pathology and management of plasma cell neoplasm and multiple myeloma

1. I.P.G.M.E.&R.
S.S.K.M. HOSPITAL

2. Plasma Cell Neoplasm
Dr Soumen Mukherjee
Dr Dharmendra Singh

3. HISTORY of Plasma Cell Neoplasm
1850 : 1st Clinical description reported in England by Dr. William Macintrye
a patient named Thomas Alexander presented to him with fatigue , diffuse bone
pain and increased frequency of urination.
1873 : The term Multiple Myeloma by Rustizky (1873) by independent observation with
similar complaints.
1899 : Ellinger described increased serum protein & E.S.R in MM.
1900 : Wright described involvement of Plasma cells in MM & for the 1st time
He used Xray to described patient’s C/F.
1929 : Development of BM aspiration technique.
1937 : Serum protein electrophoresis .
1953 : Graber described heavy & light chain monoclonal protein.
1958 : 1st use of chemotherapeutic agent (d & l mixture of phenylalanine mustard) by Blokin.
1962 : Bergsagel , reported remission in MM by using Melphalan.

4. Group of lymphoid neoplasms of terminally
differentiated B - cells that have in common the
expansion of a single clone of immunoglobulin (Ig)
- secreting plasma cells and a resultant increase in
serum levels of a single homogeneous
(monoclonal) Ig or it’s fragments.
Plasma Cell Neoplasm

5. Origin of
Plasma
cells
Pleuripotent
Stem Cells
GEMM
Precursor
Lymphoid
Progenitor
RBC
Platelet
Granulocyte
Monocyte
Eosinophil
Thymus
B-
Lymphocy
tes
T Cells
Process Ag &
forms MHC-Ag
Complex
TH1TH2
Plasma
Cells
IL-4,IL6,IL10
B-
Lymphocyt
es
Ig

6. AB
SECRET
ING
PLASM
A CELL
FIGHTING
CURRENT
INFECTION
AG
ACTIV
ATED
B-CELL
SECRETE Ig
ISOTYPE
IgG
MATU
RE
B-CELL
ENTERS
CIRCULATION
& BINDS TO
SPECIFIC
ANTIGEN
IMMA
TURE
B-CELL
GAINS
ACCESS TO
PRIMARY
LYMPHOID
FOLLICLE &
MATURES
IMMA
TURE
B-CELL
SMALL
PRE
B-CELL
LARGE
PRE
B-CELL
LATE
PRO
B-CELL
EARLY
PRO
B-CELL
STEM
CELL
BONE MARROW
IMMA
TURE
B-CELL
LEAVES BM &
ENTERS
PERIPHERAL
CIRCULATION
SECONDARY LYMPHOID ORGANS & CIRCULATION

7. • Terminally differentiated B-cells
• Not normally found in peripheral blood
• Account for less than 3.5% of nucleated
cells in the bone marrow
• Oval cells with low N:C ratio.
Cytoplasm is basophilic blue. Nucleus
(30-40% of the cell) is oval or round
and typically placed eccentrically (to
one side) of the cell.
• A clear, colorless area adjacent to the
nucleus contains Golgi apparatus
• Russell bodies : Globules (2-3 μm) of
accumulated immunoglobulins in the
cytoplasm of plasma cells. Usually
round. Russell bodies may be found in
normal bone marrow.
Plasma Cell
Plasma Cells

8. There is increased production of
immunoglobulin(Ig)
These immunoglobulins are monoclonal in nature.
Immunoglobulin secreted may be heavy chain or
light chain.
Plasma Cell Neoplasm

9. Epidemiology
As per most recent data of SEER (Surveillance
epidemiology & End Result Programme )
Males are affected more than Females
1% of all Malignancy
10% of all Haematological malignancy
2nd common after NHL among haematological malignancy
Median age of diagnosis -70 yrs
Median age of death -75 yrs
Blacks are affected more than Whites.

