Multiple myeloma

EPIDEMIOLOGY
• PLASMA CELL NEOPLASMS- 22% OF ALL MATURE B CELL
NEOPLASMS.
 MULTIPLE MYELOMA - MAJORITY
 SOLITARY PLASMACYTOMA - <6%
 PLASMA CELL LEUKAEMIA - VERY RARELY
 PLASMA CELL
• ORIGINATE FROM TERMINALLY
DIFFERENTIATED B CELL

• BONE MARROW AND LYMPHOID

TISSUE

• PRODUCE AND SECRETE ALL

CLASSES
OF IMMUNOGLOBULINS

• LIFE SPAN : 30 DAYS.

PLASMA CELL NEOPLASMS
• SPECTRUM OF DISEASES
• BENIGN :
 SOLITARY PLASMACYTOMA
 MONOCLONAL GAMMOPATHY OF UNKNOWN ORIGIN
 CASTLEMAN’S DISEASE
 ALPHA HEAVY CHAIN DISEASE
 WALDENSTORM’S MACROGLUBULINAEMIA
• MALIGNANT :
 MYELOMA
 LEUKEMIA
ETIOLOGY
EXPOSURE TO -
• Ionising Radiation (LOW DOSE).
• Exposure to metals (NICKEL).
• Agricultural chemicals ,Benzene and petroleum products.

Hereditary and genetic factors (eg:HLA-Cw2 overexpression).

MGUS (PREMALIGNANT CONDITION).

CLINICAL SPECTRUM OF MULTIPLE MYELOMA
 MULTIPLE MYELOMA
• ASYMTOMATIC
Diagnosed in • HEMATOLOGIC
routine blood work. DYSFUNCTION
• BONE RELATED SYMPTOMS
• INFECTIONS
• ORGAN DYSFUNCTION

 DIRECT BM INVOLVEMENT
 EXTRAMEDULLARY PLASMACYTOMA
 EFFECTS ON THE IMMUNE SYSTEM
 PROTEINS PRODUCED BY THE
TUMOR CELLS GET DEPOSITED IN
VARIOUS ORGANS
 CYTOKINES
 • Tumor cells in the marrow
• Inadequate erythropoietin responsiveness
• Cytokines
• Decreased renal function-----decreased
erythropoiesis
• Increased Igg levels---dilutional effects.

ANAEMIA
Normocytic normochromic

• Fatigue
• Weakness
• Occasional shortness of breath

Rx- ERYTHROPOIETIN ADMINISTRATION (IMP SUPPORTIVE CARE)

 LIGHT CHAIN TUBULAR CASTS ------ INTERSTITIAL NEPHRITIS (MYELOMA
KIDNEY)

ADDITIONAL FACTORS HYPERCALCAEMIA

• Nsaids for pain control NEPHROPATHY • Osmotic diuresis
• Nephrotoxic chemotherapy drugs • Volume depletion
• Iv contrast for radiographic • Pre-renal azotemia
studies
• Bisphosphonate therapy
• Calcium deposition and stones in
kidney

Light chain deposition leading to decrease

in GFR
BM microenvironment myeloma cells—increased in osteoclast activatin factors(IL-1beta, TNF-beta,
IL-6, MIP 1 alpha

INCREASED OSTEOCLAST ACTIVITY

DECREASED OSTEOBLAST ACTIVITY

HYPERCALCAEMIA AND BONE

DISEASE

• Mental • Osteoporosis
changes • Lytic bone lesions
• Lethargy
• Constipation
• Vomiting
 TUMOR MASS EFFECT WITH
COMPRESSION OF spinal cord, cranial or
spinal nerves.

THALLIDOMIDE
HYPERVISCOSITY NEUROLOGIC SYMPTOMS BORTEZOMIB

HYPERCALCAEMIA
 HYPERVISCOSITY COAGULOPATHY

• Increased production of • Increased levels of

immunoglobulins paraproteins interfering
normal coagulation
• Thrombosis(d/t
hyperviscosity)
• Platelet dysfunction
SUSPECTED IN:
• INCREASED LDH
• IMMUNOBLASTIC MORPHOLOGY
• INCREASED TUMOR CELL LABELLING
INDEX
• COMPLEX KARYOTYPING FEATURES

EXTRAMEDULLARY DISEASE
(advanced stage or relapse following allogenic
transplantation)

SKIN , SOFT TISSUE AND LIVER

 SUspect MYELOMA IN:

DIAGNOSIS DELAYED DUE TO NON SPECIFIC

SYMPTOMS

OLD PATIENT WITH UNEXPLAINED BONE PAIN, RECURRENT

INFECTION, ANAEMIA , RENAL INSUFFIENCY.
ADDITIONAL FEATURES:hyperproteinaemia, proteinuria, anaemia,
hypoalbuminaemia, low immunoglobulin, marked elevation of ESR.
 CONFIRM THE DIFFERENTIATE EVALUATION OF

