Updates in management of multiple myeloma

Mohamed Abdelmooti 12.2014

Management of multiple myeloma

1.  Management of transplant-eligible patients

2.  Management of transplant-ineligible patients

3.  Complications of MM and their management

Criteria for Diagnosis of symptomatic MM*: International Myeloma Workshop Consensus Panel (2011):

1. Clonal bone marrow plasma cells ≥10% 2. Presence of serum and/or urinary monoclonal protein:

Ig G > 3.5 g / dl.; Ig A > 2 g / dl.; or BJP > 1 g / 24 hr urine. (except in patients with non-secretory MM†)

3.  ≥1 CRAB features of end-organ damage: •  C: Calcium elevation (>11.5 mg/L)

•  R: Renal dysfunction (serum creatinine > 2 mg/dL)

•  A: Anemia (Hb < 10 g/dL)

•  B: Bone disease (lytic lesions, osteoporosis, fractures)

*All 3 criteria must be met. † ≥10% clonal plasma cells are required for the diagnosis of non-secretory MM.

What are factors that determine high-risk disease?

Disease-­‐specific  factors    

•  ISS  stage  (B2M  &  albumin)    

•  Extramedullary  disease    

•  Plasma  cell  leukemia    

•  LDH  •  High  prolifera>on  rate    •  Plasma  labelling  index    

•  Cytogene>c  abnormali>es    

Pa>ent-­‐specific  factors    

•  Age  •  Co-­‐morbidi>es,  e.g.  renal  failure,  spinal  cord  compression  

ISS:  Interna5onal  Staging  System    

•  t(4;14)  •  t(14;16)  •  del17p  •  1q  gain  

Response:  IMWG  uniform  Criteria  (2011)  

sCR   CR   VGPR   PR  

SPEP   Nega5ve   Nega5ve   Nega5ve   Posi5ve  

IF   Nega5ve   Nega5ve   Posi5ve   Posi5ve  

sFLC  ra5o   Normal   Abnormal   Abnormal   >50%    decrease  

Serum      M-­‐protein  

Nega5ve    

Nega5ve   ︎  >90%  reduc5on  

>50%  reduc5on  

24-­‐hr  urinary  M-­‐protein    

Nega5ve    

Nega5ve   ︎<100  mg  <100  mg   <200  mg  

PCs  in  BM    

• <5%  • No  clonal  PCs  by  IHC  

<5%    

<5%    

>50%  reduc5on    

ST  PCM   Disappearance   Disappearance   Disappearance   >50%  reduc5on  

Assessment of MRD: •  Immunophenotypic CR (by multiparametric flow

cytometry >4 colors) •  Molecular CR (by ASO*-PCR): (Sensitivity 10-4 - 10-6)

• 

Rajkumar et al, Blood 2011, 117 (18): 4691-5

Response outside BM (Imaging techniques): •  MRI: number of persisting focal lesions. •  PET-CT: negativity

• *Allele-specific oligonucleotides

Association between depth of response and outcome

1.  >VGPR is better than <VGPR (PFS) 2.  CR is better than <CR (in transplant setting and in

elderly) (PFS and OS) 3.  Sustained CR is important (OS) 4.  MRD- is better than MRD+ (PFS and OS) 5.  Number of focal lesions in whole-body MRI after

ASCT had significant impact on OS 6.  PET-CR after ASCT conferred superior PFS and OS

1.  Moreau  et  al.  Blood  2011;117:3041-­‐4                            2.  Mar6nez-­‐lopez    et  al.  Blood;    118(3):529-­‐534;  3.  Gay  F  et  al.  Blood;117:3025-­‐31.                                                                                      4.  Barlogie  et  al.  Cancer  2008;113(2):355–359  5.  Paiva  et  al;  Blood.  2008,  112:  4017-­‐4023;                              6.  López-­‐Pérez  et  al  .  Leukemia  2000  7.  Hillengass  et  al.  ASH  2011  (Abstract  1812)                            8    Zamagni  et  al.  ASH  2011  (Abstract  826)  

Front-­‐line  therapy  of  mul>ple  myeloma  

Criteria to start treatment

1.  Patients with asymptomatic MM:

Immediate chemotherapy does not offer any survival benefit over that provided by delayed chemotherapy, as convincingly demonstrated by several controlled studies and confirmed by a recent meta-analysis pooling the results of these trials

2.  Treatment must be started immediately in patients with MM and related organ damage [I, A].

ESMO Minimum Clinical Recommendations, 2005 Kyle, et al, NEJM, 2004

Front-­‐line  therapy  of  mul>ple  myeloma  

I.  Transplant-­‐eligible  Pa>ents  

Management  of  Newly  Diagnosed  Myeloma  

 Every  newly  diagnosed  myeloma  pa5ent  should  be  assessed  for  fitness  to  undergo  ASCT:  1.  Age  <  60–65  years:  not  the  only  factor  2.  Good  performance  status  3.  Adequate  organ  func5on  4.  No  significant  comorbidi5es.

Kaushansky  et  al,  William’s  Hematology  (2010)    

Combina>ons  that  include  alkyla>ng  agents  (esp.  melphalan)  should  be  avoided  à  damage  to  normal  HSCs  à    impossible  to  collect  stem  cells  for  ASCT  

Treatment  paradigm  for  pa>ents  who  are  eligible  for  autotransplanta>on  (ASCT)  

Induc5on  Therapy    

Role:  Reduc5on  of  tumor  burden  prior  to  ASCT    

Induc5on  Therapy    VAD:  Q4w    « Vincris5ne:  0.4  mg  iv  over  4-­‐24  hr  qd  d1-­‐4  « Adriamycin:  9  mg/m2  iv  over  4-­‐24  hr  qd  d1-­‐4  « Dexamethasone  :  40  mg  IV  (or  PO)  qd  d1-­‐4,  9-­‐12,  17-­‐20    

•  Has  been  the  standard  induc5on  regimen  for  many  years  •  However,  it  achieve  a  CR  rate  of  only  5-­‐10%  with  >VGPR  rate  of  18-­‐44%  