10. Classification of Plasma Cell Neoplasm
Monoclonal Gammopathy of Undetermined Significance (MGUS) ( 62%)
Malignant Monoclonal Gammopathies
•Multiple Myeloma (18%)
•Variants : Smoldering Myeloma (3%) , Non Secretory Multiple Myeloma, Light Chain Myeloma
•Plasmacytoma (2.5%) : Solitary Plasmacytoma of the bone, Extramedullary Plasmacytoma
•Plasma cell leukemia
•IgD myeloma
•POEMS syndrome ( Osteosclerotic Myeloma)
•Waldenstrom’s Macroglobulinemia (Lymphoplasmacytic Lymphoma )
Malignant Lymphoproliferative disorders
Heavy Chain disease ( Gamma HCD, Mu HCD, Alpha HCD)
Immunoglobulin Deposition diseases : Primary Amyloidosis, Systemic light chain and Heavy
chain deposition diseases

11. Investigations
• Complete Blood Count ( look for anemia)
• Comprehensive Metabolic panel
• Look for renal insufficiency(RFT), hypercalcemia and subtle clues
like decreased anion gap
• Total protein and albumin level. Determine Globulin component. Too
low globulin ( < 2gm%) or Elevated Globulin ( > 3.5gm%) is
concerning : Determine if Polyclonal vs. Monoclonal. Evaluate
further with :
• Quantitative Immunoglobulins : Increase in all components usually,
polyclonal. Increase in single component with reciprocal decrease of
uninvolved globulin usually, may suggest monoclonal .
• Serum Protein Electrophoresis with immunofixation if monoclonal
gammopathy is suspected.
• 24HR-Urine protein electrophoresis with urine immunofixation (
Serum Free Light Chain assay (κ/λ ratio) may be used in place of
UPEP}
• Bone marrow biopsy to evaluate % plasma cells if there is
monoclonal protein or abnormal UPEP or Light chain assay or if
strong clinical picture of myeloma.
• Skeletal survey if monoclonal gammopathy has been established (
Bone scans are usually, negative in MM)
• Beta-2 microglobulin and Albumin for staging and prognosis in MM
( once diagnosis is made).
Investigationsinanysuspected
onoclonalGammopathyshouldinclude,
toaccuratelyclassifythedisorder:

12. Serum is placed on special paper
treated with agarose gel and exposed
to an electric current. This separates
the serum protein components into
five classifications by size and
electrical charge : serum albumin,
alpha-1 globulins, alpha-2 globulins,
beta globulins, and gamma globulins.
Immunoglobulins ( IgG, IgM, IgA)
usually migrate to gamma region but
may sometimes extend to beta region.
SPEP should always be performed in
combination with serum
immunofixation in order to determine
clonality.
Serum Protein Electrophoresis(SPEP)

13. SPEP showing Monoclonal
Gammopathy
• Shows a tall “narrow” band in
gamma region – “M-Spike”
• Also, note reduction in the
normal polyclonal gamma band
SPEP

14. SPEP showing Polyclonal
Gammopathy
• Shows a broad based peak in
gamma region .
• Seen in chronic infections,
inflammation, connective
tissue disease,
lymphoproliferative disease.
SPEP

15. More sensitive than SPEP
Immunofixation is performed when SPEP shows a
sharp “peak” or a plasma cell disorder is
suspected despite a normal SPEP
Immunofixation always done to confirm the presence
of M-Protein and to determine the type (IgM or IgG
etc and the light chain restriction : k or λ)
Why do both SPEP and IF ? Why not just IF in
initial diagnosis ?
•Unlike SPEP, immunofixation does not give an estimate of the
size of the M protein (ie, its serum concentration), and thus
should be done in conjunction with electrophoresis.
Immunofixation

16. 18F-Fluoro-Deoxyglucose
Positron Emission Tomography (FDG-PET)
• Advantages
– Higher sensitivity vs
conventional radiography
– Detects 46% to 63% more
lesions than WBXR
– Normalization of scans after
treatment corresponds with a ≥
90% decrease in M-protein
• Disadvantages
– Less sensitive than MRI
• Especially for diffuse disease
MRI
BASELINE POST TREATMENT

17. Monoclonal
Gammopathies
Constitute Several Disorders
Examples

18. Monoclonal Gammopathy of
Undetermined Significance ( MGUS)
Denotes presence of an M-protein in a patient without a plasma cell or
lymphoproliferative disorder i.e; Undetermined Significance
M-protein <3 g/dL
<10% Plasma cells in Bone Marrow
No or small amount of M-protein in urine
Absence of lytic bony lesions , anaemia , hypercalcemia or renal
insuffciency.
No evidence of lymphoproliferative disorder
Stability of M-protein over time.

