  56. 56. 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
  57. 57. VISTA:  Survival   San Miguel et al. NEJM. 359 (9): 906 24.0 months for bortezomib vs. 16.6 months in the control group
  58. 58. 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
  59. 59. 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 )
  60. 60. 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
  61. 61. Suppor$ve  care   •  Bisphosphonates   •  An$bio$cs   •  Renal  failure  management   •  Erythropoie$c  agents/  Anemia  management   •  Preven$on  of  thrombo$c  events  
  62. 62. Bisphosphonate  Guidelines   •  In  general  18  months  to  24  months   •  Beyond  18-­‐24  months,  individualized  decision  based   on  disease  status   •  Beneficial  in  all  pa$ents,  irrespec$ve  of  ly$c  disease   •  Calcium  and  vitamin  D  supplementa$on   •  Baseline  dental  evalua$on   •  Careful  monitoring  for  ONJ  
  63. 63. 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  $me  (>  2  hours)  
  64. 64. Zoledronic  acid     •  Zoledronic  acid  is  a  highly  potent  bisphosphonate   •  4  mg  IV  over  at  least  15  minutes   •  Monitor  renal  func$on-­‐  risk  of  acute  renal  failure   •  Not  recommended  in  pa$ents  with  severe  renal   impairment  
  65. 65. Infec$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  
  66. 66. Management  of  anemia   •  Anemia  common   •  Mul$factorial,  several  mechanisms   •  Usually  improve  with  effec$ve  therapy   •  Persistent  anemia  may  reflect  treatment  agent   •  Erythropoie$n  use  may  increase  risk  of  thrombosis  
  67. 67. Renal  Failure   •  Nearly  a  third  of  pa$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$ve  renal  management  
  68. 68. Thromboprophylaxis   •  Risk  of  thrombosis  about  5%  among  pa$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  
  69. 69. What  about  when  these  fail?  
  70. 70. 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  
  71. 71. 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) Proportionofpatients 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
  72. 72. Thank  You!  
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