Presented by…

DR . AYASKANTA SINGH
PG Student
Preceptor…
DR . L . D . RAUL
Associate Professor
P .G. Department of
medicine
 Multiple myeloma represents malignant proliferation
of plasma cells derived from a single clone .1

It is a neoplastic plasma cell dyscrasia (PCD)

characterized by a clinical pentad: (a) anemia
(b) a monoclonal protein in the serum or urine or both
(c) abnormal bone radiographs and bone pain (d)
hypercalcemia and (e) renal insufficiency .2

Multiple myeloma accounts for approximately 10% of

hematological cancers and 1 % of all cancers .2
Incidence:
3 - 9 cases per 100000 population / year 2

more frequent in elderly

modest male predominance

The median age of diagnosis of 65-70 years . The disease

is uncommon under age 40 .

The disease is uniformly fatal , with a median survival of

approximately 3 years with conventional chemotherapy .
Clinical symptoms: Laboratory tests:
Bone pains, pathologic ESR > 100
fractures Anaemia, thrombocytopenia
Weakness and fatigue – Rouleaux in peripheral blood
anaemia smears
Serious infection X ray- advanced lytic bone
Renal failure lesions
Bleeding diathesis Marrow plasmacytosis > 10
Neurologic symptoms -15%
Nausea and vomiting
M protein in serum and/ or
urine
Hypercalcemia
Proteinuria
Azotemia
 Almost all cases of multiple myeloma arise
from an asymptomatic premalignant
disorder –
characterized by proliferation in bone
marrow of monoclonal plasma
cells ,derived from post germinal B
cells .

This is known as MGUS and the rate of

conversion to overt multiple myeloma is 1
% per year.
Multiple myeloma typically proceeds from a clonal proliferation of
plasma cells ,termed MGUS through intramedullary myeloma to extra
medullary disease . These changes are accompanied by progressive
genetic changes (translocations , deletions and trisomy ) followed in the
later stage by oncogene mutations .3
Monoclonal Gammopathy of Undetermined Significance (MGUS )
   Serum monoclonal protein (<30 g/L)
   Bone marrow <10% plasma cells
No evidence of other B-cell proliferative disorders
   No related organ or tissue impairment a, b

Smoldering Myeloma (asymptomatic) (SMM)

   Serum monoclonal protein (≥30 g/L) and/or
Bone marrow clonal plasma cells ≥10%
   No related organ or tissue impairment a

Multiple Myeloma (active or symptomatic) (MM)

   Monoclonal protein present in serum and/or urine
   Clonal bone marrow plasma cells or plasmacytoma
   Related organ or tissue impairment a,b

a
The absence of CRAB (calcium elevation [>1 mg/dl above upper limit of normal], renal
dysfunction [creatinine >2 g/dl], anemia [hemoglobin 2 g/dl below lower limit of normal],
bone lesions [ lytic lesions or osteoporosis with compression fracture] attributable to the
plasma cell disorder).

b
The existence of immunoglobulin light-chain amyloidosis or another paraneoplastic
disorder attributable to the monoclonal gammopathy, such as a peripheral neuropathy.
Source: International Myeloma Working Group. Br J Haematol 2003; 121:749
 Patients with symptomatic and/or
progressive disease requires treatment .

Those with MGUS or “smoldering

myeloma” , who have no symptoms or
specific laboratory abnormalities should be
observed without therapy .

In general therapy is of two sorts : A)

Systemic therapy to control the
progression of myeloma and B)
Symptomatic supportive care to prevent
serious morbidity .
 The treatment of newly diagnosed multiple
myeloma patient depends on whether the
patient is transplant eligible or not .

Patients who are transplant candidates , i.e.

A) relatively young (<65 years)
B) do not have any co morbidities like-
- renal failure – transplantation can be
done but is more toxic.
-cardiac ,hepatic ,neurologic or
pulmonary disease.
C) good functional status.
A) Conventional chemotherapy.
Melphlan + Prednisone (MP)
VAD (Vincristine, Adriamycine,
Dexamethasone)
Response rate 50-60% patients
Long term survival 5-10% patients

B) Combining THALIDOMIDE with MP

improves response rates and overall survival
than MP alone. .
C) Combination of BORTEZOMIB with MP is
recommended in patients of high risk groups.
 Multiple myeloma is relatively resistant to most
conventional chemo-therapeutic agent .

