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MULTIPLE MYELOMA
Dr. Ayush Garg
Multiple Myeloma
• Introduction
• Epidemiology
• Etiology
• Pathophysiology
• Clinical features
• Diagnostic Work Up
• Classification and staging
• Prognostic Factors
• Treatment
• Follow Up
Sarah Newbury, the first reported patient with Multiple
Myeloma.
A) Bone destruction in the sternum.
B) The patient with fractured femurs and right humerus.
C)Bone destruction involving the femur.
Timeline depicting the history of Multiple Myeloma
The term Multiple Myeloma was coined by Rustizky.
Introduction
• Multiple myeloma (MM) is characterized by the neoplastic proliferation of a
single clone of plasma cells producing a monoclonal immunoglobulin.
The Spectrum of Myeloma-
Epidemiology
• The incidence rises with advancing age, with a median age at diagnosis of
70 years, and <1% of cases are diagnosed in those younger than 35.
• Incidence : 0.7M/0.5 F per 100,000 population.
• 1/10 as common as Leukemias
Etiology
Radiation:
• Association with prior exposure to radiation (e.g., atomic bomb survivors in
Hiroshima).
Environmental or occupational causes :
• Farmers (DDT exposure)
• Wood workers
• Leather workers
• Sheet metal workers
• Nuclear industry workers
• Exposure to petroleum products
Genetic causes: Chromosomal alterations identified:
Recurrent Chromosomal Aberrations
Chromosome Frequency % Patients Gene(s) Function
11q13 30 Cyclin D1 Induces growth
4p16 25 FGFR3, MMSET Growth factor
8q24 5 C-myc Growth/ apoptosis
16q23 1 C-maf Transcription factor
6p25 <1 IRF4 transcription
factor
Differentiation and
growth
9p13 1 PAX-5 Transcription factor
20q12 1 MAFB Transcription factor
18q21 1 Bcl-2 Antiapoptosis
Structural Chromosomal Aberrations
Del 17p13 15 P53
Del 13 40-55 ?
Hypodiploidy 20-30 -
Hyperdiploidy 45-50 -
Pathophysiology
• Multiple
myeloma
arises from
malignant
transformat
ion of a
late-state B
cell.
Cytogenetic
hyperploidy
and up-
regulation of
cell cycle
control genes.
Accumulation of
these malignant
cells gradually
results in-
1. Anemia
2. Bone resorption
3. Hypercalcemia
4. Renal failure
5. Immunodeficiency
Mutations of
kinases,
deletions of
chromosomes,
and up-
regulation of
enzymes such as
c-myc
The malignant plasma cells
proliferate in the bone marrow
Producing monoclonal
proteins and causing
osteolytic bone disease.
Cytokines IL-6 and ILGF-1
Rank ligand/osteprotegrin and the WNT
signaling antagonist Dickkopf1
Clinical Features
Monoclonal Gammopathy of Unknown
Significance
• MGUS is a benign or a premalignant condition.
• In MGUS, the monoclonal protein is <3 g/dL and the bone marrow clonal
plasma cells are <10%.
• The risk of transformation to Myeloma and related diseases (such as
amyloidosis or Waldenstrom’s macroglobulinemia) has been estimated at
1% per year.
Asymptomatic Multiple Myeloma
(Smoldering Myeloma)
• The risk of transformation to Multiple Myeloma is much higher than in
MGUS (20% per year).
• These patients generally do not require therapy but should be followed
closely to monitor for progression.
Solitary Plasmacytomas
• The median age at diagnosis of solitary plasmacytoma (SP) is 55 to 65
years.
• Male-to-female ratio 2:1.
• A histologically confirmed single lesion with negative skeletal imaging
outside the primary site, normal bone marrow biopsy (<10% monoclonal
plasma cells), and no myeloma-related organ dysfunction.
• The disease more commonly presents in bone (80%).
• Such cases are considered stage I multiple myeloma according to the
Durie Salmon staging system.
• The most common location is the vertebra.
• Patients with bone involvement present with pain, neurologic compromise,
and occasionally pathologic fracture.
Multiple Myeloma
• Common tetrad of multiple myeloma is CRAB
• C = HyperCalcemia (Calcium)
• R = Renal failure
• A = Anemia
• B = Bone disease
• Osteopenia
• Multiple Lytic Bone Lesions
•Myeloma bone disease -- >proliferation of tumor cells and release of IL-6
<osteoclast activating factor :OAF>-- >stimulates osteoclasts to break down
bone-- > leading to hypercalcemia.
•These bone lesions in plain radiographs-- >
"punched-out" / lytic bone lesion
•Bone pain
•Myeloma bone pain -- >
•Involves the rib, sternum, spine, clavicle, skull, humerus
& femur.
•The lumbar vertebrae are one of the most common sites
of pain -- > may lead to spinal cord compression.
•Persistent localized pain may indicate
pathological fracture.
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%
Plasma Cell Leukemia
• This is a very rare variant of multiple myeloma, where the proliferation of
plasma cells is not confined to the bone marrow but may be detected in
the peripheral blood.
• It carries a very poor prognosis, with median survival <1 year.
Diagnostic Work UP
Diagnosis
• Serum protein electrophoresis is used to determine the type of each
protein present and may indicate a characteristic curve (ie, where the
spike is observed).
• The M protein should be measured with serum protein electrophoresis.
• If no M protein is detectable, assays for free light chains should be
performed in the serum and in the urine (Bence-Jones proteinuria).
• Urine protein electrophoresis is used to identify the presence of the Bence
Jones protein in urine.
• Immunofixation is used to identify the subtype of protein (ie, IgA lambda).
•Imaging Studies
• Skeletal series
• Skull (a very common site ), the long bones ( for
impending fractures), and the spine.
• Diffuse osteopenia may suggest myelomatous
involvement before discrete lytic lesions are
apparent.
• Do not use bone scans to evaluate myeloma
• MRI scan
• MRI to obtain a clear view of the spinal column and
to assess the integrity of the spinal cord.
Skeletal Survey
PET-CT Scan
Major Criteria and 1
Minor Criteria
Diagnostic : 0 Major Criteria and 3 Minor Criteria
Major Diagnostic Criteria
Plasmacytoma on tissue biopsy
Bone marrow plasmacytosis of > 30%
M Protein: IgG > 3.5 g/L; IgA > 2.0 g/L
Urinary kappa or lambda chain excretion of > 1g / 24
hours in absence of amyloidosis
Minor Diagnostic Criteria
Marrow plasmacytosis of 10-30%
Lytic bone lesions
Evidence of a monoclonal protein but lessor
amounts than above
Hypoglobulinemia of normal proteins: IgM < 500
mg/L, IgA < 1 g/L or IgG < 6g/L
Diagnostic Criteria :
Confirmation of 1 major and 1 minor criterion or
3 minor criteria in symptomatic patients
Major Diagnostic Criteria
Minor Diagnostic Criteria
Staging
Prognostic Factors
• Performance status 3 or 4
• Serum albumin < 3 g/dl
• Serum Cr ≥ 2.0 mg/dl
• Platelet count <150,000
• Age ≥ 70 years
• Beta-2-Microglobulin >4 mg/L
• Serum Calcium ≥ 11 mg/dl
• Haemoglobin <10 g/dl
• Bone marrow plasma cell percentage ≥50%
• Deletion of chromosome 13
• Presence of the t(4;14) translocation
• P53 deletion.