•  The  need  for  admission,  CVL,  alopecia.    •  Has  been  replaced  by  novel  drugs  à  beder  CR  rates  pre-­‐transplant  

 Reece,  Hematology  (2005)  

Ludwig  et  al.  Oncologist  2011;16(4):  388-­‐403  

+  DEXA  

+  Adria  or  CPA  

+  CPA  

T R V VT or VR

POM-­‐d  POM-­‐V  

POM:  Pomalidomide  

POMCyD  

Biaxin  [clarithromycin]  

Thalidomide-­‐Based  Induc5on  regimens:  

Regimen   Drugs   Response  before  ASCT  

Median  Survival  

VS  VAD  

CR   >VGPR   PFS   OS  

Thal/dex  (TD)      q4w  

•  Thalidomide:  100-­‐200  mg  po  qd  •  Dexamethasone:  40  mg  po  qd  d1-­‐4,  9-­‐12,  17-­‐20  for  odd  cycles  and  d1-­‐4  only  for  even  cycles  

14%   31%   47  m   65%  (5y)  

NA  

CTD      q4w  

•  Cyclophosphamide:  500  mg/w  •  Thalidomide:  50  à  200  mg/d  •  Dexamethasone:  20  mg/day  on  days  1  to  4  and  15  to  18  

13%   43%   26  m   72  m   •  Beder  RR  •  Similar  PFS    •  Similar  OS  

TAD        q4w    

•  Thalidomide:  200  mg  orally,  days  1  to  28  

•  Adriamycin:  9  mg/m2  IV  d  1-­‐4  •  Dexamethasone:  40  mg  on  d1-­‐4    

3%   37%   34  m   73  m   •  Beder  >VGPR  •  Beder  PFS    •  Similar  OS  

Lenalidomide-­‐Based  Induc5on  regimens:  

Regimen   Drugs   Response  before  ASCT  

Survival    

CR   >VGPR   OS  

RD      q4w  

•  Revlimid:  25  mg  po  qd  d1-­‐21  •  Dexamethasone  (HD):  40  mg                d  1-­‐4,  9-­‐12,  and  17-­‐20  

5%   50%   87%  (1y)    

Rd      q4w  

•  Revlimid:  25  mg  po  qd  d1-­‐21  •  dexamethasone  (LD):    40mg/w    

4%   40%   96%  (1y)    

RAD      q4w    

•  Revlimid:  25  mg  on  days  1-­‐21  •  Adriamycin:  9  mg/m2  IV  days  1-­‐4  •  Dexamethasone:  40  mg  on  days  1-­‐4  and  17-­‐20  

13%   52%   NA  

Not  Vs  conven>onal  therapy      

(p=0.0002)  (p=0.04  

Rajkumar  et  al,  Lancet  Oncol.,  2010.  

Bortezomib-­‐Based  Induc5on  regimens:  

Regimen   Drugs   Response  before  ASCT  

Median  Survival  

VS  VAD  

CR   >VGPR   PFS   OS  

Vel/dex      Q3w    

•  Velcade:  1.3  mg/m2  iv  d1,  4,  8  and  11  

•  Dexamethasone:  40  mg  po  d1,  4,  8  and  11  

15%   38%   36  m   81%  (3y)  

•  Beder  RR  •  Beder  PFS    •  Similar  OS  

PAD      Q3w    

•  Bortezomib:  1.3  mg/m2  iv  bolus  d1,  4,  8,  11  

•  Adriamycin:  4.5-­‐9  mg/m2  iv  d1-­‐4  •  Dexamethasone:  40  mg  po  d1-­‐4,  8-­‐11,  15-­‐18  of  cycle  1  then  d1-­‐4  of  cycles  2-­‐4  

11%   42%   36  m   Not  reached  

•  Beder  RR  •  Beder  PFS  •  Beder  OS  

VCD        Q3w    

•  Velcade:  1.3  mg/m2  iv  d1,  4,  8,  11  •  Cyclophosphamide:  500  mg/m2/day  IV  on  d1,  8,  and  15  

•  Dexamethasone:  40  mg  d1,4,  8,15  

15%   37%   NR   NR   •  NR  

•  Bortezomib-based induction regimens highly effective. •  Bortezomib/dex: could be considered as a backbone for induction

therapy before autologous transplantation.

Bortezomib  +  IMiD-­‐Based  Induc5on  regimens  (triplet  regimens):  VS  DOUBLET  Regimens  

Regimen   Drugs   Response  before  ASCT  

Survival   VS  Doublet  regimens  

CR   >VGPR   PFS   OS  

VTD        Q3w    

•  Velcade:  1.3  mg/m2  iv  d1,  4,  8  and  11  

•  Thalidomide:  100-­‐200  mg/d.  •  Dexamethasone:  40  mg  daily  on  8  of  the  first  12  days.  

19%   62%   68%m  (3y)  

86%  (3y)  

VS  TD:  •  Beder  RR  •  Beder  PFS    •  Similar  OS  

vtD   •  velcade:  0.8-­‐1  mg/m2  iv  d1,  4,  8  and  11  

•  thalidomide:  50  mg/d.    •  Dexamethasone:  20  mg  po  d1,  4,  8  and  11  

13%   49%   NR   NR   VS  VD:  •  Beder  RR  

VRD   •  Velcade:  1.0  or  1.3  mg/m2  d1,  4,  8,  11.  

•  Revlimid:  15  to  25  mg  d1-­‐14.  •  Dexamethasone:  40  or  20  mg  d1,  2,  4,  5,  8,  9,  11,  12.  

29%   67%   75%  (1.5y)  

97%  (1.5y)  

•  NR  

H i g h e s t 3-drug regimens are superior to 2-drug regimens

Four-­‐drug  Induc5on  regimens:  

Regimen   Drugs   Results  

VTDC        Q3w    

• Velcade:  1.3  mg/m2  d1,  4,  8,  11.  •  Thalidomide:  100  mg  daily  d1-­‐21  • Dexamethasone:  40  mg/d  on  days  1-­‐4  and  9-­‐12  •  Cyclophosphamide:  400  mg/m2  IV  on  days  1  and  8  

•  CR  31%  • OR  96%  •  Increased  G3/4  toxici5es  

RVCD          Q3w  (EVOLUTION)  

 

• Revlimid:  15  mg/day  D1-­‐14  • Velcade:  1.3  mg/m2  d1,  4,  8,  11.  •  Cyclophosphamide:  100–500  mg/m2  D1  and  8  • Dexamethasone:  40  mg  D1,  8,  15.  