Since plasma cells are not dividing cells , cell cycle

dependant cytotoxic agents are of limited effectiveness .

Melphalan and cyclophosphamide and corticosteroids are

the most effective conventional agents for the treatment
of the disease.
 Drug resistance in myeloma is due to –
1. Paucity of actively dividing cells.

2. Interleukin- 6 is a potent survival factor in

myeloma cells and induces resistance to drug
induced apoptosis.

3. Interaction of myeloma cells with extracellular

matrix proteins and bone marrow stromal cells ,
osteoblasts , osteoclast and endothelial cells.

4. The bone marrow micro-environment also

secretes anti apoptotic factors.
 To overcome drug resistance, high doses of
intravenous melphalan have been used to increase
the destruction of tumor cells. However this induces
severe and prolonged myelosuppression .

The morbidity and mortality of high dose

chemotherapy are markedly reduced by infusion of
autologous hematopoietic stem cells.

Attal et al published the first prospective

randomized control trial demonstrating an improved
survival for patients undergoing high dose of
therapy with autologous transplantation .5
 Autologous transplantation involves removal and
storage of the patients own cells with subsequent
reinfusion after the patient receives high doses of
myeloablative therapy.

Homing of haematopoetic stem cells to bone

marrow microenvironment is poorly understood .

However, there is evidence that the binding of

chemokine SDF-1(stromal derived factor 1) to
CXCR4 (CXC chemokine receptor 4) expressed on
hematopoietic stem cells has a role. 4
 Homing of Autologous Hematopoietic Stem Cells to Bone Marrow

Harousseau J and Moreau P. N Engl J Med 2009;360:2645-2654

Homing of Autologous Hematopoietic Stem Cells to Bone Marrow. Hematopoietic stem cells express the chemokine receptor CXCR4,
whereas bone marrow stromal cells express chemokine stromal cell-derived factor 1 (SDF-1). After stem cells are infused into a recipient,
SDF-1 activates CXCR4-positive stem cells, stimulating adhesion to endothelial cells through interaction between intercellular
adhesion molecule 1 (ICAM-1) and leukocyte-function-associated antigen 1 (LFA-1) and between very late antigen 4 (VLA-4) and
vascular-cell adhesion molecule 1 (VCAM-1). These stem cells then extravasate into the bone marrow stroma and adhere to stromal cells
through similar adhesion interactions between cells. Data are from Peled et al.14
Autologous stem cell transplantation has no anti-
tumor effect by itself and is a form of supportive
management after high dose therapy.

By restoring a functioning bone marrow soon after

treatment, autologous stem cell therapy makes it
possible to deliver a very high dose of melphalan
that would have been fatal .
Total duration of treatment is 4 – 6 months
 3 to 6 cycles of chemotherapy is given to
reduce the tumor burden and plasma cell
infiltration in the bone marrow .

As a general rule , induction regimen

should be containing non alkylating
agents or if alkylating containing,
number of cycles should be restricted to
four prior to stem cell mobilization .

Melphalan is not used in induction as it is

toxic for hematopoietic stem cells .
 Induction treatment is dexamethasone
based , either used alone or in combination
with VAD chemotherapy .
The dose of single agent dexamethasone is
40 mg for 4 days every 2 week .

The dose of combination VAD

chemotherapy is-
VINCRISTINE – 0.4 mg/d in a 4 day
continous infusion
DOXORUBICIN-9 mg /m2 per day in a 4 day
continuous infusion
DEXAMETHASONE-40 mg for 4 days per
week for 3 weeks
 The response rate of single agent high dose
dexamethasone is 43% which is only 15 % lower
than VAD combination therapy .

Thus single agent dexamethasone is used in lieu of

VAD for induction . It has the advantage of
avoidance of immediate placement of a long-term
central venous catheter .