 Conventional chemotherapy:
 Melphalan
 Doxorubicin
 Cyclophosphamide
• Radiation therapy
• Stem cell transplantation:
– Autologous
– Allogenic
• Novel therapeutics:
– Thalidomide
– Lenalidomide
– Bortezomib
• Steroid therapy:
– Dexamethasone
– Prednisolone
The changes in the treatment of
Multiple Myeloma
Melphalan From 1980s
Myeloablation +
ASCT
2000s
Tandem
ASCT
1999
First report on
thalidomide
1962
Prednisone +
melphalan
Bortezomib
US licence 2003, EU
licence 2004
1990s Supportive care March/April 2005
Bortezomib
approved for
second-line
in USA & Europe
2006
Lenalidomide +
Dexa improved OS
in relapsed
Myeloma
• Bortezomib/cyclophosphamide/dexamethasone
• This combination may be used in any of the following regimens:
• Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus cyclophosphamide
300 mg/m2/day PO on days 1, 8, 15, and 22 plus dexamethasone 40 mg
PO daily on days 1-4, 9-12, and 17-20; 28-d cycle for 3 or 4 cycles.
• Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus cyclophosphamide
500 mg/m2/day PO on days 1, 8, and 15 plus dexamethasone 40 mg PO
daily on days 1, 8, and 15; 21-d cycle for 3 or 4 cycles
• Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus cyclophosphamide
900 mg/m2 IV over 1 h on day 1 plus dexamethasone 40 mg PO daily on
days 1 2, 4, 5, 8, 9, 11, and 12; 21-d cycle for 3 or 4 cycles
• Bortezomib/dexamethasone
• Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus dexamethasone
40 mg PO on days 1-4 and days 9-12 (cycles 1 and 2), then 40 mg PO on
days 1-4 (cycles 3 and 4); 21-d cycle for 3 or 4 cycles
• Either of the following two regimens may be used:
• Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus doxorubicin 9
mg/m2 IV push on days 1-4 plus dexamethasone 40 mg PO daily on days
1-4, 8-11, and 15-18 (cycle 1), then days 1-4 (cycles two-four); 21-d cycle
for 3 or 4 cycles
• Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus doxorubicin 9
mg/m2 continuous IV infusion over 24 h daily on days 1-4 plus
dexamethasone 40 mg PO daily on days 1-4, 9-12, and 17-10; 28-d cycle
for 3 or 4 cycles
• Bortezomib/lenalidomide/dexamethasone
• Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus lenalidomide 25
mg PO daily on days 1-14 plus dexamethasone 20 mg PO daily on days
1, 2, 4, 5, 8, 9, 11, and 12 or 40 mg PO daily on days 1, 8, and 15; 21d
cycle for 3 or 4 cycles
• Bortezomib/thalidomide/dexamethasone
• Bortezomib 1-1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus thalidomide 50-
200 mg (titrate to tolerance) PO daily at bedtime on days 1-21 plus
dexamethasone 40 mg PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 or 40
mg on days 1-4 and 9-12 or 40 mg on days 1-4 and 8-11; 21d cycle for 3
or 4 cycles
• Lenalidomide/dexamethasone
• Either of the following two regimens may be used:
• Lenalidomide 25 mg PO daily on days 1-21 plus dexamethasone 40 mg
PO daily on days 1, 8, 15, and 22 or 40 mg PO daily on days 1-4, 9-12,
and 17-20; 28-d cycle for 3 or 4 cycles
• Lenalidomide 25 mg PO daily on days 1-28 plus dexamethasone 40 mg
PO daily on days 1-4, 9-12, and 17-20; 28-d cycle for 3 or 4 cycles
• Alternative regimens
• Any of the following four regimens may be used:
• Dexamethasone 40 mg/day for 4 d beginning on days 1, 9, and 17 for the
first two cycles and 40 mg/day for 4 d beginning on day 1 for the next 10
cycles; every 6 wk for 12 cycles
• Pegylated liposomal doxorubicin 40 mg/m2 plus vincristine 1.4 mg/m2
(maximum, 2.0 mg) as an IV infusion on day 1 plus reduced-dose
dexamethasone 40 mg PO on days 1-4
• Lenalidomide 25 mg PO on days 1-21 plus dexamethasone 40 mg daily
on days 1-4, 9-12, and 17-20; every 28 d
• Thalidomide 200 mg PO daily plus dexamethasone 40 mg PO on days 1-4
and 15-18 on even cycles and on days 1-4 on odd cycles; every 28 d
Non Transplant Candidates
• Bortezomib 1-1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32, followed by a 10-
d rest period plus Melphalan 9 mg/m2 PO plus prednisolone 60 mg/m2 PO, both
on days 1-4; every 6 wk for four cycles then a maintenance phase consisting of
bortezomib 1-1.3 mg/m2 on days 1, 8, 22, and 29, followed by a 13-d rest period
plus Melphalan 9 mg/m2 PO plus prednisolone PO 60 mg/m2; every 5 wk for five
cycles
• Melphalan 0.25 mg/kg PO plus prednisolone 2 mg/kg plus thalidomide 200 mg
PO daily (escalating to 400 mg as tolerated) on days 1-4; every 6 wk
• Lenalidomide 25 mg PO on days 1-21 plus dexamethasone 40 mg PO daily on
days 1-4, 9-12, and 17-20; every 28 d
• Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 every 3 wk plus
dexamethasone 20 mg on the day of and the day after bortezomib
• Twelve 6-wk cycles of chemotherapy, including melphalan 0.25 mg/kg PO plus
prednisolone 2 mg/kg PO for 4 d
• Lenalidomide 10 mg PO on days 1-21 plus melphalan 0.18 mg/kg PO on days 1-
4 plus dexamethasone 40 mg PO weekly; every 28 d
• Alternative treatment recommendations
• One of the following may be used:
• Pegylated liposomal doxorubicin 40 mg/m2 plus vincristine 1.4 mg/m2
(maximum, 2.0 mg) as an IV infusion on day 1 plus reduced-dose
dexamethasone 40 mg PO on days 1-4
• Vincristine 0.4 mg/day plus doxorubicin 9 mg/m2/day by continuous
infusion on days 1-4 plus dexamethasone 40 mg/day on days 1-4, 9-12,
and 17-20 (odd cycles) and 40 mg/day for 4 d on even cycles; every month
• Thalidomide may be added to standard regimens in patients with myeloma
who are not transplant candidates; a meta-analysis of trials demonstrated
improved survival with this approach
Treatment recommendations for
maintenance therapy
• Lenalidomide 10 mg/day on days 1-21 every 28d or
• Thalidomide 50 mg/day to start, escalated to 200 mg/day, titrated to
tolerance
Salvage therapy regimens
• Panobinostat 20 mg PO once every other day for three doses/week (on days
1, 3, 5, 8, 10, and 12) of weeks 1 and 2 of each 21-day cycle for eight
cycles plus bortezomib and dexamethasone; consider continuing treatment
for an additional eight cycles for patients with clinical benefit.