•  CR  36%  •  >VGPR  68%  

Ludwig,  JCO,    (2012)  Kumar  S,  et  al.  Blood.  2008;112:  [abstract  93].  

4-drug induction regimens are not superior to three-drug combinations due to higher toxicities.

ASCT in MM

ASCT for MM

Four prospective randomized European studies have established that auto-HSCT confers superior overall survival and/or event-free survival when compared to standard chemotherapy therapy.

Atta eta al, NEJM (1996) Child et al, NEJM (2003); Palumbo et al, Blood (2004) Farmland et al, JCO (2005)

International Myeloma Foundation (IMF) (Evidence-based…2011/2012):

ASCT as planned part of “frontline therapy”: Recommendations:

1.  ASCT is strongly considered in “front-line therapy for MM” à improved RRs (CR>90%) and OS with TRM <5%

2.  Standard conditioning regimen is Melphalan 200 mg/m2 (NO TBI)

3.  Stem cell purging… NOT recommended 4.  PBSCs > BM: easy & rapid. 5.  Pre-ASCT induction: Thal/Dex, Vel/Dex, VTD, Len/dex. 6.  Planned tandem ASCT: Only if did NOT attain at least

VGPR after 1st SCT, otherwise investigational!

Allogeneic SCT for Multiple Myeloma

1.  RIC Allo-SCT: Current data do not its universal use for myeloma and attention needs to be paid to RIC strategies including:

•  Conditioning •  Auto à RIC •  Immunosuppression •  Role of DLI. •  Integration of Novel Drugs in RIC-Allo programs

2.  MAC Allo-SCT should not be considered standard treatment, and should only be considered in selected population of patients in the context of a clinical trial.

Aims  of  consolida>on  or  maintenance  therapy  aeer  ASCT    

Consolida>on:    •  Improve  response/induce  deeper  response  following  therapy    

• By  administra5on  of  treatment  for  a  limited  period    

Maintenance:    • Maintain  response  achieved  following  therapy  

• By  administra5on  of  treatment  for  a  prolonged  period  Reduce  the  risk  

Reduce  the  risk  of  relapse    Extend  PFS  and  OS  

Consolidation: (V/VTD/VRD)

•  To be considered for pts who do not achieve >VGPR after ASCT.

•  Leads to improvement in depth of response •  PFS is improved with VTD or V consolidation.

Maintenance:

Thalidomide   Lenalidomide     Bortezomib  Dose   100  mg  daily  PO   10  mg  daily  PO  for  

21  days  every  month    1.3  mg/m2  either:  •  Every  2  weeks  or  •  On  days  1,  4,  8,  11  every  3  months  

Dura>on   for  at  least  1  y   Till  progression     2-­‐3  years  

PFS  improvement   In  7/8  trials   In  3/3  trials   In  2/2  trials  

OS  improvement   In  2/8  trials   In  2/3  trials   In  1  trial  

Risk  categories   In  standard-­‐risk  only  

Work  in  “all  risk”  groups    

Work  in  “all  risk”  groups    

Tolerance   Low:  PN  &  #QoL     •  Beler  tolerated  •  ++    SPM  (2/3  trials)  

Beler  tolerated    

Front-­‐line  therapy  of  mul>ple  myeloma  

(II)  Transplant-­‐ineligible  Pa>ents  

Management  of  Newly  Diagnosed  Myeloma  

 Transplant-­‐ineligible  Pa>ents:  1.  Age  >  60–65  years:  not  the  only  factor  2.  Poor  performance  status  3.  Inadequate  organ  func5on  4.  Significant  comorbidi5es  

Kaushansky  et  al,  William’s  Hematology  (2010)    

Goal of therapy: Palliative

Age and organ damage correlate with poor OS

Front-­‐line  treatment  of  MM  (II)  Non-­‐transplant  sejng:  Induc>on  

Q   Melphalan   Prednisone   Thalidomide   Velcade   Revlimid   Vs  MP  

MP   4w   8-­‐10  mg/d  PO  for  7  ds    

60  mg/d  po  for  7  days    

-­‐-­‐   -­‐-­‐    

-­‐-­‐    

NA  

MPT   4w    

4  mg/m2/d  po  for  7  ds      

40  mg/m2/d  po  for  7  ds  

100  mg/d  po  5ll  disease  progression  

-­‐-­‐   -­‐-­‐   • Beder  RR  and  PFS  (5/5)  • Beder  OS  (2/5  trials)  • 6.6-­‐month  OS  benefit  

VMP   6w   9  mg/m2d  po  for  4  ds        

60  mg/m2/d  po  for  4  ds      

-­‐-­‐   1.3  mg/m2  iv  d1,  4,  8,  11,  22,  25,  29,  32    

-­‐-­‐    

• Beder  PFS.  • Beder  OS.  • 13.3-­‐month  OS  benefit  

MPR-­‐R   4w   0.18  mg/kg  po  for  4  ds      

2  mg/kg/d  po  for  4  ds      

-­‐-­‐    

10  mg/d  po  for  21  ds  Q4w  un5l  disease  progression.  

•  Beder  PFS  •  Same  4y  OS  

These  data  lend  support  to  the  use  of  MPT  (or  VMP)  as  the  standard  of  care  in    elderly  MM  

T   VT   R  

Study   MPT  +  T  (3  studies)  

•  VMPT-­‐VT  Vs  VMP  •  VMP  Vs  VTP  à  VT  VS  VP  maintenance  

MP  vs  MPR  vs  MPR-­‐R  maintenance  

PFS   Improved  in  2/3   Improved  in  1/2   Improved  

OS   Improved  in  1/3   Improved  in  1/2   Small  OS  benefit  esp.  in  >65  yr.  

