MULTIPLE MYELOMA

1. MULTIPLE MYELOMA
Diagnosis and Overview of Management of Multiple Myeloma
Presenter : Dr. Bimalesh Preceptor: Dr. V. S. Pai
Moderator: Dr. Rajat Ranka

2. DEFINITION:
Malignant proliferation of plasma cells derived from a
single clone
Second most common hematological malignancy

3. EPIDEMIOLOGY:
• Occurs in all races and all geographic locations
• Black>white
• M>F
• Median age at diagnosis -69 years
• The incidence : 4/lac in the general population 30/lac in over 25
years population
• In India, incidence 1/100000, 50000 cases diagnosed each year
with younger median age at diagnosis-55 years

4. ETIOLOGY:
• No single common molecular pathogenic pathway has yet
emerged
• Radiation
• Farmers, wood workers , leather workers , exposed to
petroleum products
• Hyperdiploidy, translocations 14q32, 13q14 deletion,
17p del , Switch recombinations
• IL-6 ,N-ras, K-ras and B-raf

5. PATHOGENESIS

7. CLINICAL PRESENTATION
COMMON FEATURES UNCOMMON FEATURES
BONE PAIN HYPERVISCOSITY/RAYNAUD’S
INFECTION PARESTHESIA
ANEMIA HSM
HYPERCALCEMIA LYMHNODE
RENAL FAILURE :
CREATININE/CAST/RTA2/PROTEINUR
IA
SPINAL CORD COMPRESSION FROM
EXTRAMEDULLARY
PLASMACYTOMA-MED EMR
WEIGHT LOSS PLEURAL EFFUSION
GENERALISED WEAKNESS

8. WHO Classification of Plasma Cell Neoplasms

9. WHO Classification of Plasma Cell Neoplasms
A. Monoclonal gammopathy of undetermined
significance (MGUS)
B. Multiple Myeloma
-Asymptomatic
-Symptomatic
-Non-secretory
-Plasma Cell Leukemia

10. WHO Classification ..........
C. Plasmacytoma
-Solitary plasmacytoma of bone
-Extra medullary plasmacytoma
D. Deposition Disease
-Primary Amyloidosis,
-Systemic Heavy and Light Chain Disease
E. Osteosclerotic Myeloma (POEMS Syndrome)

11. Diagnostic criteria

12. A.Diagnostic criteria for MGUS
Presence of monoclonal spike on electrophoresis with
all of these features:
1. Serum monoclonal protein <30 gm/L
2. Clonal bone marrow plasma cells <10%,
3. Absence of MDE or amyloidosis that can be attributed to
the plasma cell proliferative disorder

13. B. SMOULDERING MULTIPLE MYELOMA
Both criteria must be met:
1. Serum monoclonal protein (IgG or IgA) ≥ 30gm/L or 24 hr
urinary monoclonal protein ≥500 mg and/or clonal bone
marrow plasma cells 10-60%
2. Absence of myeloma defining event or amyloidosis

14. C. SYMPTOMATIC MULTIPLE MYELOMA
 Bone marrow plasma cells ≥10% or biopsy proven bony or extramedullary plasmacytoma
and any one or more of myeloma defining events including:
 Myeloma defining events:MDE
I. Evidence of end organ damage due to underlying plasma cell proliferative disorder
1. HyperCalcemia: >1 mg/dl higher than upper limit or >11 mg/dl
2. Renal insufficiency: serum creatinine >2 mg/dl or creatinine clearance <40 ml/min
3. Anemia: Hb<10 gm/dl or >2gm/dl below the lower limit of normal
4. Bone lesion: one or more osteolytic lesions on skeletal radiography, CT or PET-
CT
II Any one or more biomarker of malignancy including:
1. Clonal bone marrow plasma cells ≥ 60%
2. Free light chain ratio ≥ 100
3. >1 focal lesions on MRI