• Lenalidomide 25 mg/day PO on days 1-21 plus dexamethasone 40 mg/day
PO on days 1-4, 9-12, and 17-20 of each 28-d cycle for the first four cycles of
therapy and then 40 mg/day PO on days 1-4 thereafter, every 28 d, who have
received at least one prior treatment
• Pomalidomide is a thalidomide analogue indicated for patients who have
received at least two prior therapies (including lenalidomide and bortezomib)
and have disease progression on or within 60 days of completion of the last
therapy ; Dosage is 4 mg PO QD on days 1-21 of repeated 28-day cycles until
disease progression; may be given in combination with dexamethasone
• Carfilzomib : A proteasome inhibitor, is indicated as monotherapy, in
combination with dexamethasone, or in combination with lenalidomide plus
dexamethasone for relapsed or refractory multiple myeloma in patients
who have received at least 1 prior line of therapy
• Lenalidomide or thalidomide can be used as single agents in salvage
therapy
• Daratumumab is an anti-CD38 monoclonal antibody for patients who have
received at least three prior treatments, including a proteasome inhibitor
(PI) and an immunomodulatory agent (IMiD), or whose disease is
refractory to both a PI and an IMiD; dosage is 16 mg/kg IV infusion once
weekly (weeks 1 to 8); reduce frequency to q2 wk (weeks 9-24) and
ultimately q4 wk (week 24 and thereafter) until disease progression
• Ixazomib is a reversible proteasome inhibitor indicated in combination with
lenalidomide and dexamethasone for patients who have received at least
1 prior therapy; starting dose is 4 mg PO on days 1, 8, and 15 of a 28-day
cycle until disease progression [41]
• Elotuzumab is a humanized IgG1 monoclonal antibody targeting SLAMF7
indicated in combination with lenalidomide and dexamethasone for
patients who have received 1-3 prior therapies; the dose is 10 mg/kg IV
weekly for the first two 28-day cycles, and then 10 mg/kg IV q2wk (on days
1 and 15)
• Bisphosphonates The second- and third-generation bisphosphonates,
pamidronate and zoledronate, reduce skeletal complications and bone
pain.
Renal Impairment
• In patients with renal impairment, the combination of bortezomib and
highdose dexamethasone is the preferred therapy
• Autologous transplantation should be reserved for younger patients with
chemosensitive disease.
• Because of the common occurrence of renal involvement in myeloma, the
use of nephrotoxic agents—most notably, nonsteroidal anti inflammatory
drugs (NSAIDs) and IV contrast agents —should be minimized or avoided
Panobinostat
• On February 23, 2015, FDA gave approval to Panobinostat in combination
with bortezomib and dexamethasone for the treatment of patients with
multiple myeloma who have received at least two prior regimens, including
bortezomib and an immunomodulatory agent.
• Panobinostat is a histone deacetylase inhibitor.
• A randomized trial was done evaluating panobinostat (or placebo) in
combination with bortezomib and dexamethasone.
• The primary efficacy endpoint was PFS determined by investigators. The
median PFS values were 10.6 and 5.8 months in the panobinostat-
containing arm (panobinostat-bortezomib-dexamethasone) and control
(placebo-bortezomib-dexamethasone), respectively.
Overall response rates were 58.5% vs 41.4%.
• The most common adverse reactions (>20%) are diarrhea, fatigue,
nausea, peripheral edema, decreased appetite, pyrexia, and
vomiting. Serious adverse reactions included pneumonia, diarrhea,
thrombocytopenia, fatigue, and sepsis.
• The most common hematologic abnormalities included thrombocytopenia
and neutropenia; the most common chemistry abnormalities were
hypophosphatemia and hypokalemia.
• ECG changes, including new T-wave changes and ST-segment
depressions and Arrhythmias.
Recommended Treatment Regimen for Panobinostat
• Treatment Phase 1: Cycles 1-8, 3 week cycles (Total time 24 weeks):
• Panobinostat 20 mg orally once daily 3 times a week for 2 weeks per 3 week cycle
• Bortezomib 1.3mg/m2 intravenously twice weekly for 2 weeks per 3 week cycle
• Dexamethasone 20 mg orally per day of bortezomib and the day after each dose
• Treatment Phase 2: Cycles 9-16, 3 week cycles (Total time 24 additional weeks):
• Patients achieving clinical benefit without unresolved severe or medically significant
toxicity may be considered for another 8 cycles of therapy at modified dosing.
• Panobinostat 20 mg orally once daily 3 times a week for 2 weeks per 3 week cycle
• Bortezomib 1.3mg/m2 intravenously once weekly for 2 weeks per 3 week cycle
• Dexamethasone 20 mg orally per day of bortezomib and the day after each dose
DETERMINING TRANSPLANT ELIGIBILITY
• Autologous hematopoietic cell transplantation (HCT) results in superior
event-free and overall survival rates when compared with combination
chemotherapy
• All patients should be evaluated at diagnosis for transplant eligibility so
that the risks and benefits of autologous HCT can be reviewed with those
eligible
• A minority of patients will be eligible for allogeneic HCT, but the value of
allogeneic approaches in myeloma remain investigational
NOT Eligible for Autologous HCT
• Age >77 years
• Direct bilirubin>2.0 mg/dL (34.2 µmol/liter)
• Serum creatinine>2.5 mg/dL (221 µmol/liter)
• ECOG performance status 3 or 4 unless due to bone pain
• New York Heart Association functional status Class III or IV
• Autologous transplantation
• Patients < 65-70 years
• Treatment related mortality 10-20%
• Response rate 80%
• Long term survival 40-50%
• Conventional allogeneic transplantation
• Patients < 45-50 years with HLA-Identical donor
• Treatment related mortality 40-50%
• Long term survival 20-30%
Sources of Hematopoietic stem cells
• Bone marrow (BM)
• Peripheral blood (PBSC)
• Umbilical cord blood (UCB)
Transplant process: 1-Stem cells collection
• Bone marrow harvesting.
 Marrow aspirated from pelvis.
• Peripheral blood harvesting.
Stem cells mobilised – G-CSF
On day 5 : stem cell collection
is done(apheresis ) by machine
Transplant process: 2-Processing & Cryopreservation
• Processing
BM /PBSC processed and stem
cells concentrated and purify and
prepared for freezing process.
• Cryopreservation.
Stem cells are preserved by
freezing to keep stem cells alive
until day of infusion into the
patient.
Transplant process:
3-Conditioning (Chemotherapy Regimen)
 By delivery of chemotherapy and/or radiation
 To eliminate any existing malignant cell.
 To suppress the patient’s immune system from rejecting the new stem
cells
 To create space for the new cells.
I. Chemotherapy regimen
 Chemotherapy agents used in conjunction with TBI include
cyclophosphamide, etoposide, and cytosine, arabinoside, with
cyclophosphamide at 120 mg/kg over 2 days being the most common.