AEs   Higher  rate  of  G  3-­‐4  PN     Increased  SPM  

Front-­‐line  treatment  of  MM  (II)  Non-­‐transplant  sejng:  Maintenance    

In  Maintenance  

X2  

Summary/Conclusions:  

Elderly  pa5ents:  Op5mizing  treatment  tolerability  through  modified  treatment  schedules  

Considera>ons  when  trea>ng  elderly  pa>ents:  •  Decrease  in  func5onal  capacity:  PS,  ac5vi5es  of  daily  living,  cogni5ve  func5on  

•  Comorbidity  (renal,  pulmonary,  hepa5c,  cardiac,  bone  marrow  insufficiency,  polyneuropathy)  

•  Disability  and  Frailty  (weakness,  poor  endurance,  weight  loss,  low  physical  ac5vity,  slow  gait  speed)  

•  Increased  prevalence  of  unfavorable  prognos5c  factors  (B2M>3.5  ug/mL,  albumin  <3.5  g/dL,  Hb  <  10  g/dL,  ISS  stage  III)1  

•  Polypharmacy  (?drug  interac5ons)  •  Decreased  capacity  to  tolerate  toxicity:  

―  Increased  rates  of  therapy  discon5nua5on  ― Decreased  Cumula5ve  dose  intensity      

             1Ludwig  et  al.  J  Clin  Oncol  2010;28(9):1599-­‐605    

 2Ludwig  et  al.  Blood  2009;113(15):3435-­‐42  

Strategies  to  improve  the  tolerability  of  treatment:  

•  Changing  treatment  schedules    

         –Reduc5on  in  frequency  of  dosing  (e.g.  weekly  bortezomib)  à  reduced  PN.        

               –Reduc5on  in  drug  dosage:  (THAL100,  LEN15,  v1  in  vtD)    

•  Changing  the  route  of  administra5on    

         –  e.g.  SC  bortezomib  à  reduced  PN.  

Relapsed/Refractory Myeloma

Management  of  Mul5ple  Myeloma  (Cont.)  

Patterns of relapse in myeloma

Biochemical Symptomatic M-component Increased Increased Symptoms Asymptomatic Symptomatic CRAB Criteria Absent Present Soft tissue PCM & lytic bone lesions

No new lesions •  New lesions •  >50% increase in

existing lesions Re-treatment •  Should not be immediately

started •  Initiate therapy with doubling

of serum M-protein within 2 months or increase of urine M-protein >500 mg/24hr

Immediate treatment

IMWG Consensus Statement, 2011

Treatment at relapse Consider SCT

       

Front-line with novel agent?

 Survival is extended with novel agent

Yes No

Bortezomib-based, e.g. •  Bortezomib +/- dex •  Bortezomib/PLD* •  VCD, PAD

IMiD-based, e.g. •  Len/dex* •  Thal +/- dex •  CTD

Bortezomib + IMiD-based, e.g. •  VMPT •  VTD

*Data available from phase 3 randomized clinical trials Ludwig et al. Oncologist. 2011;16:388-403

Use novel agent

Treatment at relapse

Repeat or change front-line treatment?

treatment after:  

•  Long remission •  No toxicity concerns

from first-line treatment

class after:

•  Short remission •  Toxicity concern from previous line

Yes

Switch drug Repeat

Consider SCT  

Front-line with novel agent?

No

Ludwig et al. Oncologist. 2011;16:388-403

Front-­‐line  consisted  of  

Thal-­‐based   Bortz-­‐based  

Thal-­‐based  Bortz-­‐based   LEN-­‐based  

t

Considera>ons  in  case  of  specific  complica>ons  

•  Renal  impairment  

― Bortezomib-­‐based  

― Thalidomide-­‐based  

― Lenalidomide-­‐based  (dose  modifica5on  mandatory)  

•  Current  or  recent  thromboembolic  or  cardiovascular  events:  

― Bortezomib-­‐based  

― Lenalidomide-­‐based  following  prophylaxis  guidelines  

•  Treatment-­‐related  peripheral  neuropathy  

― Lenalidomide-­‐based  

Dimopoulos et al. ASH 2013 (Abstract 3177), poster presentation

Bortezomib + dex versus bortezomib monotherapy in relapsed MM (n=218)

*P < 0.001

Bortezomib-Dex 13.6 months

Single-agent Bortezomib: 7 months P=0.003

OS comparable between arms

Response rates Bortezomib-Dex Single-agent bortezomib (n=109) (n=109) ORR (CR + PR) 75%* 41%* CR 10% 8% PR 65% 33%

TTP

Better with Bor-Dex

Retrospective matched-pairs analysis:

Salvage ASCT: Myeloma-X Ph 3 prospective study (n= 174)

Cook et al. ASH 2013 (Abstract 765), oral presentation

•  Results (median follow-up 12 months):  

•  Conclusion  – First prospective study to demonstrate superior duration of

response for 2nd salvage ASCT

ASCT Cyclophosphamide weekly

(No=98) (No=85) P

Median TTP 19 months 11 months < 0.0001

3year OS 80.3% 62.9% 0.2332

•  Pts in relapse following prior ASCT •  PAD induction (bortezomib, doxorubicin, dexamethasone) •  Randomization: MEL200-ASCT versus CPA weekly x 12

Newer agents for R/R myeloma:

1. Carfilzomib (Kyprolis) IV: G2 proteasome inhibitor

2. Pomalidomide (Pomalyst capsule): G3 IMiD

3. Bendamustine (Trenada) IV: alkylating agent

4. Oral Proteasome Inhibitors: Ixazomib, Oprozomib.

Carfilzomib (Kyprolis vial 60mg ) in in rel/ref MM

•  Carfilzomib is a G2 proteasome inhibitor that selectively and irreversibly binds to the proteasome,

•  Provides sustained proteasome inhibition without off-target effects

•  No significant treatment-related PN

•  Dose: 20 mg/m2/day IV (10 min) in cycle 1 (days 1,2,8,9,15,16) and if tolerated increase Cycle 2 & subsequent cycles daily doses to 27 mg/m2/day (repeat cycle every 28 days).