19. Monoclonal Gammopathy of
Undetermined Significance ( MGUS)
Incidence of MGUS increases with age :
1% of adults in US
3% of adults over age 70 years
11% of adults over age 80 years
14% of adults over age 90 years
Significance : Can progress to monoclonal Disease
IgG or IgA MGUS Ig M MGUS
Multiple Myeloma
Primary Amyloidosis
Related Plasma cell
disorder
NHL
CLL
Waldenstrom’s
Macroglobulinemia

20. MGUS - Progression
Predictors of Progression :
• Size of the M-protein at the time of recognition of MGUS - most
important predictor of progression
• IgM & IgA monoclonal proteins have a greater risk of progression
than an IgG M-protein.
• Risk of progression does not go away with time!
• Risk of progression 1% per year
CUMULATIVE RISK
10% at 10 years, 25% at 25 years from diagnosis
• So, Management :
Periodic monitoring of serum protein electrophoresis
Interval of monitoring based on initial M-Protein level
Monitoring should be at least annually LIFELONG

21. Pathogenesis
Normally human B-cells expresses
TLRs
These are essential for B-cells to
recognise
Infectious agent & PAMP
(Pathogen Associated Molecular
Pattern)
Then initiates host defence (Ig
production)

22. Pathogenesis
Normally human B-cells expresses
TLRs
These are essential for B-cells to
recognise
Infectious agent & PAMP
(Pathogen Associated Molecular
Pattern)
Then initiates host defence (Ig
production)

23. Pathogenesis
Normally human B-cells expresses
TLRs
These are essential for B-cells to
recognise
Infectious agent & PAMP
(Pathogen Associated Molecular
Pattern)
Then initiates host defence (Ig
production)

24. Pathogenesis
Normally human B-cells expresses
TLRs
These are essential for B-cells to
recognise
Infectious agent & PAMP
(Pathogen Associated Molecular
Pattern)
Then initiates host defence (Ig
production)
IL-6
Ig
Ck

25. Pathogenesis Aberrent Expression of TLR by Plasma cells
TLR + Specific ligand = Abnormal reaction to
Infection
Increased expression of IL-6
MGUS(abnormal plasma cells)
contains CD126(IL-6 receptor α chain)
In compare to normal plasma cells
Increased production of Ig due
to activation or proliferation of MGUS
Proliferation may acquire
Cytogenetic abnormality
Normally human B-cells expresses
TLRs
These are essential for B-cells to
recognise
Infectious agent & PAMP
(Pathogen Associated Molecular
Pattern)
Then initiates host defence (Ig
production)

26. MM Cell in the BM Microenvironment

27. Multiple Myeloma
and its variations :

28. Smoldering Myeloma
• Both criteria should be met :
• Serum monoclonal protein ≥3 g/dL and/or bone marrow
plasma cells ≥10 percent
• No end organ damage related to plasma cell dyscrasia (see
CRAB)
• Management :
• Does not require any intervention
• Close surveillanace is necessary to ensure stability of the disease (
SPEP, CBC, Creatinine and calcium every 3 to 4 month and Skeletal
Survey annually to pick up asymptomatic bone lesions)

29. Non-Secretory Myeloma
• Rare variant : About 1% of Myelomas
• May present with Bone lesions ( most common presenting symptom
bone pain)
• No serum or urine monoclonal protein ( diagnosis can be missed if
one is not aware of this entity, NSMM).
• Renal failure and hypercalcemia are generally lacking
• Anemia may be present
• Bone marrow biopsy must be performed in suspected cases:
Immunostaining for a monoclonal protein on bone marrow sections
may establish the diagnosis, Clonal plasma cell population in marrow.
• Must rule out IgD and IgE myeloma

30. Solitary Plasmacytoma
• No M protein in serum / urine
• Single area of bone destruction due to clonal plasma cell .
• Bone marrow not consistent with M.M.
• Normal skeletal survey.
• No end organ damage(other than solitary bone lesion)
Younger median Age at Presentation (55yrs)
50-60% will convert to Multiple Myeloma within 10 yrs
Treatment : Radiation(40-50Gy) to the site of Solitary
Plasmacytoma

31. Extramedullary Plasmacytoma
•No M protein in serum / urine
•Extramedullary tumor of clonal plasma cells
•Normal bone marrow
•Normal skeletal survey
•No end organ damage(including bone lesions)

32. Extramedullary Plasmacytoma
• Plasma cell tumors that arise outside the bone
marrow and no features of Multiple Myeloma
• Most Common Primary Sites - Head and
Neck region: Upper air passages and
oropharynx (May involve draining lymph
nodes.
• Less Common Sites – Lymph nodes (primary),
salivary glands, spleen, liver, etc.
• 25% have small monoclonal spike
• Rare dissemination, rarer evolution to myeloma
• Management :
• If completely resected during biopsy, no
further therapy
• If incompletely resected, radiation therapy
locally(40-50Gy)