However this approach is being replaced with the

advent of novel agents like thalidomide ,
bortezomib and lenalidomide .
Reference Regimen phase N CR (%) VGPR PR (%) OR
(%) (%)
Raj kumar et al DEX 3 104 0 0 41 41
2006

THAL-DEX 3 99 4 0 59 63

Weber et al THAL-DEX 2 40 16 0 56 72
2003
Demopolos et al VAD 3 127 13 0 49 62
2003
Goldshmidt et al VAD 3 406 3 0 60 63
2006
Jaganath et al BORTEZ 2 32 3 9 28 40
2005
BORTEZ+ DEX 2 32 6 19 63 88

Popat et al 2005 LD - PAD 2 19 11 28 50 89

Wintrobe’s clinical hematology

According to European group for Blood and Bone
Marrow Transplant (EBMT ) criteria :-

CR-COMPLETE RESPONSE : bone marrow

plasma cells(BMPC) < 5% ; 100 % decrease in
serum and urine M protein within 6 months .

VGPR- Very Good Partial Response : BMPC <

5 % ; > 90% reduction in serum and urine M
protein .

PR – Partial Response : BMPC < 5% ; 50-90 %

reduction in serum and urine M protein
1. Thalidomide

2. Bortezomib

3. Lenalidomide
 Thalidomide is an immune modulatory drug (IMiD) . It
inhibit angiogenesis , modulate adhesion molecules of
myeloma cells and their surrounding stroma, modulate
cytokines and affect natural killer cells, induces apoptosis
and G1 growth arrest in myeloma cells .

As a single agent, response rates occur in about one

third of patients . The combination of thalidomide and
dexamethasone results in response rates of 63 to 72 % .6

Major adverse effects are deep vein thrombosis and

thromboembolic complications.
 Bortezomib is a reversible and selective
proteasome inhibitor. Myeloma cells, are heavily
dependent on proteasome-regulated proteins for
their growth and interaction with stromal cells.

Bortezomib cause growth arrest, to induce

apoptosis, and to inhibit angiogenesis .

The side effects of bortezomib are –

Peripheral neuropathy .
Myelosuppression .
Gastrointestinal – nausea and vomiting .
* Modified EBMT criteria Harousseau JL,et al ASCO 2008
 Lenalidomide (thalidomide derivative) is more
potent than thalidomide.

Rajkumar et al. treated 34 patients with

lenalidomide 25 mg orally on days 1 to 21 and
dexamethasone 40 mg on days 1 to 4, 9 to 12,
and 17 to 20, both repeated every 28 days.
Aspirin was given as DVT prophylaxis. The
overall response rate was 91%, with 6%
achieving a complete response and 32% a very
good partial response .

Adverse effects included thrombo-embolism ,

peripheral neuropathy, neutropenia and
thrombocytopenia
 Peripheral blood progenitors have replaced bone
marrow (aspirated from iliac crest ) as the source of
stem cells because of – (1) Easier availability. (2)
faster haematopoetic recovery after
transplantation .(3) Reduced contamination by tumor
cells .7

Cells (CD-34+ cells) are collected during aphaeresis

procedures after stem cell mobilization with the use
of G-CSF or GM-CSF.

After collection, stem cells are cryopreserved in

dimethyl sulfoxide until transplantation .
The standard preparative regimen
before ASCT is high dose melphalan (
200 mg per square meter of body
surface area ) .

It is administered as a single
intravenous infusion lasting 30 to 60
minutes or as two infusions of 100
mg per meter square during a two
day period .
The hematopoietic stem cells are infused 48
hours after melphalan administration through
central venous catheter .

The patient is pre-medicated with an anti

histamine, an anti emetic, an anti pyretic and
corticosteroids to mitigate transfusion
reactions.

Patients are discharged after resolution of

any adverse effects and when the neutrophil
count is greater than 5,000/dl . The duration of
hospital stay is 2 to 3 weeks.
 The autologous stem cell product can be
contaminated with tumor cells that could lead to
relapse .