•  With Low dose dex à ORR of 67%

Berenson  et  al.  ASH  2013  (Abst.  1934)

         Thalidomide  analog  (3-­‐amino-­‐thalidomide):  

1.  Less  myelosuppressive  effects  than  lenalidomide.    

2.  Less  cons5pa5on  &  neuropathy  than  thalidomide.    

Pomalidomide (Pomalyst Capsule 4 mg):  

Dose:  4  mg  once  daily  orally  on  Days  1-­‐21  of  repeated  28-­‐day  cycles  un5l  disease  progression.  

MM-003 Phase 3 : Pomalidomide + low-dose dex versus high-dose dex in rel/ref MM

Dimopoulos et al. ASH 2013 (Abstract 408), oral presentation

Updated PFS and OS results median follow-up 15.4 months

POM + LoDex HiDex

(n=302) (n=153) P

ORR 31% 10% < 0.001

Median PFS 4.0 months 1.9 months <0.001

Median OS 13.1 months 8.1 months 0.009

Regardless  of  the  presence  of  del17p  or  t(4;14)    

ORR (>PR) of Carfilzomib and Pomalidomide combinations in in rel/ref MM

Carfilzomib   Pomalidomide  

Each  +  LD  Dex   67%1   31%2-­‐48%3  

Both  +  LD  Dex   64%4  

With  LD  Dex  &  LEN   78%5   -­‐-­‐-­‐  

With  LD  Dex  &  Bor   -­‐-­‐   75%6  

1. Berenson et al. ASH 2013 (Abst. 1934) 2. Dimopoulos et al. ASH 2013 (Abstract 408), 3. Baz et al. ASH 2013 (Abst. 3200)

4. Shah et al. ASH 2013 (Abst. 690) 5. Wang et al. JCO. 2011; 29: (Abst. 8025) 6. Richardson et al. ASH 2013 (Abst. 1969)

New Therapeutic Algorithm  

<65  years   65-­‐75  years   >75  years  1st  Line   •  Induc>on:  VD  (VCD-­‐VTD)  

• ASCT  • Maintenance:  LEN  

Full-­‐dose  combina>on:  MVP  (MPT-­‐RD)  

Reduced-­‐dose  combina>on:  mpt  (rd-­‐mvp)*  

1st  Relapse   VD   RD   vd*  2nd  Relapse   RD   VD   rd*  3rd  Relapse   •  Carfilzomib  

•  Pomalidomide  4th  Relapse   TD  

VD:  Velcade  +  Dexamethasone        VCD:  Velcade  +  Cyclophosphamide  +  Dexamethasone  RD:  Revlimid  +    Dexamethasone        VTD:  Velcade  +  Thalidomide  +  Dexamethasone  TD:  Thalidomide  +  Dexamethasone      MPT:  Melphalan    +  Prednisone  +  Thalidomide  MVP:  Melphalan    +  Velcade  +  Prednisone    *Reduced-­‐dose  

Complications of Multiple Myeloma

RenalFailure

Hyperviscosity Amyloidosis

MonoclonalProtein

Anaemia

LL 6

BonePains

Hypercalcaemia

Bone Destruction

Release ofCytokines

MarrowInfiltration

Infections

ImmuneDeficiency

MM

MULTIPLE MYELOMA: Complications

70%

<2% 25%

70%

25%

12-15%

98%

◗ Lytic lesions ◗ Fractures ◗ Osteopenia

Bone pains

• IL6

• IgA • AL

SC compression

5-10%

Mechanism of bone resorption:

Plasma cells à macrophage inflammatory protein 1α (MIP-1) à

•  ++osteoblasts à ++Receptor Activator of Nuclear Factor-κB Ligand (RANKL) à osteoclastic activation

•  -- bone lining cells à Reduction in the level of osteoprotegerin (OPG) (natural antagonist of RANK ligand)

•  Increase in the ratio of RANKL:OPG à activation of osteoclasts à bone resorption.

Bone pains

§  Sites: back > chest > extremities §  Causes: osteolytic lesions, fractures and osteoporosis §  Worsen with movement, not at night (unlike metastasis) §  Management:

•  Morphia or transdermal fentanyl •  Avoid NSAIDs: precipitate RF or exaggerate

corticosteroid-induced gastritis •  Splinting or vertebroplasty •  Increase mobility when pain is controlled to avoid

increase in bone decalcification, hypercalcemia and DVT.

Sattva and Dunbar, Bethesda Clin. Oncol. (2005)

Management of Bone Disease

Cellular Effects of Bisphosphonates: 1.  Osteoclast inhibition and apoptosis 2.  Inhibit production of cytokines that stimulate osteoclasts (IL-6,

VEGF, RANKL) 3.  Tumor cell apoptosis 4.  Synergistic anti-tumor effects with anticancer treatments 5.  Inhibition of adhesion molecules 6.  Anti-angiogenic 7.  Direct effect on Myeloma (may slow tumor growth)

Djulbegovic, et al Cochrane Database of Systematic Reviews(2002)

Bisphosphonates:

Meta-analysis of 10 trials: Adding bisphosphonates to the treatment of myeloma reduces vertebral fractures and pain but not mortality

Management of Bone Disease IV Bisphosphonates: Side Effects

• Flu-like symptoms (fever, myalgias, arthralgias) • Occurs usually 12-48 hrs following the infusion • Lasts 6-24 hrs • Occurs in a minority of pts (10-20%) • Not observed with continued dosing • Similar frequency with different drugs

•  Renal dysfunction •  Ocular (rare, with pamidronate): scleritis •  Osteonecrosis of the jaw

Use of Bisphosphonate in MM: {ASCO recommendations 2007}

Indications: ◗  Plain radiograph(s) à lytic destruction of bone ◗  Compression fracture of the spine from osteopenia ◗  Osteopenia with no radiographic evidence of lytic bone

disease.