15. D.Non-secretory myeloma
1. No M protein in serum and/or urine with immunofixation
2. Bone marrow clonal plasmacytosis >=10% or plasma
cytoma
3. Myeloma related organ or tissue impairment (end organ
damage )

16. E. SOLITARY PLASMACYTOMA
1. Biopsy proven solitary lesion of bone or soft tissue
with evidence of clonal plasma cells
2. Normal bone marrow with no evidence of clonal plasma
cells
3. Normal skeletal survey and MRI/CT of spine and pelvis
(except for the primary solitary lesion)
4. Absence of end organ damage (No CRAB)

17. F. Plasma Cell Leukemia (PCL)
Any one ofthe following:
1. More than 20% abnormal plasma cells in the differential
WBC lineage or
2. If there is an absolute number of more than 2000/µL of
plasma cells in PBS.

18. INVESTIGATIONS

19. INVESTIGATIONS:
SPEP
SERUM IMMUNO-
ELECTROPHORESIS
SERUM FREE
LIGHT CHAIN
ASSAY

20. INVESTIGATIONS
Bone marrow examinations
• Monoclonal plasma cells=>10%
• Eccenteric nucleus,
• Course basophilic cytoplasm,
• Clock face chromatin
Immunophenotype-
• CD79a, CD38,CD138, VS38c: Positive
• CD19: Negative
PLASMA CELLS IN BM

21. INVESTIGATIONS
IMAGING:
• CT: Bone abnormalities
• PET CT: most sensitive for extamedullary disease
• MRI: most sensitive for bone lesions

22. CLINICAL PRESENTATION....
PUNCHED OUT LYTIC LX COLLAPSED VERTEBRAE

23. INVESTIGATIONS
A. Investigations to evaluate for clonal plasma cells
1. Histology (BME)
2. Clonality by kappa/lambda immunostaining by flow cytometry
or immunohistochemistry
B.Investigations to evaluate clonal paraprotein
1. SPEP and immunofixation
2. Quantitative serum Ig levels
3. 24-h urine protein electrophoresis and immunofixation
4. S. free light chain and ratio

24. INVESTIGATIONS
C. Investigations to evaluate End Organ Damage
1. Hemogram to assess for anemia
2. Chemistry panel for renal function and calcium
3. Skeletal survey to evaluate bone lesions
4. PET/CT or MRI if smoldering MM or solitary plasma cytoma
with no other MDE or extramedullary disease

25. INVESTIGATIONS
D.Investigations for Risk stratification
1. B2-microglobulin and serum albumin for ISS stage
2. Fluoroscent in situ hybridisation for hyperdiploidy on BM for:
1. del17p,
2. t(4,14)
3. t(11,14)
4. t(14,16),
5. t(14,20)
6. amp1q34
7. del13
3. LDH

26. INVESTIGATIONS
E. Specialized Investigations in selected cases
1. Abdominal fat pad for amyloid
2. Serum viscosity if IgM component or high IgA levels or serum
M component>7g/dl
3. Myd88 and CXCR4 mutation analysis if IgM component

27. RISK STRATIFICATION IN MULTIPLE MYELOMA

28. RISK STRATIFICATION IN MM
METHOD STANDARD RISK (80%)
EXPECTED SURVIVAL 6-7+
YEARS
HIGH RISK (20%)
EXPECTED SURVIVAL 2-3
YEARS
KARYOTYPE No CA Any abnormality on
conventional karyotype
FISH t(11,14)
del13
1. del17p,
2. t(4,14)
3. t(14,16),
4. t(14,20)
5. amp1q34
CHROMOSOMAL ABNORMALITIES(CA)

29. RISK STRATIFICATION IN MM
OTHER FEATURES SUGGESTING HIGH RISK
1. De novo plasma cell leukemia
2. Extramedullary disease
3. Elevated LDH
4. High risk gene expression profile
5. IgD myeloma-worst
6. Lambda
7. Beta-2 microglobulins