1ST STEP

2ND STEP

3RD STEP
PRESENCE, TYPE & MGUS, SMM, PROGNOSTIC
QUANTITY OF SYMPTOMATIC VARIABLES
MONOCLONAL MULTIPLE MYELOMA
PROTEIN.
DETECTION &
QUANTIFICATION OF
CLONAL PLASMA
CELLS

• Sr pr electrophoresis
• LAB: • CYTOGENETICS(metapha
• Quantitative Igg
RFT,Calcium,Albumin, se karyotype & FISH)
• 24 hr urine: total pr & bence
Uric acid, LDH, BETA- • SERUM B2
jones pr
2 Microglobulin,CRP MICROGLOBULIN
• Immunofixation of urine and
• Sr LDH
serum
• SKELETAL SURVEY • Sr ALBUMIN
• Sr free light chain and ratio
• MRI AND STIR
IMAGES
 Bone marrow aspirate &
• BONE
biopsy-
DENSITOMETRY
histology, clonality, flow
cytometry,cytogenetics & FISH.
• 70% IgG
• 20% IgA
• 5-10% monoclonal
light chains only
• <1% - monoclonal
IgD, IgE, IgM or
nonsecretory
myeloma.

 No difference in
therapeutic
approach
 IgA MYELOMA
PTS HAS POOR
PROGNOSIS
 RADIOGRAPHIC EVALUATION
• SKELETAL SURVEY:A skeletal survey is comprised of various x-rays of all the bones in the body.
Typically, this procedure involves radiographs of the skull, spine, humeri, ribs, pelvis and femora.
 Osteopenia in early stages
 Lytic bone lesions in advanced disease
 Osteosclerotic lesions in POEMS syndrome.(exception)

• BONE SCAN: NOT USEFUL

 Due to predominant osteoclastic acivity and OSTEOBLASTIC INACTIVITY.

• DEXA SCAN: IMPORTANT TOOL

 measurement of bone mineral density by dual energy X-ray absorptiometry detects osteopenia.

• MRI:
 Spine and pelvis-in all patients with solitary plasmacytoma and SMM( detect occult and progression)
 Defines pattern of marrow inv-diffuse /focal
 Cord compression
• PET:
 Detection of extraosseous soft tissue masses
 Evaluation of ribs and appendicular bone lesions.
SKELETAL SURVEY: LYTIC BONE LESIONS (PUNCHED OUT LESIONS)
DIAGNOSTIC CRITERIA FOR MYELOMA AND
ITS VARIANTS
 MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE

• M protein in serum < 30g/dl.

• Bone marrow plasma cells < 10% .
• No evidence of other B cell proliferative disorders.
• No myeloma related organ or tissue impairment.

 NON SECRETORY MYELOMA

• Bone marrow plasma cells > 10% MYELOMA RELATED ORGAN

• No M protein in serum or urine DAMAGE :
• No organ damage
• C-HYPERCALCAEMIA
• R-RENAL INSUFFIENCY
 ASYMPTOMATIC MYELOMA ( SMOLDERING MYELOMA) • A-ANAEMIA
• M protein in serum >30% and/or
• B-BONE LESIONS
• Bone marrow clonal plasma cells >/= 10%.
• No related organ damage

 SYMPTOMATIC MULIPLE MYELOMA

• M protein in serum/urine.
• Bone marrow clonal plasma cells or plasmacytoma > 10%.
• Organ damage.
• Flow cytometry: >90% plasma cells – neoplastic phenotype.
 UPDATE (NCCN)

Active multiple myeloma is no longer diagnosed using the CRAB criteria for end-
organ damage. The current diagnostic criteria are as follows
 SOLITARY PLASMOCYTOMA OF BONE

• Single area of bone destruction due to clonal plasma cells

• M protein - ABSENT
• Bone marrow
• Skeletal survey NORMAL.
• Organs

 EXTRAMEDULLARY PLASMACYTOMA

• Extramedullary tumor of clonal plasma cells.

 MUTIPLE SOLITARY PLASMACYTOMA(+/- RECURRENT)

• >1 area localized area of bone destruction or extramedullary tumor of clonal plasma cells (which may be
recurrent).
• M protein – ABSENT
• Bone marrow
• Skeletal survey NORMAL.
• Organs
PROGNOSTIC VARIABLES
 TUMOR BURDEN RELATED FACTORS
• Sr.Beta 2 macroglobulin
• >3 lytic lesions
• Hb
• Sr calcium
 TUMOR MICROENVIRONMENT RELATED
• Bone marrow microvessel density
• Sr syndecan-1 levels
• MMP-9 levels
• Soluble CD16
 PATIENT RELATED FACTORS
• Age
• Albumin
• Performance status
• Comorbidities
 TUMOR BIOLOGY RELATED FACTORS
• Cytogenetics/FISH abnormality
• Gene expression profile pattern
• Plasma cell labelling index
• Bartl grade
• Mitotic activity
• IgA myeloma
• CRP
• LDH
• Soluble IL6 receptor
• Renal failure
 TUMOR RELATED FACTORS
• Tandem transplant
• Achieving complete or very good partial response.
 DURIE AND SALMON STAGING: predictive
for clinical outcomes after standard dose
chemotherapy
62 months NOT FOR HIGH DOSE OR NOVEL BASED
CHEMOTHERAPY.
NO LONGER USED CLINICALLY