Not recommended in: ◗  Patients with solitary plasmacytoma or smoldering or

indolent myeloma without documented lytic bone disease ◗  Patients with MGUS.

Management of Bone Disease

Kyle et al., JCO 2007.

Use of Bisphosphonate in MM: {ASCO recommendations 2007} Drugs used : ◗  Pamidronate (Aredia) 90mg IV (≥2hours) every 4 weeks or

◗  Zoledronic acid (Zometa) 4 mg IV (15 min) every 4 weeks

◗  9.5-fold greater risk for the development of osteonecrosis of the jaw with zoledronic acid compared with pamidronate, patients may prefer pamidronate to zoledronic acid

Management of Bone Disease

Kyle et al., JCO 2007.

Use of Bisphosphonate in MM: {ASCO 2007} Duration of therapy: ◗  Therapy with bisphosphonates be given monthly for a

period of two years ◗  At two years, the physician should seriously consider

stopping bisphosphonates in patients with responsive or stable disease, but their further use is at the discretion of the treating physician.

◗  For those patients in whom bisphosphonates were withdrawn after two years, the drug should be resumed upon relapse with new onset skeletal related events.

Management of Bone Disease

Kyle et al., JCO 2007.

Use of Bisphosphonate in MM: {ASCO 2007}

Rate of infusion is the key factor in prevention of renal dysfunction: Rates faster than 0.3-0.7 mg/min are associated with renal dysfunction

Pre-existing Renal impairment: ◗  Mild-to-moderate (cr cl 30 to 60 mL/min):

v  Should receive a reduced dosage of zoledronic acid. v  No changes in infusion time or interval are required.

◗  Severe renal impairment (cr cl <30 mL/min): v  Zoledronic acid is not recommended v  Pamidronate reduced dose administered over 4 to 6

hours is recommended

Kyle et al., JCO 2007.

Use of Bisphosphonate in MM: {ASCO 2007} Renal monitoring: Serum creatinine should be monitored before each dose of pamidronate or zoledronic acid: •  Renal deterioration without apparent cause during

bisphosphonate therapy, zoledronic acid or pamidronate should be withheld.

•  When the serum creatinine returns to within 10% of the baseline levelà Bisphosphonate therapy can be resumed, at the same dosage as that before treatment interruption.

Management of Bone Disease

Kyle et al., JCO 2007.

Osteonecrosis of the Jaws (ONJ):

•  A severe "bone" disease, associated with bisphosphonate therapy that affects the jaws

•  Incidence 5% •  Although ONJ can occur spontaneously, most

cases occur in patients after a tooth extraction or other invasive dental procedure

•  Exposed infected necrotic bone in the maxillofacial region that does not heal within 8 weeks.

•  Presents as pain and/or numbness in the affected area, soft-tissue swelling, drainage, and tooth mobility.

Terpos et al, Ann Oncol (2009)

Osteonecrosis of the Jaws (ONJ):

Risk factors: –  Duration of bisphosphonate exposure (5-15% at 4 yr).

–  Invasive dental procedures such as extractions (50%).

Prevention: (ASCO 2007) –  Dental evaluation prior to starting bisphosphonates –  Maintain excellent oral hygiene –  Avoid dental procedures while receiving

bisphosphonate. –  Antibiotic prophylaxis before dental procedures.

Dimopoulos et al, Ann Oncol (2009)

Osteonecrosis of the Jaws (ONJ): Management:

–  Usually conservative: •  Discontinuation of bisphosphonates •  Limited debridement •  Antibiotic therapy •  Topical mouth rinses.

–  Surgical resection of necrotic bone should be reserved for refractory cases.

–  Healing of ONJ in 75% patients.

Khan et al, J Rheumatol (2008)

Hypercalcemia

Clinical presentation: 1.  GIT: Anorexia, nausea, vomiting, constipation 2.  Dehydration 3.  Neurological: weakness, depression, apathy, coma 4.  Renal tubular damage: polyuria, polydipsia, rising

creatinine. 5.  ECG : Short QT interval, arrhythmias.

Mellstedt , Ann Oncol (2007)

Hypercalcemia: Management: Treatment of MM-related hypercalcemia should be started at a corrected serum Ca level > 12 mg/dL:

• Aggressive hydration: with 3-4 L saline / 24 hrs.

• Dexamethasone: 40 mg I.V. daily for 4 days.

• Intravenous diuretic therapy (e.g. furosemide) à ++ renal clearance of calcium

• Bisphosphonates are given if no response occurs or if the hypercalcemia is severe. A single dose of pamidronate or Zoledronic acid will normalize the calcium levels within 24-72 hours in most patients.

He et al, Cochrane Database Syst Rev (2003)

Pathological Fracture: •  Fractures of long bones: fixation and

medullary nail à PO irradiation. •  In vertebral fractures: surgery is usually not

indicated. Send for radiotherapy. •  I.V. bisphosphonate therapy. •  If the heart is in the irradiation field, delay

adriamycin and cyclophosphamide treatment.

•  All patients should immediately receive high-dose dexamethasone therapy (grade A).

•  Patients who have neurologic impairment (deficits and/or symptoms) should also receive local radiotherapy within 24 h of diagnosis (grade C).

•  Surgery (laminectomy or Kyphoplasty) is not indicated unless there is spinal instability or vertebral collapse à post-operative radiotherapy (grade B).

BAROSI et al, Haematologica (2004)

Spinal cord compression (SCC)

•  C/P: pain (local or radicular), weakness, sensory disturbance and/or sphincter dysfunction

Radiotherapy:

Indications: •  To control pain that is refractory to narcotics •  Big osteolytic lesions. •  Significant osteolytic lesions in weight-bearing bone (for fear

of pathological fracture). •  Cord compression. •  Extramedullary plasmacytoma.

Supportive care in myeloma

Caution: •  Limit the amount of radiation that is administered because

radiation to large areas of bone can limit the amount of systemic chemotherapy that can be administered

•  Should be discouraged if stem cell transplant is planned.

