1. Benefits of Bortemozib and other novel therapy in Relapsed Multiple Myeloma
Dr Smita Singh
(BDS,PGDCR,MBA)
Introduction: Multiple myeloma is a cancer of plasma cells. Normal Plasma cells are found in Bone
marrows and plays an important role in the immune system. When a single plasma cells become
cancerous, it is called as plasmacytoma whereas when there are more than one plasmacytoma is
called as multiple myeloma. Multiple myeloma is the second most common hematologic malignancy
and responsible for 21,000 deaths in European Union an in 2008 and more than 10,00 deaths in the
United states in 2009.
Immune system
White blood
cells
Lymphocytes
Produces
antibodies
Bcells
produces
Plasma
cells
Abnormal
Plasma cell
are in one
place and
form one
tumor
Plasmacyto
ma
Abnormal
plasma cells
forms tumor
in many
bone
Multiple
myeloma
Abstract
Multiple myeloma is a cancer of plasma cells present in bone marrow characterized by low blood
count, anemia, bone disorder, kidney dysfunctionand also increase in calcium level. Newly
diagnosed myeloma shows quick response to therapies like melphalan, predinisone, dexamethasone,
doxorubicin however, results from preclinical and clinical studieshave demonstrated that novel
therapies like combination of dexamethasone and Bortemozib has been successful in exhibiting a
superior response in relapsed and refractory myeloma.
T cells matures
in thymus
B cells matures in
bone marrow
2. Multiple myeloma is characterized by various features like
Low blood counts: In multiple myeloma, overgrowth of plasma cells overcrowd the normal cells,
leading to anemia, i.e. reduction in red blood cells, fatigue, weakness and also thrombocytopenia
(platelets count become low).
Infections: Cancerous plasma cells are not able to protect against infection as the normal cell does.
High blood levels of calciuman further effect kidney leading to kidney failure.
Bone problems like pain, weakness and fracture of bone.
Hyperviscosity: Excessivedeposition of myeloma protein causes the blood to thicken, leading to
hyper viscosity. This can further hinder the blood supply to the brain.
Multiple myeloma may be staged by means ofDurieSalmon staging system: This system is
based on 4 Factors:-
S
NO
FACTORS STAGE1 STAGE2 STAGE3
1 Amount of Abnormal
monoclonal immunoglobulin
in blood and urine
A relatively
small
amount
Features are
between
stage 1 and
stage3
Large amount
2 Amount of calcium in blood Normal High blood calcium level
3 The severity of bone damaged
on x-rays
Normal or
show one
area of
damage
3 or more areas of bone
damage
4 Amount of hemoglobin in the
blood
Slightly
below
Low HB-8.5G/DL
Monoclonal gammopathy
<3g myelomaprotein
<10 Bone marrowplasma
cells
No multiplemyeloma
SmolderingMyeloma
>3g Myelomaprotein
>10 Bone marrowcells
No Multiple myeloma
Multiple myeloma
>_10 bone marrow plasma
cells
>_CRAB
Calcium
Elevation>11,5mg/L
Renal Dysfunction>2mg/Dl
AnemiaHb,1og/Dl
Bone Dysfunction
Types of plasma cell Neoplasm
3. normal
The initial diagnosis of multiple myeloma includes laboratory and radiological surveys to support
diagnosis, stages and to find immediate intervention.
Relapsed/Refractory Multiple Myeloma
Relapsed multiple myeloma refers to the circumstances wherein patient treated to the point of
maximal response experiences progressive disease. Refractoryrefers to the clinical scenario in which
patient is either unresponsive to current therapy or progress within 60 days of last treatment.
There are two types of refractory multiple myeloma
Primary refractory patients who never attain a response and progress while still on induction
therapy.
Secondary refractory patients who do respond to induction therapy but don’t respond to the
treatment after relapse.
Multiple myeloma disease trajectory characterized by malignant transformation; serial
cycles of response, remission, and relapse in the presence oftreatment; and clonal evolution
with diminished depth and duration of response over time. Information from Agarwal
&Ghobrial (2013), Borrello (2012), Durie et al. (2003), Keats et al. (2012).
Diagnisis and Treatment :
4. Newly diagnosed multiple myeloma shows quick response to treatment with a combination of
melphalan, predinisone, dexamethasone, doxorubicin, immunomodulary drugs such as thalidomide,
lenalidomide and protease inhibitor such as bortezomib.
However, several studies have also beenconducted to ascertain the effect of Bortezomib inrelapsed
and refractory multiple myeloma
S.No Trial Type of trial No.0f subject Duration
of trial
Outcome
1 Randomized phase 3
apex trial, which
compared bortezomib
with high dose
dexamethasone
Phase 3,
randomized
controlled trial
669 with
relapsed and
refractory
multiple
myeloma
6.5
Months
The trial was
stopped as
interim analysis
demonstrated
superiority in
terms of
response rate.
median time to
progression, and
survival.
2 Randomizedphase 3
trail comparing
bortezomib and the
combination of
pegylatedliposomnal
doxorubicin with
bortezomib
Phase 3
randomized
controlled trial
636 patients
with relapsed
and refractory
multiple
myeloma
9.3
Months
Time to
progression was
significantly
longer withthe
combinationthan
with
boretezomib
alone
3 Summit trial Phase 2 202 Response rate
alone -37%
Response rare
with
dexamethasone-
50%
4 Crest Study Phase 2 54 Respone rate
alone-33%
Response rate
with
dexamethasone-
44% and 66%
5 Bortezomib in
combination with the
heat shock protein-90
inhibitor
tanespimycin
-------------- -------------- ------------- Positive
Responses were
seen in 32% with
minimal side
effects
5. List of another novel agents in relapsed and refractory multiple myeloma
Agent Class Effects Response
with
single
agent
Response in
combination
with
dexamethasone
Toxicity
Thalidomide IMiD Decreased
adhesion,
cytokine
production,
angiogenesis,
increased
antimyeloma
immunity
30% 50% Teratogenicity,
PN,sedation,
rash,constipation, VTE
Bortezomib Protease
inhibitor
Decreased
adhesion,
cytokine
production,
angiogenesis,
NFkB,
DNA repair
30% to
43%
40% to 55% Fatigue, PN, GI toxicity,
decrease in neutrophils,
platelets,and
lymphocytes
Lenaidomide IMiD Decreased
adhesion,
increased T-cell
proliferation, NK
cell
cytotoxicity, IFN-
g
and IL-2
25% to 40
%
65% to 70% Myelosuppression,VTE,
rash, fatigue, diarrhea
GI, gastrointestinal; PN, peripheral neuropathy; IFN, interferon
Conclusion: Myeloma is treatable in multiple case, but unfortunately it relapse over a period of time
or patient become unresponsive to the current therapy. Several preclinicaland rational Clinical
studies have been successful inrecognizing the positive effect of Combinationtherapylike
dexamethasone and bortezomibin relapsed and refractory multiple myeloma. Advantages of
combination therapy includes higher response rate and survival rate.
Reference