33. All three criteria must be met
Presence of a serum or urinary monoclonal protein
Presence of 10 percent or more clonal plasma cells in the
bone marrow or a plasmacytoma
Presence of end organ damage felt related to the plasma cell
dyscrasia, such as: CRAB : Hypercalcemia (calcium >
11.5gm%), Renal Insufficiency, Anemia (Hb < 10gm%) or
Lytic bone lesions
Multiple Myeloma

34. PRESENTING FEATURES OF MYELOMA

35. Multiple Myeloma - Cytogenetics
Deletion 17p and Abnormalities associated with chromosome 13
carry a particularly unfavorable prognosis & respond poorly to
therapy

36. Recurring Chromosomal Translocations in
Multiple Myeloma
Cyclin D Induces Growth
MMSET Growth factor
C-Maf Transcription factor
C-Myc Growth/apoptosis
Mum Transcription factor

37. •Complete Blood Count ( look for anemia)
•Comprehensive Metabolic panel
•Look for renal insufficiency(RFT), hypercalcemia and subtle clues like decreased
anion gap
•Total protein and albumin level. Determine Globulin component. Too low globulin ( <
2gm%) or Elevated Globulin ( > 3.5gm%) is concerning :
Determine if Polyclonal vs. Monoclonal. Evaluate further with :
•Quantitative Immunoglobulins : Increase in all components usually,
polyclonal. Increase in single component with reciprocal decrease of
uninvolved globulin usually, may suggest monoclonal .
•Serum Protein Electrophoresis with immunofixation if monoclonal
gammopathy is suspected.
•24HR-Urine protein electrophoresis with urine immunofixation ( Serum
Free Light Chain assay (κ/λ ratio) may be used in place of UPEP}
•Bone marrow biopsy to evaluate % plasma cells if there is monoclonal
protein or abnormal UPEP or Light chain assay or if strong clinical picture
of myeloma.
•Skeletal survey if monoclonal gammopathy has been established ( Bone
scans are usually, negative in MM)
•Beta-2 microglobulin and Albumin for staging and prognosis in MM (
once diagnosis is made).
Investigations:

38. Salmon-Durie Staging System
STAGE SURVIVAL
Ì 61 months
ÌÌ 55 months
ÌÌÌ 30 months

39. Multiple Myeloma
STAGE PARAMETER MEDIAN SURVIVAL
Stage Í Serum β2-microglobulin<3.5mg/L 62 months
Stage ÍÍ Not fitting stage Í & ÍÍ 44 months
Stage ÍÍÍ Serum β2-microglobulin>5.5mg/L 29 months

40. *High lactate dehydrogenase and plasma cell leukemia are also considered high-risk myeloma.
RISK STRTIFICATION OF MULTIPLE MYELOMA
(MYO CLINIC)
Standard Risk
• Hyperdiploidy
• t(11;14)
• t(6;14)
Intermediate Risk
• t(4;14)
High Risk*
•17p deletion
• t(14;16)
• t(14;20)

42. More effective, less toxic mechanism-based TXs
Paradigm Shift in Oncology
1960-1990 2000
EMPERICAL
APPROACH
NON SPECIFIC
CYTOTOXIC
AGENT
MOLECULAR
BASED
APPROACH
TARGETED AND
SELECTED
BIOLOGICAL
APPROACH

43. Clearly not transplantation
candidate based on age, performance
score, and comorbidity
MPT, MPV, Len/dex
or clinical trial*
Potential transplantation
candidate
Nonalkylator-based
induction x 4 cycles
Stem cell harvest
*Thal/dex or dex are additional
options especially if immediate
response is needed.
Initial Approach to Treatment of MM

44. ELIGIBILITY FOR STEM CELL
TRANSPLANTATION
Autologous Hematopoietic Stem Cell Transplantation
1.Age ≤ 70 years
2.Cardiac Function: ejection fraction ≥ 45%
3.Pulmonary Function: DLCO ≥ 60% predicted
4.Serologies: Patients cannot be HIV + or have active Hepatitis B, Hepatitis C or HTLV-1
5.Renal Function : creatinine clearance ≥ 50 ml/min
6.Liver Function: Bilirubin ≤ 2.0 mg/dl and transaminases ≤ 2x normal,
7.Karnofsky performance status >: 80%
8.No significant co-morbid medical or psychiatric illness which would significantly
compromise the patient's clinical care and chances of survival.
Allogeneic Hematopoietic Stem Cell/Bone Marrow Transplantation
1.Age ≤ 50 years
2.Availability of an HLA-matched sibling donor (six of six or five of six HLA-match).
3.Normal LFT's (unless related to disease).
4.Cardiac function: ejection fraction ≥ 45%.