Trea5ng  the  myeloma  pa5ent  with  renal  impairment  

   

Causes of renal failure in MM

1.  Cast nephropathy 2.  Hypercalcemia 3.  Volume depletion (dehydration) 4.  Primary amyloidosis 5.  IV contrast dye 6.  Nephrotoxic meds

Causes of renal failure in MM

1.  Cast nephropathy 2.  Hypercalcemia 3.  Volume depletion (dehydration) 4.  Primary amyloidosis 5.  IV contrast dye 6.  Nephrotoxic meds

Decreased  renal  clearance  of  FLC  à  ++  sFLC  à  direct  tubular  injury.    

How  to  reduce  sFLC  levels?  

― Effec5ve  chemotherapy  -­‐-­‐-­‐  Novel  agents  

― Direct  removal  of  FLCs  from  serum  -­‐-­‐-­‐  PE,  HD  

Management  of  myeloma  kidney:  Time  to  target  FLCs?  

Hutchison  et  al.  Am  Soc  Nephrology  (2011);22(6):  1129-­‐1136  

Drugs used in myeloma kidney

In  RI*   HD  Dexa   Thalidomide   Lenalidomide   Bortezomib  +DEX  

Rate  of  improvement  

Rapid   Slow   Rapid   Very  Rapid  (1-­‐2.5  ms)  

Dura5on  of  response  

Not  sustained   Sustained   Sustained   Sustained    

Response  rate  

Not  high   Most  pts  with  moderate  RI    

In  some  pa5ents  with  Len/Dex    

60%  

Safety   Safe   Safe   Increased  myelosuppression    

Safe  

Dose  reduc5on    

Not  needed   Not  needed   Mandatory   Not  needed  

Conclusion   Highly  ac5ve   Used  with  cau5on  

Feasible  and  effec5ve  with  dose  adjustments    

The  recommended  treatment  in  any  degree  of  RI.  

*renal impairment

HDT/ASCT  (Mel140);  procedure:  restricted  to  pa5ents  <60  years  with  chemotherapy-­‐sensi5ve  disease  and  good  PS  

Why does plasma exchange (PE) not work? •  Effectively clears the intra-

vascular volume

•  Therefore extra-vascular component is not cleared

•  FLCs are 80% extra-vascular

•  Therefore, total body load of FLCs is not significantly reduced

Clark et al Ann Int MED (2005)

•  Extended (6 h) High Cut-Off (HCO) Hemodialysis is more effective for FLC removal than PE

Direct  removal  of  FLCs  from  serum    

Light chain amyloidosis (AL) :

•  C/P: carpal tunnel syndrome or generalized edema (NS)

•  < 60 years + <2 organs involved and no severe heart involvement à HDC/SCT.

◗  Between 60 and 65 years or creatinine > 2 mg/dL à SCT should be considered with caution and the melphalan dose should be reduced.

◗  Not eligible for HDC/SCT à standard MP

◗  Refractory or relapsing patients: intermediate dose dexamethasone and thalidomide

BAROSI et al, Haematologica (2004)

Anemia:

◗  Treatment of reversible causes of anemia such as iron, folate, or vitamin B12 deficiency

◗  Treatment of the underlying disease and improvement in renal function.

◗  Blood transfusion

◗  Erythropoietin

Supportive care in myeloma

Anemia: Erythropoietin therapy (ASCO recommendations 2010) •  Strong recommendation against the use of ESAs to treat

patients with MM who are not receiving concurrent CT.

•  Begin treatment with CT and observe the hematologic outcomes achieved solely through tumor reduction before considering epoetin.

•  If an increase in Hb is not observed after CT à treatment with epoetin or darbepoetin can be initiated.

•  Risk of thromboembolism: previous history of thromboses, prolonged periods of immobilization and treatment with thalidomide or lenalidomide and doxorubicin or corticosteroids

Supportive care in myeloma

Infections: •  Suppressed humoral and cell-mediated immunity from

the disease and the added effects of therapy.

•  Principal organisms: S. pneumoniae and H. influenzae.

•  HZ activation is also common and requires antiviral therapy to prevent dissemination (esp. with bortezomib)

•  Patients should be vaccinated against S. pneumoniae, H. influenzae, and influenza (annual vaccine).

BAROSI et al, Haematologica (2004)

Supportive care in myeloma

Hyperviscosity: ◗  Specially with Ig A MM

◗  C/P: Mucosal hemorrhage, visual abnormalities, HF, seizures, vertigo.

◗  The serum viscosity levels do not correlate well with the symptoms.

◗  Symptomatic hyperviscosity should be treated with plasma exchange (every 3-5 days) until definite therapy can be initiated.

◗  A decision to perform plasmapheresis depends on the symptoms and changes in the ocular fundus.

◗  Chemotherapy should be started promptly once hyperviscosity has been stabilized by plasma exchange

BAROSI et al, Haematologica (2004)

Supportive care in myeloma

Complications of New Myeloma Therapy

1. Venous Thromboembolism (VTE)

2. Peripheral Neuropathy (PN)

3. Hematological adverse events

Emergent Complications of New Myeloma Therapy

1.  Venous Thromboembolism (VTE): Type: •  Oral regimens à DVT or pulmonary embolism •  Infusional regimens à CVL-related thrombosis (~50%) Incidence: •  Highest during the first 3 to 4 months following diagnosis •  Most VTEs occur within the first 60 days of therapy,

coinciding with maximum cytoreduction. •  Varied according to drugs used à

Johnson et al, Blood (2008)

Emergent Complications of New Myeloma Therapy

1.  Venous Thromboembolism (VTE) (DVT, Pulmonary):

Thalidomide:

Facon et al, Lancet (2007)

%VTE Therapy

~3-4% Dexamethasone alone or MP

~2-3% Thalidomide alone

14-26% THAL/DEX

12-20% MPT

1.  Venous Thromboembolism (VTE) (DVT, Pulmonary)

Lenalidomide: •  Single-agent: does not appear to increase VTE •  Lenalidomide + dexamethasone à marked increased in

VTE risk. •  The risk is higher with higher dexamethasone doses,

administration of erythropoietin, and concomitant administration of other agents ( with CPA 14%)

Bortezomib: •  Did not seem to increase the risk of VTE, at least not in

patients with relapsed or refractory disease.