30. STAGING

31. INTERNATIONAL STAGING SYSTEM (ISS)
STAGE FEATURES
I • B2-MICROGLOBULIN <3.5mg/L
• ALBUMIN>=3.5gm/dl
II • NOT I OR III
III • B2-MICROGLOBULIN>5.5mg/L

32. REVISED INTERNATIONAL STAGING SYSTEM (RISS)
STAGE FEATURES
I ISS I + STANDARD RISK FOR CA + NORMAL LDH
II NOT I OR III
III ISS III + HIGH RISK FOR CA OR HIGH LDH

33. TREATMENT OVERVIEW

35. TREATMENT OF MGUS
MGUS HIGH RISK MGUS MGUS WITH
POLYNEUROPATHY
F/U ONCE A
YEAR OR LESS
F/U 6 MONTHLY
• CBC
• CALCIUM
• CREATININE
• SPEP
Plasmapheresis
Rituximab
Treat like MM

36. TREATMENT: ASYMPTOMATIC MM-SMM
• No specific therapeutic intervention is indicated
• SMM require antitumor therapy when myeloma-defining
events are identified.
• F/U with CBC, KFT, SPEP,UPEP, Immunofixation at
2-3 months
if stable
4-6 monthly for 1 year
every 6-12monthly

37. Treatment of solitary plasmacytomas
• Local RT
• Prolonged disease-free survival after local radiation
therapy at a dose of ∼40 Gy

38. TREATMENT: SYMPTOMATIC MM
Transplant ineligibility:
a) Age>70 year
b) significant cardiopulmonary insufficiency
c) other comorbidities
Phases of therapy:
a) Eligible for transplant : Induction phase f/b HCT f/b
Maintenance
b) Ineligible for transplant: Induction phase f/b Maintenance

39. MM -HCT ELIGIBLE-STANDARD RISK
INDUCTION REGIMEN:
• Lenalidomide, Bortezomib, Dexamethasone (RVD)
• Lenalidomide, Dexamethasone
- 3 to 4 months prior to stem cell collection (4-6 cycles)

40. MM -HCT ELIGIBLE -STANDARD RISK-cont........
Following induction therapy and stem cell collection
• Early transplant strategy
• Delayed transplant strategy
• Allogeneic HCT
 Early/Delayed autologous HCT> either chemotherapy
alone or allogeneic HCT
MAINTENANCE AFTER HCT
• Lenalidomide based

41. MM-HCT ELIGIBLE - HIGH RISK
 Induction:8-12 Cycle Triplet based f/b Early ASCT
 Maintenance: proteosome inhibitor based

42. MM-HCT INELIGIBLE-STANDARD RISK
• Induction:
– RVD-lite triplet regimen for 8-12 cycles
– Patients who are frail and not suitable for triplet therapy :
lenalidomide-Low Dose Dexamethasone
• Maintenance: lenalidomide

43. SYMPTOMATIC MM-HCT INELIGIBLE-HIGH RISK
• Do poorly with all conventional treatment options
• Should be encouraged to enroll in a clinical trial
 Induction: 8-12 cycles of Triplet based therapy
 Maintenance: proteosome inhibitor based

44. EVALUATING RESPONSE TO TREATMENT
• Evaluated before each treatment cycle
– Measurement of M-protein in serum and urine
– FLC assay
• Patients without measureable M-protein or abnormal FLC
– Periodic bone marrow aspirate and biopsies
– Whole body PET-CT

46. TREATMENT OF RELAPSED DISEASE
• Options:
– ASCT (delayed approach)
– Rechallenge of previous chemotherapy regimen
– A trial of new regimen
• The second-generation proteasome inhibitor carfilzomib
Immunomodulatory agent pomalidomide

48. • Bortezomib:
– Herpes zoster prophylaxis
– Neuropathy can be decreased both by its subcutaneous
administration and by administration on a weekly schedule
• Lenalidomide :
– Prophylaxis for deep-vein thrombosis (DVT) with either aspirin
or, if patients are at a greater risk of DVT, warfarin, low-
molecular-weight heparin, or direct-acting anticoagulants