45. CLINICAL FOLLOW UP
Active Therapy
Pre Transplant
Disease
Assessment
Post Transplant
Disease
Assessment
Surveillance
•quantitative
paraprotein
•CBC
•calcium
•albumin
•creatinine monthly
•paraprotein
assessment
(serum, urine)
•skeletal survey
•CBC
•calcium
•albumin
•creatinine
•B2 microglobulin
•see pre transplant
disease
assessment
•bone marrow
investigation
if absence of
monoclonal
protein to determine
complete remission
status
•Q3 monthly
assessment with
quantitative
paraprotein
measurement
CBC, calcium,
albumin, creatinine
•skeletal survey
annually
•bone marrow
examination as
clinically
indicated
BCSH

46. Primary therapy (transplant candidates)
Relapse after transplant:
*A second (tandem) autologous stem cell transplant is recommended for
patients who relapse more than 12months after the first transplant.
*Patients who relapse within 12 months of the initial transplant are best treated with
agents they have not received before
*Patients who relapse after the second autologous transplant may be candidates
for allogeneic transplant or salvage chemotherapy
Main Component 3 Drug regimen 2 Drug regimen 4 Drug regimen
Bortezomib based PAD, VCD VD
Bortezomib+IMiD based VRD, VTD VRDC, VDTC
Lenalidomide based LD, Ld
Thalidomide based TAD, CTD TD
If none of Novel drug
available
VAD

47. Progressive Improvement in
response to combination Therapy

48. Disease category Response criteria7
sCR, stringent complete response *Normal free light chain (FLC) and absence of
clonal cells in bone marrow by
immunohistochemistry / immunofluorescence
CR, complete response *Negative immunofixation on the serum and
urine and disappearance of any soft tissue
plasmacytomas and ≤ 5% plasma cells in bone
marrow
VGPR, very good partial response *Serum and urine M-protein detectable by
immunofixation but not on electrophoresis
PR, partial response *≥50% reduction of serum M-protein AND
reduction 24h urinary M-protein by ≥90% OR
to <200mg per 24hour
SD, stable disease *Not meeting criteria for CR, VGPR, PR or
progressive disease

49. Primary treatment (non-transplant candidates)
Once the best remission has been achieved, maintenance
therapy with lenalidomide or thalidomide, with or
without steroids, can prolong remission, although not survival
Main Component 3 Drug regimen 2 Drug
regimen
4 Drug
regimen
Thalidomide MPT, CTD TD
Bortezomib MPV, VCD VD, vD VMPT
Thalidomide +Bortezomib VTD
Lenalidomide LD, lD
If none of Novel drugs available MP, BP

50. Treatment recommendations for
salvage therapy
Salvage therapy is used in patients who have relapse following allogeneic or
autologous stem cell transplant or in patients with primary progressive disease
following initial autologous or allogeneic stem cell transplant
Salvage therapy can also be used in patients who are ineligible for stem cell
transplant with progressive or relapsing disease after initial induction therapy
Salvage therapy includes the regimens, that were not previously selected

51. Therapy for relapse / refractory myeloma
Thalidomide*
Lenalidomide*
Bortezomib*
Liposomal doxorubicin*
*All of the drugs mentioned above can be used with or without Dexamethasone
Newer agents
•Pomalidomide(Thalidomde analogue)
•Carfilzomib(2nd generation Proteosome inhibitor)
•Vorinostat , Panobinostat (HDAC Inhibitor)
•Perifosine (AKT Inhibitor)
•Elotozumab(Anti CS-1 cell surface molecule)

52. Comparative trials of high-dose therapy (HDT) versus standard-dose chemotherapy (SDT). IFM-
90 (Intergroupe Francais de Myelome) randomized trial with 100 patients accrued to each arm
comparing SDT with VMCP-VBAP and HDT with melphalan 140 mg/m2 plus total-body
irradiation (8 Gy). Higher complete remission rates and significantly longer event-free and
overall survival were noted with HDT
High dose with TBI Vs Standard Dose