Palumbo et al Leukemia (2008) Richardson et al, Blood (2006)

Prevention of VTE:

Based on the assessment for number of risk factors for VTE:

1.  Myeloma-related (hyperviscosity, newly diagnosed status) 2.  Therapy-related (most important)

•  High-dose dexamethasone (>480 mg/month) •  Doxorubicin, Multiagent chemotherapy •  EPO •  CVL

3.  Patient-related : –  Age >60. –  History of VTE –  Inherited thrombophilia (e.g. deficiencies of antithrombin III,

proteins C, and S) –  Immobilization –  Surgery

4.  Comorbidities: infections, DM, cardiac or renal, obesity.

Palumbo, et al Leukemia (2008)

1.  Venous Thromboembolism (VTE):

Thromboprophylaxis: (ASCO guidelines 2013)

(1) Low-dose aspirin for patients with <1 risk factor for VTE (2) LMWH: once a day, or (3) Full-dose warfarin for:

–  Patients with > 2 risk factors for VTE –  All patient receiving concurrent HD DEX or doxorubicin.

•  Randomized study showed no differences in incidence in VTE among the three prophylaxis regimens in patients receiving thalidomide combinations

•  In elderly pts: WAR showed less efficacy than LMWH •  Recommended duration of prophylaxis is 6-12 months

Emergent Complications of New Myeloma Therapy

2.  Peripheral Neuropathy Drugs: •  Bortezomib:

•  Grade 3/4 PN: ~20% of newly diagnosed & 30% of relapsed •  When combined with lenalidomide à neuroprotective effect.

•  Thalidomide`: •  PN in 75%: esp. high dose (400 mg), long duration of therapy. •  Switching to lenalidomide will usually improve PN

Should be distinguished from other causes such as: –  Paraneoplastic neuropathies, –  AL amyloidosis. –  Neurotoxic chemotherapy (vincristine or cisplatinum) –  Diabetes mellitus

Richardson, Br J Hematol, (2009)

Emergent Complications of New Myeloma Therapy

2.  Peripheral Neuropathy:

Clinical findings:

Type Presenting symptom Thalidomide Bortezomib Sensory Hypoesthesia, paresthesia:

numbness, tingling, pin-prick sensation, hyperesthesia

Common Rare

Neuropathic pain Rare Common Ataxia, gait disturbance Rare Rare

Motor Tremors Common Rare Weakness Rare Rare

Autonomic GIT Constipation Constipation CVS Bradycardia Orthostatic

hypotension Others Impotence ---

Sonneveld et al. ASH Educ Program 2010

2.  Peripheral Neuropathy: Dose adjustment:

PN Sensory (Paraesthesiae)

Motor (Weakness)

Thalidomide Dose Bortezomib Dose

G1 •  Mild, or •  Loss of tendon

reflexes

On exam/testing only

• Asymt.: no action • Symt.: 50% reduction

•  Asymt.: no action •  Symt.: reduction to

1mg/m2 or Weekly administration Not interfering with function* or ADL**

G2 •  Moderate, •  Mild •  Discontinue •  If PN resolves, restart

at 50% reduction.

•  Reduction to 1mg/m2

weekly. Interfering with function*, but not

interfering with ADL**

G3 •  Intolerable •  Marked Discontinue •  Discontinue. •  If PN resolves, restart

at 0.7 mg/ m2 weekly. Interfering with ADL**; bracing or

assistance to walk (cane or walker)

G4 •  Disabling •  Paralysis Discontinue Discontinue

Time to resolution of symptoms Longer time 3 months-2 years

Sonneveld et al. ASH Educ Program 2010

*Function (instrumental): preparing meals, shopping for groceries or clothes, using telephone **Activities of Daily Living: bathing, dressing and undressing, feeding self, using the toilet

2.  Peripheral Neuropathy:

•  Change of schedule (e.g. weekly Bortezomib), •  Change of administration route (e.g. S.C. Bortezomib) •  Switch to non-neurotoxic agent •  Chemoprotectives: Vit. B12, folic acid, antioxidants (vit

E), glutathione, L-carnitine . •  Symptom relief:

•  Pain relievers: NSAIDs, tramadol, lidocaine patch •  Anti-seizure medications: gabapentin (Neurontin),

pregabalin (Lyrica), carbamazepine (Tegretol). •  Neurotrophic drugs: Cerebrolysin •  Antidepressants: Amitriptyline, Nortriptyline,

Duloxetine, Venlafaxine.

Apfel and Zochodne, Neurology (2004) Sonneveld et al. ASH Educ Program 2010

Emergent Complications of New Myeloma Therapy

3.  Hematological adverse events:

Bortezomib Lenalidomide Thalidomide Toxic effect on BM No Yes No Neutropenia: •  G3/4 (<1000) •  Pattern

•  FN

14% Transient, with rapid recovery to baseline Uncommon

40-70% Need for HGFs in 34-49% 3.4%

13%

7%

Thrombocytopenia: •  G3/4 (<50.000) •  Pattern

30% Cyclical: with recovery to baseline

15% Progressive

Uncommon

Anemia: •  G3/4 (<8 g)

10%

13%

Rare

Bortezomib: • Withheld at the onset of G4 toxicity (ANC<500, PLT<25.000). • Once the toxicity has resolved, treatment may be restarted at a 25%

reduced dose

Dose Modifications in Hematological adverse events

Lenalidomide: •  PLT <30,000: Interrupt LEN. If PLT return to ≥30,000, restart at 15 mg. •  ANC <1,000: Interrupt LEN. If ANC return to ≥1,000, restart at 25 mg. •  For each subsequent ANC or PLT drop, interrupt & resume at 5 mg less

than the previous dose. • Do not dose below 5 mg daily

Thalidomide: •  ANC= 500–1,000: consider G-CSF or reduce thalidomide dose by 50%. •  ANC <500: Stop the thalidomide and consider G-CSF until ANC > 500. •  Thalidomide may then be restarted at a 50% dose reduction.

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