multiple myeloma

1. Multiple myeloma
DR.SWARNITA SAHU
DNB RESIDENT
RADIATION ONCOLOGY
BATRA HOSPITAL AND MEDICAL RESEARCH CENTRE
NEW DELHI

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

4. PLASMA CELL
• ORIGINATE FROM TERMINALLY
DIFFERENTIATED B CELL
• BONE MARROW AND LYMPHOID
TISSUE
• PRODUCE AND SECRETE ALL
CLASSES
OF IMMUNOGLOBULINS
• LIFE SPAN : 30 DAYS.

5. 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

6. 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).

7. CLINICAL SPECTRUM OF MULTIPLE MYELOMA

8. MULTIPLE MYELOMA
• ASYMTOMATIC
Diagnosed in
routine blood work.
• HEMATOLOGIC
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

10. ANAEMIA
Normocytic normochromic
• Tumor cells in the marrow
• Inadequate erythropoietin responsiveness
• Cytokines
• Decreased renal function-----decreased
erythropoiesis
• Increased Igg levels---dilutional effects.
• Fatigue
• Weakness
• Occasional shortness of breath
Rx- ERYTHROPOIETIN ADMINISTRATION (IMP SUPPORTIVE CARE)

11. NEPHROPATHY
LIGHT CHAIN TUBULAR CASTS ------ INTERSTITIAL NEPHRITIS (MYELOMA
KIDNEY)
ADDITIONAL FACTORS
• Nsaids for pain control
• Nephrotoxic chemotherapy drugs
• Iv contrast for radiographic
studies
• Bisphosphonate therapy
• Calcium deposition and stones in
kidney
HYPERCALCAEMIA
• Osmotic diuresis
• Volume depletion
• Pre-renal azotemia
Light chain deposition leading to decrease
in GFR

12. HYPERCALCAEMIA AND BONE
DISEASE
• Osteoporosis
• Lytic bone lesions
• Mental
changes
• Lethargy
• Constipation
• Vomiting
BM microenvironment myeloma cells—increased in osteoclast activatin factors(IL-1beta, TNF-beta,
IL-6, MIP 1 alpha
INCREASED OSTEOCLAST ACTIVITY
DECREASED OSTEOBLAST ACTIVITY

13. NEUROLOGIC SYMPTOMS
HYPERCALCAEMIA
HYPERVISCOSITY
THALLIDOMIDE
BORTEZOMIB
TUMOR MASS EFFECT WITH
COMPRESSION OF spinal cord, cranial or
spinal nerves.

14. HYPERVISCOSITY COAGULOPATHY
• Increased production of
immunoglobulins
• Increased levels of
paraproteins interfering
normal coagulation
• Thrombosis(d/t
hyperviscosity)
• Platelet dysfunction

15. EXTRAMEDULLARY DISEASE
(advanced stage or relapse following allogenic
transplantation)
SKIN , SOFT TISSUE AND LIVER
SUSPECTED IN:
• INCREASED LDH
• IMMUNOBLASTIC MORPHOLOGY
• INCREASED TUMOR CELL LABELLING
INDEX
• COMPLEX KARYOTYPING FEATURES

16. 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.

18. 1STSTEP
CONFIRM THE
PRESENCE, TYPE &
QUANTITY OF
MONOCLONAL
PROTEIN.
DETECTION &
QUANTIFICATION OF
CLONAL PLASMA
CELLS
2NDSTEP
DIFFERENTIATE
MGUS, SMM,
SYMPTOMATIC
MULTIPLE MYELOMA
3RDSTEP
EVALUATION OF
PROGNOSTIC
VARIABLES
• LAB:
RFT,Calcium,Albumin,
Uric acid, LDH, BETA-
2 Microglobulin,CRP
• SKELETAL SURVEY
• MRI AND STIR
IMAGES
• BONE
DENSITOMETRY
• CYTOGENETICS(metapha
se karyotype & FISH)
• SERUM B2
MICROGLOBULIN
• Sr LDH
• Sr ALBUMIN
• Sr pr electrophoresis
• Quantitative Igg
• 24 hr urine: total pr & bence
jones pr
• Immunofixation of urine and
serum
• Sr free light chain and ratio
 Bone marrow aspirate &
biopsy-
histology, clonality, flow
cytometry,cytogenetics & FISH.

19. • 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

21. 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.

22. SKELETAL SURVEY: LYTIC BONE LESIONS (PUNCHED OUT LESIONS)

25. DIAGNOSTIC CRITERIA FOR MYELOMA AND
ITS VARIANTS

26.  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%
• No M protein in serum or urine
• No organ damage
 ASYMPTOMATIC MYELOMA ( SMOLDERING MYELOMA)
• M protein in serum >30% and/or
• 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.
MYELOMA RELATED ORGAN
DAMAGE :
• C-HYPERCALCAEMIA
• R-RENAL INSUFFIENCY
• A-ANAEMIA
• B-BONE LESIONS

27. UPDATE (NCCN)
Active multiple myeloma is no longer diagnosed using the CRAB criteria for end-
organ damage. The current diagnostic criteria are as follows

29.  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

30. PROGNOSTIC VARIABLES

31.  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.

32. DURIE AND SALMON STAGING: predictive
for clinical outcomes after standard dose
chemotherapy
NOT FOR HIGH DOSE OR NOVEL BASED
CHEMOTHERAPY.
NO LONGER USED CLINICALLY
62 months
44 months
29 months

33. TREATMENT

34. 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.
TREATMENT RECOMMENDATIONS FOR MULTIPLE MYELOMA

40. 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.

43. 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.

44. 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.

45. RADIATION THERAPY IN MULTIPLE
MYELOMA

46. • Considered mainstay of treatment prior to chemotherapeutic
options.
• NOW – VERY LIMITED ROLE in multiple myeloma.
• Definitive role – solitary bone and extramedullary
plasmacytoma.

47. 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
(200mg/m2)
MELPHALAN (140mg/m2) + TBI(8Gy/4#)
Increased gr 3 & 4 toxicity.
Heavier transfusion requirement & longer hospital stay.
Decreased OS.

48. 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.

49. 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#)

50. 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)

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