53. HDT versus conventional therapy also showed a superior CR
rate in the HDT arm, with a trend for prolonged EFS and OS in
the HDT arm

54. Novel Biologically Based Agents
Immunomodulatory drugs (IMiDs)
Thalidomide
Lenalidomide
Proteasome inhibitors
Bortezomib
Carfilzomib

55. Thalidomide:
Proposed Mechanism of Action
Inhibition of TNF- synthesis.
Suppression of angiogenesis(inhibition of
FGF,VEGF,IL-6)
Increase in cell-mediated cytotoxic effects
Modulation of cell surface adhesion
molecule expression
Dose : 50 – 400 mg/day orally
Toxicity : Somnolence , Constipation , Neuropathy , DVT, SJS , Teratogenic

56. Lenalidomide
Immunomodulatory derivative of thalidomide
More potent than thalidomide .
Dose-dependent decrease in TNF-α and interleukin-6
Directly induces apoptosis, G1 growth arrest
Enhances activity of dexamethasone
More favorable toxicity profile than thalidomide
Difficult to use in renal insufficiency ( dose adjust)
Dose : 25 mg /day oral D1-D21 . 28 day cycle.

57. Renal Impairment (CrCl)
Moderate (30 to < 60 mL/min)
Severe (< 30 mL/min, not requiring
dialysis)
ESRD (< 30 mL/min, requiring
dialysis)
Lenalidomide Dosage
10 mg QD
15 mg Q 48 hrs
5 mg QD
On dialysis days, administer
following dialysis
Lenalidomide Dosing for MM and
Impaired Renal Function

58. Bortezomib:
A Reversible Proteasome Inhibitor
Chymo-
tryptic
Site
Post-
Glutamyl
Site
Tryptic
Site
β1 β2
b3
b4
β5
b6
b7
Cross section of b ring
Bortezomib
H
N B
N
H
O
O
OH
N
N
OH
Interferes with intracellular pathway that
degrades proteins regulating cell cycle,
apoptosis,angiogenesis

59. Mechanism of Action
•Blockade of NFkB activation and related pracrine IL-6 production by BMScs
•Acts directly on MM cells to induce apoptosis through Caspases 8,9 activation
•Reversible inhibitor of 26s proteosome
•Adds to antiMM effects of dexamethasone.
•It inhibits the secretion of Growth Promoting cytokines.
It has been shown to overcome the adverse outcome
associated with chromosome 13 abnormality
Dose : 1.3 mg/m2 I.V. twice weekly for 2 weeks (1,4,8,11 days)
Followed by a 10 day rest period (day 12 to 21 )
Toxicity : fatigue, diarrhoea, impaired LFT , orthostatic
hypotension, reversible thrombocytopenia, peripheral neuoropathy

60. Peripheral Neuropathy Following
Bortezomib Therapy in Advanced MM
Peripheral neuropathy was reported in 90/256 (35%)
patients with MM treated with bortezomib in phase II trials
80% of patients entered these trials with preexisting peripheral
neuropathy
3% patients without vs 16% with baseline peripheral neuropathy
developed grade 3 peripheral neuropathy

61. Treatment of complications:
Anaemia : blood transfusion , supportive management ,
inj. Erythropoietin 40000U/week
Nephropathy : correction of hypercalcaemia , dose reduction of
chemotherapeutic agents . e.g. Lenalidomide.
Hyperviscocity : plasmapheresis.
Infections : antibiotics , IVIG for recurrent life threatnening infections
Prophylaxis :Herpes zooster prophylaxis Before bortezomib therapy ,
antipneumococcal / anti influenza vaccine prophylaxis.
Pain : NSAIDS , Spinal braces
Bone pain & Skeletal complications : Bisphophonates ,
fixation of fracture of bone , +/- RT.
Pal RT for impending pathological fracture or to treat spinal cord compression,
Dose 8 Gy in single fraction / 20 Gy in 5 fractions.