A varieties of techniques have developed to “purge

“ autologous products of tumor cells .

In vitro incubation with cyclophosphamide

derivatives or monoclonal antibodies have shown to
diminish tumor cell numbers in stem cell products.

Another technique is positive selection of stem cells

using antibodies to CD 34+, leaving tumor cell
behind.
Related to high dose melphalan chemotherapy-
Severe and prolonged myelosuppression .
Gastrointestinal toxic effects like mucosities.
Transient alopecia
Gonadal toxic effects
Rarely Atrial fibrillation and veno-occlusive hepatic disease
Related to infusion of autologous stem cells .
Nausea and vomiting , headache , chills and fever .8
Anaphylaxis and cardiac arrest may rarely occur
 HDT
+ASC
T

CC

Conventional Chemotherapy (CC) versus Autologous

Hematopoietic Stem Cell Transplantation (ASCT),
IFM 90 Trial.
Allogenic transplant has the following advantages –
Eliminates stem cell contamination by tumor cells.
Graft versus myeloma effect.

However allogenic transplantation is not preferred in MM

patients because –
Toxicity is excessively high, with a transplant-related mortality
in excess of 50% in studies due to GVH disease .
Chances of graft rejection.
Only a small minorities of patients had HLA identical siblings.
Could not be given in patients more than 60-65 years .

Hematology 2007
Two planned autologous SCTs within 6
months .
-stem cell is collected before initial
transplant.
-half of the stem cell is used for each
procedure.

Second transplant may benefit :

-patients who do not respond or
respond marginally to 1st transplant.
Hypercalcemia –
- bisphosphonates.
-adequate hydration.
-glucocorticoid therapy.
-calcitonin.
Bone lesions – analgesics and chemo therapy.
Anaemia – erythropoetin and hematinics.
Renal failure – dialysis.
Hyperviscosity – plasmapheresis.

-
 High dose chemotherapy and ASCT should be part of
initial therapy in patients with newly diagnosed multiple
myeloma who are 65 years of age or younger .

Conditioning with a high dose of melphalan ( 200 mg

per m 2 ) is recommended .

There is no consensus regarding double

transplantation .

The addition of novel agents before and after

transplantation improves the results , but use of such
drugs have not been approved in any country .9
1. Nikhil C. Munshi , Dan L.Longo kenneth C. Anderson ,Harrison’s
Principles of Internal Medicine 17 th;2007 ;106: 700-706

2. Angela Dispenzieri,Martha Q. Lacy,Philip R. Greipp ,multiple

myeloma . Wintrobes Clinical Hematology 12th;2009 ;99 :

3. Harousseau J-L, Moreau P. Autologous hematopoietic stem-cell

transplantation for multiple myeloma. N Engl J Med 2009;360:2645-
2654.
4. Peled A, Kollet O, Ponomaryov T, et al. The chemokine SDF-1
activates the integrins LFA-1, VLA-4, and VLA-5 on immature human
CD34(+) cells: role in transendothelial/stromal migration and
engraftment of NOD/SCID mice. Blood 2000;95:3289-3296 .
5. Attal M, Harousseau J-L, Stoppa A-M, et al. A prospective,
randomized trial of autologous bone marrow transplantation and
chemotherapy in multiple myeloma. N Engl J Med 1996;335:91-97
6. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR.
Phase III clinical trial of thalidomide plus
dexamethasone compared with dexamethasone alone
in newly diagnosed multiple myeloma: a clinical trial
coordinated by the Eastern Cooperative Oncology
Group. J Clin Oncol 2006;24:431-436

7.Harousseau JL. Optimizing peripheral blood progenitor

cell autologous transplantation in multiple myeloma.
Haematologica 1999;84:548-553
8. Sauer-Heilborn A, Kadidlo D, McCullough J. Patient care
during infusion of hematopoietic progenitor cells.
Transfusion 2004;44:907-916
9. San-Miguel J, Harousseau JL, Joshua D, Anderson KC.
Individualizing treatment of patients with myeloma in
the era of novel agents. J Clin Oncol 2008;26:2761-
2766.