44 months

29 months
TREATMENT
 TREATMENT RECOMMENDATIONS FOR MULTIPLE MYELOMA

STAGE RECOMMENDED TREATMENT

I or systemic smoldering Observe or systemic therapy
II OR III • 2 or 3 agent combination of either alkylators, proteasome inhibitors,
immunomodulatory agents, histone deacetylase inhibitors or newer
monoclonal antibodies + bisphosphonate for bone disease.

• Consider high dose therapy followed by stem cell transplant.

• RT to be considered for palliation

• New MM with cord compression and organ damage- steroids + bortezomib with
RT to spine.(hold lenalidomide until after RT)

• Surgical consideration for impending fractures.

 STEM CELL TRANSPLANTATION

• Myeloma and normal cells are killed by high dose chemotherapy ( Melphalan)

• Stem cells are bone marrow like cells harvested from the peripheral blood

• Sources of stem cells:

AUTOLOGOUS:
• from the patient
• Standard of care for eligible candidates
• Treatment related mortality <2%
• Outpatient procedure
• Melphalan (200mg/m2 ) most commonly used (reduced use in elderly or renal insuffiency).

ALLOGENIC:
• from a donor
• VERY LIMITED USE
• d/t lack of donors, age restriction, high treatment related mortality and graft versus host disease.
 TANDEM TRANSPLANTATION

• Tandem/second transplant : planned second ASCT

• Tandem vs single transplant : overall survival better with
tandem.
• To be considered in patients with suboptimal response to
the first ASCT.
 RELAPSE AFTER ASCT

CONVENTIONAL THERAPY:
• Repeated course of alkylator based therapy(melphalan).
• Cyclophosphamide and steroids
TRANSPLANTATION:
• Second autologous stem cell transplant
HIGH DOSE CHEMOTHERAPY:
• High dose cyclophosphamide
• DTPACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide)
NOVEL AGENTS:
• Thalidomide
• Bortezomib
• Lenalidomide
COMBINATION OF CONVENTIONAL & NOVEL AGENT.
RADIATION THERAPY IN MULTIPLE
MYELOMA
• Considered mainstay of treatment prior to chemotherapeutic
options.
• NOW – VERY LIMITED ROLE in multiple myeloma.
• Definitive role – solitary bone and extramedullary
plasmacytoma.
 TOTAL BODY IRRADIATION
• TBI + HIGH DOSE CHEMOTHERAPY as conditioning regimen.
• Toxicity concerns - mucosal and hematological d/t TBI
• IFM 9502:
282 pts with MM undergoing conditioning regimen before autologous stem cell transfusion

MELPHALAN MELPHALAN (140mg/m2) + TBI(8Gy/4#)

(200mg/m2)
Increased gr 3 & 4 toxicity.
Heavier transfusion requirement & longer hospital stay.
Decreased OS.
 HEMIBODY IRRADIATION
• Palliation of diffuse bone pain.
• 5-8Gy in single #.
• UNIRRADIATED MARROW: serves as stem cells which
repopulated the irradiated marrow after treatment.
• RARELY USED NOW.
• Remain useful for palliation of advanced disease in
chemotherapy refractory patients.
 LOCAL EBRT FOR PALLIATION:
• Most common use of radiotherapy.
• Relief of compression of spinal / cranial / peripheral nerves.
• Reduces incidence of impending fractures.
ROLE UNCLEAR
High risk lesions - referred for surgical stabilization.
RT preferred for RESIDUAL disease ,post surgery.
• Bone lesions- treat entire bone except for long bones and pelvis (to decrease
the dose in bone marrow)
• Vertebrae- treat 1-2 vertebrae above and below the diseased vertebrae

• PAIN- 10-20Gy/5-10# - pain relief is often partial.

• SPINAL CORD COMPRESSION- Motor improvement in 50% of the
patients.
(30Gy/10# better neurologic response than 20Gy/5# or 8Gy/1#)
RADIOIMMUNOTHERAPY APPROACHES (TARGETED RADIATION
THERAPY)
• SAMARIUM
• HOLIUM
• Emits gamma rays- permitting scanning to locate areas of
uptake
• Agents used for palliation
• Higher doses than TBI can be given
• 30-60Gy (sparing dose limiting normal tissues-lung, mucosa,
kidneys)
 SUPPORTIVE CARE

• Erythropoietic agents.
• Bisphosphonates (even has an effect on overall survival).
• Local RT.
• Newer surgical techniques: vertebroplasty & kyphoplasty.