62. MM & Skeletal Complications
~ 80% of patients with
multiple myeloma will have
evidence of skeletal
involvement on skeletal
survey
– Vertebrae: 65%
– Ribs: 45%
– Skull: 40%
– Shoulders: 40%
– Pelvis: 30%
– Long bones: 25%

63. The Central Role of the Osteoclast in
Osteolytic Bone Destruction
Growth
factors
Osteoclast differentiation
Osteolysis
Direct effects on
osteoclast differentiation
Tumor cells
Bone loss
Active
osteoclast

64. Mechanism of Bisphosphonate
Inhibition of Osteoclast Activity
Bisphosphonates
inhibit osteoclast
activity, and promote
osteoclast apoptosis[1]
Bisphosphonates
are released locally
during bone resorption[1]
Bisphosphonates are
concentrated under
osteoclasts[1]
Bisphosphonates may modulate
signaling from osteoblasts
to osteoclasts
New bone
X
Bone
 Increased OPG production[2]
 Decreased RANKL expression[3]

65. Recommended Doses and Infusion
Times
Drug Dose/Infusion Time Interval
Estimated CrCl > 60 mL/min
Pamidronate
Zoledronic acid
90 mg over 2-3 hrs
4 mg over 15 mins
3-4 wks
3-4 wks
Estimated CrCl 30 to < 60 mL/min
Pamidronate
Zoledronic acid
90 mg over 2-3 hrs*
Reduced dosage†
3-4 wks
3-4 wks
Estimated CrCl < 30 mL/min
Pamidronate
Zoledronic acid
90 mg over 4-6 hrs*
Not recommended
3-4 wks
*Consider dose reduction .
†3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39
mL/min).
Kyle R, et al. J Clin Oncol. 2007;25:2464-2472.

66. Bisphosphonates and Osteonecrosis
Uncommon complication causing
avascular necrosis of maxilla or
mandible
Suspect with tooth or jaw pain
or exposed bone
May be related to duration of
therapy
True incidence unknown
Always enquire recent dental
therapy or tooth related
problems before starting
bisphosphonates

67. • Transplant-eligible patients
–Bortezomib/Thalidomide/Dexamethasone (VTD) vs Thalidomide/Dexamethasone (TD)
–Bortezomib/dexamethasone
–Lenalidomide/low-dose Dexamethasone (Rd)
• Transplant-ineligible patients
–VISTA: Bortezomib/Melphalan/Prednisone (VMP) vs Melphalan/Prednisone (MP)
–Lenalidomide/low-dose Dexamethasone (Rd)
• New combinations and early studies
–Transplant-eligible patients
• Bortezomib/Lenalidomide/Dexamethasone
• Bortezomib/Lenalidomide/Dexamethasone vs Bortezomib/Dexamethasone
–Transplant-ineligible patients
• MTP vs MPR (Phase III)
• VMP vs Bortezomib/Thalidomide/Prednisone (VTP) (Phase III)
–Early studies
• Bortezomib/Vorinostat (Phase I)
Recent and Ongoing Clinical Studies

68. VTD vs. TD in Patients
Who Are Transplant Eligible
• Study objective
– VTD vs TD in preparation for autologous stem cell
transplantation (ASCT)
• Study design
– Randomized trial
– Three cycles of induction therapy
• Methods
– Pts. randomized to either VDT (n=199) or TD (n=200).
– Stem cells were collected.
– Consolidation therapy with same treatment to pts.
– Results drawn from a final analysis of 399 patients.
Phase III Bortezomib-Thalidomide-Dexamethasone (VTD) vs
Thalidomide-Dexamethasone (TD) Prior to Stem Cell
Transplantation (SCT)
Cavo et al. Blood 2008 112: Abstract 158

69. • Prophylaxis
– Acyclovir prophylaxis against reactivation of VZV.
– TEE prophylaxis with low molecular weight heparin, aspirin,
or warfarin; fixed low-dose warfarin is effective.
• Conclusions:
– In comparison with TD, 3 21-d cycles of VTD as primary
therapy significantly increased CR+nCR rates.
– These response rates translated into significantly higher
CR+nCR after first ASCT in the VTD arm.
– Combinations of novel induction agents, such as VTD, can
have a remarkable impact on both pre- and post-ASCT
clinical outcome.
Conclusions From VTD vs. TD
Cavo et al. Blood 2008 112: Abstract 158

70. Bortezomib and Dexamethasone Prior
to ASCT in Transplant-Eligible Patients
• Phase III, active control, multicenter, open label, randomized
– Objective: compare the CR rate with vincristine/adriamycin/dexamethasone
(VAD) and bortezomib/dexamethasone combinations as induction therapy.
• Number of severe AE was similar between the arms:
Post Induction Post ASCT
CR/nCR ≥VGPR ≥PR CR/nCR ≥VGPR ≥PR
VAD 9% 24% 71% 28% 50% 88%
Bortezomib/
Dexamethasone
22% 50% 89% 38% 66% 87%
P-value 0.0085 0.0001 NS 0.127 0.021 NS
Harousseau et al, Blood 2007 110: Abstract 450.