II. TBI IN STEM CELL TRANSPLANT
 Successful hematopoietic stem cell engraftment requires
(a) eradication of the recipient bone marrow
(b)immunosuppression to prevent rejection of donor marrow in the case of an
allotransplant
(c) relative sparing of the recipient’s bone marrow stromal cells.
 Immunosuppression in the setting of allogeneic bone marrow
transplantation is necessary to avoid rejection of donor marrow, and TBI is a
very efficient immunosuppressant
II. TBI IN STEM CELL TRANSPLANT
 The conditioning regimen for hematopoietic stem cell transplantation has
several functions.
 One is cytotoxicity: to contribute to the eradication of any residual cancer.
 Another important function of the conditioning regimen is
immunosuppression so that the host does not reject the allogeneic donor
stem cells.
 TBI in the broad range of 2 to 15 Gy in conjunction with chemotherapy
serves these functions well
Transplant process: 4-Stem cells infusion
 Infusion - 20 minutes to an hour, varies
depending on the volume infused.
 Infused through a central venous line
(CVL), much like a blood transfusion.
 Premedication with acetaminophen and
diphenhydramine to prevent reaction.
Transplant process: 5-Recovery
Neutropenic phase
During this period the patient essentially has no effective immune system
Supportive care (GCSF) and antibiotic therapy are the mainstays of successful
passage through this phase.
ENGRAFTMENT PHASE
Recovery of normal levels cells is called engraftment
Bone Marrow (2-6 weeks)
PBSC ( 8-10 days for neutrophil & 10-12 days for platelets )
Cord blood (Neutrophil is 4 weeks)
Platelets are the next to return with red cells last (Commonly patients require
transfusion of red cells and platelets).
Radiation Therapy
Total Body Irradiation
• A phase III French study (IFM [Intergroupe Francophone du Mye’lome] trial
9502) examined melphalan, 200 mg/m2 alone (M200) versus melphalan
140 mg/m2 with TBI, 8 Gy in 4 fractions (M140/TBI), and found that
patients in the TBI-containing arm suffered more grade 3 or 4 mucosal
toxicity, heavier transfusion requirement, and longer hospitalization stay.
• There was a higher toxic death rate in the M140/TBI arm (3.6% vs. 0% for
the M200 arm).
• The event-free survival was no different between the two treatments, but
the 45-month overall survival favoured the M200 arm (M200: 65.8%;
M140/TBI: 45.5%; P = .05).
• Hemibody Radiation
• Half-body radiation with single doses of 5 to 8 Gy.
• The bone marrow in the unirradiated half-body serves as a stem cell
reserve and will slowly repopulate the irradiated marrow after treatment.
• The dose for upper half-body should not exceed 8 Gy due to lung
tolerance.
• The main toxicity is myelosuppression.
• It is not used now a days.
Radioimmunotherapy Approaches
• β-emitting isotope is conjugated to a phosphonate complex, such as
Samarium-153-ethylene diamine tetramethylene phosphonate (153Sm-
EDTMP).
• Holmium-166-DOTMP (166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-
tetramethylene-phosphonic acid), with a higher energy β emission
(maximum energy 1.85 MeV) than 153Sm and a shorter T1/2 of 26.8 hours.
It also has a γ emission (81 KeV) suitable for imaging.
Assessment of Response
TREATMENT OPTIONS FOR RELAPSED
MULTIPLE MYELOMA
Future Direction
• Anti-CS1 antibody Elotuzumab,
• Anti-CD38 antibody Daratumumab,
• HDAC6 inhibitor Ricolinostat,
• Heat shock protein 90 inhibitor (AUY 922)
• Telomerase inhibitor (GRN 163L)
Conclusions
• Care should be taken with IMiD-based therapy to include aspirin
prophylaxis for DVT/PE.
• Care should be taken with bortezomib-based regimens to include herpes
zoster prophylaxis.
Thank
You
Thalidomide:
• Proposed mechanisms
• Inhibition of TNF-
• Suppression of angiogenesis
• Increase in cell-mediated cytotoxic effects
• Modulation of adhesion molecule expression
Lenalidomide
• Immunomodulatory derivative of thalidomide
• More potent than thalidomide in preclinical models
• 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
Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950.
Bortezomib:
A Reversible Proteasome Inhibitor
Chymo-
tryptic
Site
Post-
Glutamyl
Site
Tryptic
Site
b1 b2
b3
b4
b5
b6
b7
Cross section of b ring
Bortezomib
Adams J, et al. Invest New Drugs. 2000;18:109-121.
Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338.
H
N B
N
H
O
O
OH
N
N
OH
Summary: Mechanism of Action
of Bortezomib (VELCADE)
The 26S proteasome is a
large protein complex that
degrades tagged proteins
Bortezomib
is a reversible
inhibitor of the chymotrypsin-like
activity of the 26S proteasome
Inhibition of the 26S
proteasome prevents
proteolysis of tagged
proteins which can affect multiple signaling
cascades with the cellNonclinical studies
showed bortezomib to
be cytotoxic to a variety
of cancer cell types
1
2
3
4
Millennium Pharmaceuticals, Inc., 2003.
Adams J. Drug Discov Today. 2003;8:307-315.
Bortezomib (VELCADE)
IkB/NFkB
 Apoptosis Inhibitors
(IAP, FLICE)
Caspases 8,3
FAS
MAPKPI3K
Decreased
Proliferation
antiapoptotic
Intracellular level
proliferation
Increased
Apoptosis
IL-6, VEGF
Block
activation
Inhibition
DNA-repair effectors
 Adhesion  Cytokine  Angiogenesis
BMSC
MM cells
VEGF
IGF-I
TNF
IL-6 BM Vessels
X



Disruption of unfolded
protein response
San Miguel J. Hematol J. 2003;4(suppl 3):201-207.
Chromosomal Alterations
13q14 deletions
17p13 deletions
11q abnormalities
Common translocations
t(11;14)(q13;q32) and t(4;14)(p16;q32)
Overexpression of myc or ras genes has
been noted in some cases
Mutations in p53 and Rb1 have also been
described
Complete Response No M-protein detected in serum or urine. Fewer than 5% plasma
cells in bone marrow, no hypercalcemia
Partial Response >50% reduction in serum paraprotein level and/or 90%
reduction in urine free light chain excretion. In non-secretory
disease at least 75% reduction in bone marrow plasma cells
number
Minimal Response 25-49% reduction in serum M-protein or <90% reduction in
urinary light chain excretion.
Stable Disease No evidence of continuing myeloma-related organ damage, less
than 25% change in serum M-protein levels for 3 months
Progressive Disease Organ damage continuing despite therapy or its re-appearance
in plateau-phase
Relapse Reappearance of disease in patients previously in CR
Mechanism of Bone Destruction
Graft Verses Host Disease (GVHD)
 GVHD results from the activation and proliferation of mature
donor T cells that recognize recipient alloantigen presented as
peptide molecules by antigen-presenting cells (APCs).