49. SUPPORTIVE THERAPY:
• Hypercalcemia:
 Bisphosphonates, glucocorticoid therapy, hydration, and
natriuresis and rarely requires calcitonin as well.
• Infection:
Pneumococcal conjugate vaccines
Prophylactic IVIG for recurrent serious infection

50. TAKE HOME MESSAGE
Suspect MM when:
1. Bone pain with lytic lesion
2. Unexplained anemia with high ESR
3. Hypercalcemia with AKI
4. Recurrent infection with hypogamaglobulinemia
5. A:G Ratio reversal with Mprotein in serum/urine

51. References:
1. Harrison's-Principles of Internal Medicine 21st Edition
2. Indian Council Of Medical Research-Consensus
document for management of Multiple Myeloma
3. Multiple myeloma: EHA-ESMO Clinical Practice
Guidelines for diagnosis, treatment and follow-up
4. UpToDate

52. 10 MCQ
1. M/c symptom in MM
a) Easy fatiguibility
b) Bone pain
c) Oliguria
d) Fever

53. 2. True regarding MM
a) Increased monoclonal Ig G is primarily responsibe for
hyperviscosity
b) Most of the MGUS progresses to MM
c) Decreased Anion Gap
d) Radioisotope bone scanning is preferred

54. 3. A 72 year old man presented with complaints of
fatiguibility and chronic lower back pain .
Lab-Hb: 9 gm/dl, S. Ca: 11.5 mg/dl, S. M protein:5 gm/dL,
BM Bx: 15% clonal plasma cells.
Dx?
a) MM
b) SMM
c) MGUS
d) Non-secretory MM

55. 4.M/C cause of RF in MM?
a) Light chain deposition
b) Amyloidosis
c) Recurrent infections
d) Hypercalcemia

56. 5. A pt. was brought to the hospital with dehydration and
generalised weakness . He was diagnosed with MM 2 years
ago. He has metabolic acidosis with hypokalemia, urine ph
5.1, glycosuria, and proteinuria. Dx?
a) RTA Type 1
b) RTA Type 2
c) RTA Type 3
d) RTA Type 4

57. 6. You diagnosed a 69 yr old business tycoon as MM.
Lab: Beta 2 microglobulin 3 mg/L , S. albumin 3 gm/dl
ISS Stage ?
a) I
b) II
c) III
d) Can’t be predicted

58. 7. A 65 year old pt. presented with multiple fractures and
bone pain. SPEP revealed elevated M protein. What is the
most likely nature of M protein?
a) IgM
b) IgG
c) Albumin
d) Lambda light chains

59. 8. A 70 yr old man presented with fatiguability
and back pain since 3 months.
Lab: Hb 7 g/dl, s. protein :6 gm%, S
albumin 3.5 g/dl, BM clonal
plasmacytosis:15%, SPEP as Shown:
Dx?
a) MM
b) SMA
c) MGUS
d) Non-secretory myeloma

60. 9. You diagnosed a 69 yr old business tycoon as MM. He
asks you how long will he survive. Which of the following is
best predictor for this ?
a) Durie-salmon staging system
b) Percentage of circulating plasma cells
c) Beta -2 microglobulin levels
d) Plasma cell labelling index

61. 10. A 68 year old male patient presented with
multiple fractures. He has been suffering from
recurrent infections for past 6 months . Bone
marrow bx showed :
T/t of choice?
a) LENALIDOMIDE+BORTEZOMIB+
DEXAMETHASONE
b) THALIDOMIDE+
CYCLOPHOSPHAMIDE
c) BORTEZOMIB+CYCLOPHOSPHAMIDE
+ DEXAMETHASONE
d) RITUXIMAB + CYCLOPHOSPHAMIDE