71. • Post-induction complete remission (CR) was
increased by VD compared to VAD.
• One-year PFS and OS rates were 93% and 97%
with VD and 90% and 95% with VAD, respectively.
Conclusions From Bortezomib and
Dexamethasone Prior to ASCT
Harousseau et al, Blood 2007 110: Abstract 450.

72. VISTA Trial: VMP vs MP
in Transplant-Ineligible Patients
A Phase 3 Study Comparing Bortezomib/Melphalan/Prednisone (VMP) With
Melphalan/Prednisone (MP)
• Study objective:
–Define the differences in efficacy and outcome between VMP vs MP
• Study design and method:
–VMP arm (IV Bortezomib in combination with oral prednisone and oral melphalan) vs
MP arm (oral melphalan and prednisone)
• Primary endpoint:
–Time to progression (TTP)
• Secondary endpoints:
–Progression-free survival (PFS), overall survival (OS), overall response rate (ORR),
time to progression (TTP) and duration of response (DOR), and safety
San Miguel et al Blood 2007 110: Abstract 76; San Miguel et al Blood 2008 112: Abstract 650; Harousseau et al Blood 2008 112: Abstract 650
Mateous et al. Haematologica 2008; 93(4), 560-565

73. VISTA Trial: VMP vs. MP
Most Common Adverse Events (in ≥30% Patients)
receiving VMP (n=60)
Adverse Event % Toxicities All Grades % Toxicities Grades 3/4
Anemia 86 10
Thrombocytopenia 93 51
Infection 75 16
Neutropenia 85 43
Asthenia 63 5
Nausea 55 2
Diarrhea 55 16
Peripheral Neuropathy 55 17
Constipation 52 8
Anorexia 38 2
Vomiting 30 2
Mateos, et al. Haematologica 2008; 93(4) 560-565

74. Conclusions
• Adverse events
– 46% with VMP
– 36% with MP
• Patients remained on therapy longer with VMP:
– 46 weeks with VMP
– 39 weeks with MP
• Patients had a longer time to next therapy.
• Patients also had longer treatment-free survival.
VISTA Trial: VMP vs. MP
These results establish VMP as another option for patients
not eligible for SCT.
San Miguel et al Blood 2007 110: Abstract 76; San Miguel et al. Blood 2008 112: Abstract 650.

75. • Randomized multicenter Phase III ECOG
E4A03 study
–RD arm (223 patients)
• Lenalidomide 25 mg (days 1-21)
• Dexamethasone 40 mg (days 1-4,9-12,17-20)
–Rd arm (222 patients)
• Lenalidomide 25 mg (days 1-21)
• Dexamethasone 40 mg (days 1,8,15,22)
–Primary endpoint: response rate at 4 months
Lenalidomide/Dexamethasone (RD)
vs Lenalidomide/Low-Dose
Dexamethasone (Rd) in Transplant-
Ineligible Patients
Rajkumar et al, Blood 2007 110: Abstract 74

76. Rajkumar et al, Blood 2007 110: Abstract 74; Jacobus et al., Blood 2008 112: Abstract 1740
Results From Lenalidomide/Dexamethasone
(RD) vs Lenalidomide/Low-Dose Dexamethasone
(Rd)
Toxicity (Grade >3) RD (N=223) Rd (N=222)
Neutropenia 2.7% 3.2%
Thrombocytopenia 1.8% 1.4%
DVT/PE 25.6% 11.4%
Atrial Fibrillation/Flutter 3.1% 0.0%
Infection/Pneumonia 16.1% 9.0%
Fatigue 11.7% 4.1%
Hyperglycemia 5.8% 2.3%
Neuropathy 0.4% 1.4%
Efficacy RD Rd
1-year Survival 88% 96%
2-year Survival 75% 87%
OS in Pts<65 (1 year) 92% 97%
OS in Pts>65 (1 year) 83% 94%
Deaths 42 16

77. Results From RD vs Rd
• Rd is associated with superior OS compared to
RD in NDMM patients.
• Increased mortality in RD arm is due to
disease progression as well as increased
toxicity.
– Prevention of venous thrombotic events is a
priority for both combinations.
Rajkumar et al, Blood 2007 110: Abstract 74; Jacobus et al., Blood 2008 112: Abstract 1740