 In the setting of allogeneic transplantation, despite HLA
matching, a repertoire of peptides displayed on recipient cells
can be recognized as minor histocompatibility antigens by donor
T cells due to the polymorphisms in genes outside the HLA
system
Graft Verses Host Disease (GVHD)
 The activation of donor T cells after contact with specialized APCs
leads to differentiation to effector cells that produce cytokines such
as interferon-gamma and tumor necrosis factor, as well as mediate
cytotoxicity against normal recipient organs.
 Acute GVHD includes clinical damage to skin, gastrointestinal tract,
and liver, but other organs can also be involved.
 Later GVHD may present as a chronic form with more varied clinical
symptoms similar to rheumatologic or connective tissue diseases.
Graft Verses Host Disease (GVHD)
 More than half of the recipients undergoing HLA
matched sibling hematopoietic transplants develop some
degree of GVHD
monitoring of the engraftment
• Chimerism test / Engraftment
Analysis
• The test performed by the
analysis of genomic
polymorphisms short tandem
repeat (STR) sequences in
multiple chromosome
• STR test is done 1,2,3,6
months and 1 year

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Multiple myeloma

  • 2. Multiple Myeloma • Introduction • Epidemiology • Etiology • Pathophysiology • Clinical features • Diagnostic Work Up • Classification and staging • Prognostic Factors • Treatment • Follow Up
  • 3. Sarah Newbury, the first reported patient with Multiple Myeloma. A) Bone destruction in the sternum. B) The patient with fractured femurs and right humerus. C)Bone destruction involving the femur.
  • 4. Timeline depicting the history of Multiple Myeloma The term Multiple Myeloma was coined by Rustizky.
  • 5. Introduction • Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. The Spectrum of Myeloma-
  • 6. Epidemiology • The incidence rises with advancing age, with a median age at diagnosis of 70 years, and <1% of cases are diagnosed in those younger than 35. • Incidence : 0.7M/0.5 F per 100,000 population. • 1/10 as common as Leukemias
  • 7. Etiology Radiation: • Association with prior exposure to radiation (e.g., atomic bomb survivors in Hiroshima). Environmental or occupational causes : • Farmers (DDT exposure) • Wood workers • Leather workers • Sheet metal workers • Nuclear industry workers • Exposure to petroleum products
  • 8. Genetic causes: Chromosomal alterations identified: Recurrent Chromosomal Aberrations Chromosome Frequency % Patients Gene(s) Function 11q13 30 Cyclin D1 Induces growth 4p16 25 FGFR3, MMSET Growth factor 8q24 5 C-myc Growth/ apoptosis 16q23 1 C-maf Transcription factor 6p25 <1 IRF4 transcription factor Differentiation and growth 9p13 1 PAX-5 Transcription factor 20q12 1 MAFB Transcription factor 18q21 1 Bcl-2 Antiapoptosis Structural Chromosomal Aberrations Del 17p13 15 P53 Del 13 40-55 ? Hypodiploidy 20-30 - Hyperdiploidy 45-50 -
  • 9. Pathophysiology • Multiple myeloma arises from malignant transformat ion of a late-state B cell. Cytogenetic hyperploidy and up- regulation of cell cycle control genes. Accumulation of these malignant cells gradually results in- 1. Anemia 2. Bone resorption 3. Hypercalcemia 4. Renal failure 5. Immunodeficiency Mutations of kinases, deletions of chromosomes, and up- regulation of enzymes such as c-myc The malignant plasma cells proliferate in the bone marrow Producing monoclonal proteins and causing osteolytic bone disease. Cytokines IL-6 and ILGF-1 Rank ligand/osteprotegrin and the WNT signaling antagonist Dickkopf1
  • 11. Monoclonal Gammopathy of Unknown Significance • MGUS is a benign or a premalignant condition. • In MGUS, the monoclonal protein is <3 g/dL and the bone marrow clonal plasma cells are <10%. • The risk of transformation to Myeloma and related diseases (such as amyloidosis or Waldenstrom’s macroglobulinemia) has been estimated at 1% per year.
  • 12. Asymptomatic Multiple Myeloma (Smoldering Myeloma) • The risk of transformation to Multiple Myeloma is much higher than in MGUS (20% per year). • These patients generally do not require therapy but should be followed closely to monitor for progression.
  • 13. Solitary Plasmacytomas • The median age at diagnosis of solitary plasmacytoma (SP) is 55 to 65 years. • Male-to-female ratio 2:1. • A histologically confirmed single lesion with negative skeletal imaging outside the primary site, normal bone marrow biopsy (<10% monoclonal plasma cells), and no myeloma-related organ dysfunction. • The disease more commonly presents in bone (80%). • Such cases are considered stage I multiple myeloma according to the Durie Salmon staging system. • The most common location is the vertebra. • Patients with bone involvement present with pain, neurologic compromise, and occasionally pathologic fracture.
  • 14. Multiple Myeloma • Common tetrad of multiple myeloma is CRAB • C = HyperCalcemia (Calcium) • R = Renal failure • A = Anemia • B = Bone disease • Osteopenia • Multiple Lytic Bone Lesions
  • 15. •Myeloma bone disease -- >proliferation of tumor cells and release of IL-6 <osteoclast activating factor :OAF>-- >stimulates osteoclasts to break down bone-- > leading to hypercalcemia. •These bone lesions in plain radiographs-- > "punched-out" / lytic bone lesion •Bone pain •Myeloma bone pain -- > •Involves the rib, sternum, spine, clavicle, skull, humerus & femur. •The lumbar vertebrae are one of the most common sites of pain -- > may lead to spinal cord compression. •Persistent localized pain may indicate pathological fracture.
  • 16. 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%
  • 17. Plasma Cell Leukemia • This is a very rare variant of multiple myeloma, where the proliferation of plasma cells is not confined to the bone marrow but may be detected in the peripheral blood. • It carries a very poor prognosis, with median survival <1 year.
  • 19. Diagnosis • Serum protein electrophoresis is used to determine the type of each protein present and may indicate a characteristic curve (ie, where the spike is observed). • The M protein should be measured with serum protein electrophoresis. • If no M protein is detectable, assays for free light chains should be performed in the serum and in the urine (Bence-Jones proteinuria). • Urine protein electrophoresis is used to identify the presence of the Bence Jones protein in urine. • Immunofixation is used to identify the subtype of protein (ie, IgA lambda).
  • 20. •Imaging Studies • Skeletal series • Skull (a very common site ), the long bones ( for impending fractures), and the spine. • Diffuse osteopenia may suggest myelomatous involvement before discrete lytic lesions are apparent. • Do not use bone scans to evaluate myeloma • MRI scan • MRI to obtain a clear view of the spinal column and to assess the integrity of the spinal cord.
  • 22.
  • 24. Major Criteria and 1 Minor Criteria Diagnostic : 0 Major Criteria and 3 Minor Criteria Major Diagnostic Criteria Plasmacytoma on tissue biopsy Bone marrow plasmacytosis of > 30% M Protein: IgG > 3.5 g/L; IgA > 2.0 g/L Urinary kappa or lambda chain excretion of > 1g / 24 hours in absence of amyloidosis Minor Diagnostic Criteria Marrow plasmacytosis of 10-30% Lytic bone lesions Evidence of a monoclonal protein but lessor amounts than above Hypoglobulinemia of normal proteins: IgM < 500 mg/L, IgA < 1 g/L or IgG < 6g/L Diagnostic Criteria : Confirmation of 1 major and 1 minor criterion or 3 minor criteria in symptomatic patients Major Diagnostic Criteria Minor Diagnostic Criteria
  • 26.
  • 27.
  • 28.
  • 29.
  • 30. Prognostic Factors • Performance status 3 or 4 • Serum albumin < 3 g/dl • Serum Cr ≥ 2.0 mg/dl • Platelet count <150,000 • Age ≥ 70 years • Beta-2-Microglobulin >4 mg/L • Serum Calcium ≥ 11 mg/dl • Haemoglobin <10 g/dl • Bone marrow plasma cell percentage ≥50% • Deletion of chromosome 13 • Presence of the t(4;14) translocation • P53 deletion.
  • 31.  Conventional chemotherapy:  Melphalan  Doxorubicin  Cyclophosphamide • Radiation therapy • Stem cell transplantation: – Autologous – Allogenic • Novel therapeutics: – Thalidomide – Lenalidomide – Bortezomib • Steroid therapy: – Dexamethasone – Prednisolone
  • 32. The changes in the treatment of Multiple Myeloma Melphalan From 1980s Myeloablation + ASCT 2000s Tandem ASCT 1999 First report on thalidomide 1962 Prednisone + melphalan Bortezomib US licence 2003, EU licence 2004 1990s Supportive care March/April 2005 Bortezomib approved for second-line in USA & Europe 2006 Lenalidomide + Dexa improved OS in relapsed Myeloma
  • 33.
  • 34. • Bortezomib/cyclophosphamide/dexamethasone • This combination may be used in any of the following regimens: • Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus cyclophosphamide 300 mg/m2/day PO on days 1, 8, 15, and 22 plus dexamethasone 40 mg PO daily on days 1-4, 9-12, and 17-20; 28-d cycle for 3 or 4 cycles. • Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus cyclophosphamide 500 mg/m2/day PO on days 1, 8, and 15 plus dexamethasone 40 mg PO daily on days 1, 8, and 15; 21-d cycle for 3 or 4 cycles • Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus cyclophosphamide 900 mg/m2 IV over 1 h on day 1 plus dexamethasone 40 mg PO daily on days 1 2, 4, 5, 8, 9, 11, and 12; 21-d cycle for 3 or 4 cycles
  • 35. • Bortezomib/dexamethasone • Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus dexamethasone 40 mg PO on days 1-4 and days 9-12 (cycles 1 and 2), then 40 mg PO on days 1-4 (cycles 3 and 4); 21-d cycle for 3 or 4 cycles • Either of the following two regimens may be used: • Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus doxorubicin 9 mg/m2 IV push on days 1-4 plus dexamethasone 40 mg PO daily on days 1-4, 8-11, and 15-18 (cycle 1), then days 1-4 (cycles two-four); 21-d cycle for 3 or 4 cycles • Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus doxorubicin 9 mg/m2 continuous IV infusion over 24 h daily on days 1-4 plus dexamethasone 40 mg PO daily on days 1-4, 9-12, and 17-10; 28-d cycle for 3 or 4 cycles
  • 36. • Bortezomib/lenalidomide/dexamethasone • Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus lenalidomide 25 mg PO daily on days 1-14 plus dexamethasone 20 mg PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 or 40 mg PO daily on days 1, 8, and 15; 21d cycle for 3 or 4 cycles • Bortezomib/thalidomide/dexamethasone • Bortezomib 1-1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus thalidomide 50- 200 mg (titrate to tolerance) PO daily at bedtime on days 1-21 plus dexamethasone 40 mg PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 or 40 mg on days 1-4 and 9-12 or 40 mg on days 1-4 and 8-11; 21d cycle for 3 or 4 cycles
  • 37. • Lenalidomide/dexamethasone • Either of the following two regimens may be used: • Lenalidomide 25 mg PO daily on days 1-21 plus dexamethasone 40 mg PO daily on days 1, 8, 15, and 22 or 40 mg PO daily on days 1-4, 9-12, and 17-20; 28-d cycle for 3 or 4 cycles • Lenalidomide 25 mg PO daily on days 1-28 plus dexamethasone 40 mg PO daily on days 1-4, 9-12, and 17-20; 28-d cycle for 3 or 4 cycles
  • 38. • Alternative regimens • Any of the following four regimens may be used: • Dexamethasone 40 mg/day for 4 d beginning on days 1, 9, and 17 for the first two cycles and 40 mg/day for 4 d beginning on day 1 for the next 10 cycles; every 6 wk for 12 cycles • Pegylated liposomal doxorubicin 40 mg/m2 plus vincristine 1.4 mg/m2 (maximum, 2.0 mg) as an IV infusion on day 1 plus reduced-dose dexamethasone 40 mg PO on days 1-4 • Lenalidomide 25 mg PO on days 1-21 plus dexamethasone 40 mg daily on days 1-4, 9-12, and 17-20; every 28 d • Thalidomide 200 mg PO daily plus dexamethasone 40 mg PO on days 1-4 and 15-18 on even cycles and on days 1-4 on odd cycles; every 28 d
  • 39. Non Transplant Candidates • Bortezomib 1-1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32, followed by a 10- d rest period plus Melphalan 9 mg/m2 PO plus prednisolone 60 mg/m2 PO, both on days 1-4; every 6 wk for four cycles then a maintenance phase consisting of bortezomib 1-1.3 mg/m2 on days 1, 8, 22, and 29, followed by a 13-d rest period plus Melphalan 9 mg/m2 PO plus prednisolone PO 60 mg/m2; every 5 wk for five cycles • Melphalan 0.25 mg/kg PO plus prednisolone 2 mg/kg plus thalidomide 200 mg PO daily (escalating to 400 mg as tolerated) on days 1-4; every 6 wk • Lenalidomide 25 mg PO on days 1-21 plus dexamethasone 40 mg PO daily on days 1-4, 9-12, and 17-20; every 28 d • Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 every 3 wk plus dexamethasone 20 mg on the day of and the day after bortezomib • Twelve 6-wk cycles of chemotherapy, including melphalan 0.25 mg/kg PO plus prednisolone 2 mg/kg PO for 4 d • Lenalidomide 10 mg PO on days 1-21 plus melphalan 0.18 mg/kg PO on days 1- 4 plus dexamethasone 40 mg PO weekly; every 28 d
  • 40. • Alternative treatment recommendations • One of the following may be used: • Pegylated liposomal doxorubicin 40 mg/m2 plus vincristine 1.4 mg/m2 (maximum, 2.0 mg) as an IV infusion on day 1 plus reduced-dose dexamethasone 40 mg PO on days 1-4 • Vincristine 0.4 mg/day plus doxorubicin 9 mg/m2/day by continuous infusion on days 1-4 plus dexamethasone 40 mg/day on days 1-4, 9-12, and 17-20 (odd cycles) and 40 mg/day for 4 d on even cycles; every month • Thalidomide may be added to standard regimens in patients with myeloma who are not transplant candidates; a meta-analysis of trials demonstrated improved survival with this approach
  • 41. Treatment recommendations for maintenance therapy • Lenalidomide 10 mg/day on days 1-21 every 28d or • Thalidomide 50 mg/day to start, escalated to 200 mg/day, titrated to tolerance
  • 42.
  • 43. Salvage therapy regimens • Panobinostat 20 mg PO once every other day for three doses/week (on days 1, 3, 5, 8, 10, and 12) of weeks 1 and 2 of each 21-day cycle for eight cycles plus bortezomib and dexamethasone; consider continuing treatment for an additional eight cycles for patients with clinical benefit. • Lenalidomide 25 mg/day PO on days 1-21 plus dexamethasone 40 mg/day PO on days 1-4, 9-12, and 17-20 of each 28-d cycle for the first four cycles of therapy and then 40 mg/day PO on days 1-4 thereafter, every 28 d, who have received at least one prior treatment • Pomalidomide is a thalidomide analogue indicated for patients who have received at least two prior therapies (including lenalidomide and bortezomib) and have disease progression on or within 60 days of completion of the last therapy ; Dosage is 4 mg PO QD on days 1-21 of repeated 28-day cycles until disease progression; may be given in combination with dexamethasone
  • 44. • Carfilzomib : A proteasome inhibitor, is indicated as monotherapy, in combination with dexamethasone, or in combination with lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma in patients who have received at least 1 prior line of therapy • Lenalidomide or thalidomide can be used as single agents in salvage therapy • Daratumumab is an anti-CD38 monoclonal antibody for patients who have received at least three prior treatments, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or whose disease is refractory to both a PI and an IMiD; dosage is 16 mg/kg IV infusion once weekly (weeks 1 to 8); reduce frequency to q2 wk (weeks 9-24) and ultimately q4 wk (week 24 and thereafter) until disease progression
  • 45. • Ixazomib is a reversible proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for patients who have received at least 1 prior therapy; starting dose is 4 mg PO on days 1, 8, and 15 of a 28-day cycle until disease progression [41] • Elotuzumab is a humanized IgG1 monoclonal antibody targeting SLAMF7 indicated in combination with lenalidomide and dexamethasone for patients who have received 1-3 prior therapies; the dose is 10 mg/kg IV weekly for the first two 28-day cycles, and then 10 mg/kg IV q2wk (on days 1 and 15) • Bisphosphonates The second- and third-generation bisphosphonates, pamidronate and zoledronate, reduce skeletal complications and bone pain.
  • 46. Renal Impairment • In patients with renal impairment, the combination of bortezomib and highdose dexamethasone is the preferred therapy • Autologous transplantation should be reserved for younger patients with chemosensitive disease. • Because of the common occurrence of renal involvement in myeloma, the use of nephrotoxic agents—most notably, nonsteroidal anti inflammatory drugs (NSAIDs) and IV contrast agents —should be minimized or avoided
  • 47.
  • 48. Panobinostat • On February 23, 2015, FDA gave approval to Panobinostat in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. • Panobinostat is a histone deacetylase inhibitor. • A randomized trial was done evaluating panobinostat (or placebo) in combination with bortezomib and dexamethasone. • The primary efficacy endpoint was PFS determined by investigators. The median PFS values were 10.6 and 5.8 months in the panobinostat- containing arm (panobinostat-bortezomib-dexamethasone) and control (placebo-bortezomib-dexamethasone), respectively. Overall response rates were 58.5% vs 41.4%.
  • 49. • The most common adverse reactions (>20%) are diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting. Serious adverse reactions included pneumonia, diarrhea, thrombocytopenia, fatigue, and sepsis. • The most common hematologic abnormalities included thrombocytopenia and neutropenia; the most common chemistry abnormalities were hypophosphatemia and hypokalemia. • ECG changes, including new T-wave changes and ST-segment depressions and Arrhythmias.
  • 50. Recommended Treatment Regimen for Panobinostat • Treatment Phase 1: Cycles 1-8, 3 week cycles (Total time 24 weeks): • Panobinostat 20 mg orally once daily 3 times a week for 2 weeks per 3 week cycle • Bortezomib 1.3mg/m2 intravenously twice weekly for 2 weeks per 3 week cycle • Dexamethasone 20 mg orally per day of bortezomib and the day after each dose • Treatment Phase 2: Cycles 9-16, 3 week cycles (Total time 24 additional weeks): • Patients achieving clinical benefit without unresolved severe or medically significant toxicity may be considered for another 8 cycles of therapy at modified dosing. • Panobinostat 20 mg orally once daily 3 times a week for 2 weeks per 3 week cycle • Bortezomib 1.3mg/m2 intravenously once weekly for 2 weeks per 3 week cycle • Dexamethasone 20 mg orally per day of bortezomib and the day after each dose
  • 51. DETERMINING TRANSPLANT ELIGIBILITY • Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy • All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible • A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational
  • 52. NOT Eligible for Autologous HCT • Age >77 years • Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) • Serum creatinine>2.5 mg/dL (221 µmol/liter) • ECOG performance status 3 or 4 unless due to bone pain • New York Heart Association functional status Class III or IV
  • 53. • Autologous transplantation • Patients < 65-70 years • Treatment related mortality 10-20% • Response rate 80% • Long term survival 40-50% • Conventional allogeneic transplantation • Patients < 45-50 years with HLA-Identical donor • Treatment related mortality 40-50% • Long term survival 20-30%
  • 54. Sources of Hematopoietic stem cells • Bone marrow (BM) • Peripheral blood (PBSC) • Umbilical cord blood (UCB)
  • 55. Transplant process: 1-Stem cells collection • Bone marrow harvesting.  Marrow aspirated from pelvis. • Peripheral blood harvesting. Stem cells mobilised – G-CSF On day 5 : stem cell collection is done(apheresis ) by machine
  • 56. Transplant process: 2-Processing & Cryopreservation • Processing BM /PBSC processed and stem cells concentrated and purify and prepared for freezing process. • Cryopreservation. Stem cells are preserved by freezing to keep stem cells alive until day of infusion into the patient.
  • 57. Transplant process: 3-Conditioning (Chemotherapy Regimen)  By delivery of chemotherapy and/or radiation  To eliminate any existing malignant cell.  To suppress the patient’s immune system from rejecting the new stem cells  To create space for the new cells.
  • 58. I. Chemotherapy regimen  Chemotherapy agents used in conjunction with TBI include cyclophosphamide, etoposide, and cytosine, arabinoside, with cyclophosphamide at 120 mg/kg over 2 days being the most common.
  • 59. II. TBI IN STEM CELL TRANSPLANT  Successful hematopoietic stem cell engraftment requires (a) eradication of the recipient bone marrow (b)immunosuppression to prevent rejection of donor marrow in the case of an allotransplant (c) relative sparing of the recipient’s bone marrow stromal cells.  Immunosuppression in the setting of allogeneic bone marrow transplantation is necessary to avoid rejection of donor marrow, and TBI is a very efficient immunosuppressant
  • 60. II. TBI IN STEM CELL TRANSPLANT  The conditioning regimen for hematopoietic stem cell transplantation has several functions.  One is cytotoxicity: to contribute to the eradication of any residual cancer.  Another important function of the conditioning regimen is immunosuppression so that the host does not reject the allogeneic donor stem cells.  TBI in the broad range of 2 to 15 Gy in conjunction with chemotherapy serves these functions well
  • 61. Transplant process: 4-Stem cells infusion  Infusion - 20 minutes to an hour, varies depending on the volume infused.  Infused through a central venous line (CVL), much like a blood transfusion.  Premedication with acetaminophen and diphenhydramine to prevent reaction.
  • 62. Transplant process: 5-Recovery Neutropenic phase During this period the patient essentially has no effective immune system Supportive care (GCSF) and antibiotic therapy are the mainstays of successful passage through this phase.
  • 63. ENGRAFTMENT PHASE Recovery of normal levels cells is called engraftment Bone Marrow (2-6 weeks) PBSC ( 8-10 days for neutrophil & 10-12 days for platelets ) Cord blood (Neutrophil is 4 weeks) Platelets are the next to return with red cells last (Commonly patients require transfusion of red cells and platelets).
  • 64. Radiation Therapy Total Body Irradiation • A phase III French study (IFM [Intergroupe Francophone du Mye’lome] trial 9502) examined melphalan, 200 mg/m2 alone (M200) versus melphalan 140 mg/m2 with TBI, 8 Gy in 4 fractions (M140/TBI), and found that patients in the TBI-containing arm suffered more grade 3 or 4 mucosal toxicity, heavier transfusion requirement, and longer hospitalization stay. • There was a higher toxic death rate in the M140/TBI arm (3.6% vs. 0% for the M200 arm). • The event-free survival was no different between the two treatments, but the 45-month overall survival favoured the M200 arm (M200: 65.8%; M140/TBI: 45.5%; P = .05).
  • 65. • Hemibody Radiation • Half-body radiation with single doses of 5 to 8 Gy. • The bone marrow in the unirradiated half-body serves as a stem cell reserve and will slowly repopulate the irradiated marrow after treatment. • The dose for upper half-body should not exceed 8 Gy due to lung tolerance. • The main toxicity is myelosuppression. • It is not used now a days.
  • 66. Radioimmunotherapy Approaches • β-emitting isotope is conjugated to a phosphonate complex, such as Samarium-153-ethylene diamine tetramethylene phosphonate (153Sm- EDTMP). • Holmium-166-DOTMP (166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetramethylene-phosphonic acid), with a higher energy β emission (maximum energy 1.85 MeV) than 153Sm and a shorter T1/2 of 26.8 hours. It also has a γ emission (81 KeV) suitable for imaging.
  • 68.
  • 69.
  • 70. TREATMENT OPTIONS FOR RELAPSED MULTIPLE MYELOMA
  • 71. Future Direction • Anti-CS1 antibody Elotuzumab, • Anti-CD38 antibody Daratumumab, • HDAC6 inhibitor Ricolinostat, • Heat shock protein 90 inhibitor (AUY 922) • Telomerase inhibitor (GRN 163L)
  • 72. Conclusions • Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE. • Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis.
  • 74. Thalidomide: • Proposed mechanisms • Inhibition of TNF- • Suppression of angiogenesis • Increase in cell-mediated cytotoxic effects • Modulation of adhesion molecule expression
  • 75. Lenalidomide • Immunomodulatory derivative of thalidomide • More potent than thalidomide in preclinical models • 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 Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950.
  • 76. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of b ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH
  • 77. Summary: Mechanism of Action of Bortezomib (VELCADE) The 26S proteasome is a large protein complex that degrades tagged proteins Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome Inhibition of the 26S proteasome prevents proteolysis of tagged proteins which can affect multiple signaling cascades with the cellNonclinical studies showed bortezomib to be cytotoxic to a variety of cancer cell types 1 2 3 4 Millennium Pharmaceuticals, Inc., 2003. Adams J. Drug Discov Today. 2003;8:307-315.
  • 78. Bortezomib (VELCADE) IkB/NFkB  Apoptosis Inhibitors (IAP, FLICE) Caspases 8,3 FAS MAPKPI3K Decreased Proliferation antiapoptotic Intracellular level proliferation Increased Apoptosis IL-6, VEGF Block activation Inhibition DNA-repair effectors  Adhesion  Cytokine  Angiogenesis BMSC MM cells VEGF IGF-I TNF IL-6 BM Vessels X    Disruption of unfolded protein response San Miguel J. Hematol J. 2003;4(suppl 3):201-207.
  • 79. Chromosomal Alterations 13q14 deletions 17p13 deletions 11q abnormalities Common translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) Overexpression of myc or ras genes has been noted in some cases Mutations in p53 and Rb1 have also been described
  • 80. Complete Response No M-protein detected in serum or urine. Fewer than 5% plasma cells in bone marrow, no hypercalcemia Partial Response >50% reduction in serum paraprotein level and/or 90% reduction in urine free light chain excretion. In non-secretory disease at least 75% reduction in bone marrow plasma cells number Minimal Response 25-49% reduction in serum M-protein or <90% reduction in urinary light chain excretion. Stable Disease No evidence of continuing myeloma-related organ damage, less than 25% change in serum M-protein levels for 3 months Progressive Disease Organ damage continuing despite therapy or its re-appearance in plateau-phase Relapse Reappearance of disease in patients previously in CR
  • 81. Mechanism of Bone Destruction
  • 82. Graft Verses Host Disease (GVHD)  GVHD results from the activation and proliferation of mature donor T cells that recognize recipient alloantigen presented as peptide molecules by antigen-presenting cells (APCs).  In the setting of allogeneic transplantation, despite HLA matching, a repertoire of peptides displayed on recipient cells can be recognized as minor histocompatibility antigens by donor T cells due to the polymorphisms in genes outside the HLA system
  • 83. Graft Verses Host Disease (GVHD)  The activation of donor T cells after contact with specialized APCs leads to differentiation to effector cells that produce cytokines such as interferon-gamma and tumor necrosis factor, as well as mediate cytotoxicity against normal recipient organs.  Acute GVHD includes clinical damage to skin, gastrointestinal tract, and liver, but other organs can also be involved.  Later GVHD may present as a chronic form with more varied clinical symptoms similar to rheumatologic or connective tissue diseases.
  • 84. Graft Verses Host Disease (GVHD)  More than half of the recipients undergoing HLA matched sibling hematopoietic transplants develop some degree of GVHD
  • 85. monitoring of the engraftment • Chimerism test / Engraftment Analysis • The test performed by the analysis of genomic polymorphisms short tandem repeat (STR) sequences in multiple chromosome • STR test is done 1,2,3,6 months and 1 year