Detailed Discussion

2. Multiple Myeloma
Dr Sadia Sadiq
PGR 2,INMOL

3. Presentation Overview
 Introduction
 Definitions
 Clinical Presentation
 Work up
 Staging
 Management
 Transplant Procedure
 SupportiveTreatment
 Treatment Regimens

4. Plasma Cell Dyscrasias
 1)Monoclonal Gammopathy of Unknown
Significance (MGUS)
 2)“Smoldering” Asymptomatic Myeloma
 3)Multiple Myeloma
 4)Solitary Plasmacytoma
 5)Plasma cell leukemia

5. 1)Monoclonal Gammopathy of Unknown
Significance (MGUS)
 Accumulation of bone marrow plasma cells derived from
a single abnormal clone
 Monoclonal Immunoglobulin Level ≤3 g/dL.
and/or
 Bone marrow colonal plasma cells<10%.
 No related organ or tissue impairment or symptoms.

6. 2)“Smoldering” Asymptomatic Myeloma
 Monoclonal Immunoglobulin Level ≥ 3 g/dL.
and/or
 Bone marrow colonal plasma cells> 10%.
 No related organ or tissue impairment or symptoms.
 Intermediate form of myeloma.

7. 3)Multiple Myeloma
 Monoclonal Immunoglobulin Level ≥ 3 g/dL.
and/or
 Bone marrow colonal plasma cells> 10%.
Plus requires one of following (CRAB Criteria).
 Calcium Elevation (>11.5mg/dl).
 Renal insufficiency (creatinine > 2mg/dl).
 Anemia (Hb < 10g/dl or 2g/dl<normal).
 Bone disease (lytic or Osteopenic).

8. 4)Solitary Plasmacytoma of Bone
 Solitary bone lesion due to plasma cell tumor.
 Normal Skeletal Survey.
 Normal Bone marrow plasmacytosis.
 No Anemia, Hypercalcemia or Renal disease.
 Preserved levels of uninvolved immunoglobulins.

9. 5)Plasma cell leukemia
 A very rare variant of MM, 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 of only 3 to 6 months.

10. Multiple myeloma
 MM is a malignant neoplasm of monoclonal
plasma cells that accumulate in bone
marrow,leading to bone marrow destruction
and marrow failure.
 Accounts for 15% of all hematologic cancers.

11. MM:Epidemiology

12. Etiology and risk factors
 No predisposing factors for the development of
multiple myeloma have been confirmed.
 Environment
o Radiation exposure
o Occupational exposure (agricultural, chemical,
metallurgical, rubberplant, pulp, wood and paper
workers, and leather tanners).
o Chemical exposure to formaldehyde, epichlorohydrin,
hair dyes, paint sprays, and asbestos

13. Cytogenetics
 DNA aneuploidy is observed in more than
90%;predominantly hyperdiploid, with less than
10% being hypodiploid.
 Specific chromosomal abnormalities have been
identified in patients with MM involving
 Translocations eg..t(11;14)t(4;14)t(14;16),
 Deletions eg..chromosome 13,17p13
 Amplifications..chromosome 1

14. Cytogenetics…

15. Pathophysiology
 Interactions between multiple myeloma cells and their microenvironment allow myeloma cells to
survive, grow, migrate, and resist apoptosis induced by traditional chemotherapies.These effects are
partially mediated through adhesion-mediated signalling and partly through various cytokines,
including IL-6,VEGF, IGF-1,TNF-α.
 The molecular signals mediating the proliferative effects include the MAPK pathway, whereas the P13
kinase pathway provides cell survival and drug resistance signals.
 Improved understanding of these interactions and the molecular mechanisms mediating them has
allowed the evaluation of novel therapies that directly target multiple myeloma cells as well as act
on the bone marrow microenvironment and other milieus, including cortical bone.

16. Pathophysiology…

17. Clinical Presentation

18. The initial work-up
1) History and Physical Examination
2) CBC and Peripheral Blood Smear.
3) Routine serum chemistry (e.g., calcium, blood
urea nitrogen, creatinine,albumin).
4) Bone marrow aspirate and trephine biopsy or
biopsy of mass if solitary lesion
Clonality, immunophenotype and cytogenetic
studies, plasma cell labeling index to assess
plasmacytosis.

19. Bone marrow
 Bone marrow examination usually reveals an increased number of
plasma cells(>10%). Immaturity of the plasma cells is evident with
the presence of prominent nucleoli (“myeloma cells”).
 These cells are strongly positive for CD38, CD138, and
cytoplasmic immunoglobulin.
 Myeloma cells are negative for CD5, CD19, and surface Ig (sIg)
expression.
 The pattern of bone marrow involvement in plasma cell myeloma
may be macrofocal. As a result, plasma cell count may be normal
when an aspirate misses the focal aggregates of plasma cells that
are better visualized radiographically.

20. Work- up…
M-Protien Assessment
 Serum protein electrophoresis and
immunofixation to define protein type.
 Serum free light chain.
 24-hour urine protein, electrophoresis, and
immunofixation .
 Quantitative serum Ig levels.

21. Skeletal survey

22. Work-up…
Prognostic Factors
• Cytogenetics by FISH
• Beta-2-microglobulin .
• Serum albumin.
• C reactive protein (CRP).
• Lactate dehydrogenase (LDH) levels.
 PET/CT scan.
 MRI is an excellent tool for evaluation of spinal cord
compression/impingement

23. MRI

24. Normal plasma cells help
protect the body from germs
and other harmful substances
Myeloma cells make
antibodies called M proteins
and other proteins. These
proteins can collect in the
blood, urine, and organs

25. Monoclonal proteins
IgG (60%).
 IgA (20%).
IgD (2%).
IgE (< 0.1%).
 light-chain κ or λ only (18%).
Biclonal < 1% of patients.
Nonsecretory disease < 5%.

26. Staging
 Either the Durie-Salmon system at diagnosis
or the International Staging System (ISS),
which is determined at the time systemic
therapy is begun
 The Durie-Salmon staging system better
provides information on tumor burden,
whereas the ISS staging system better serves
as a prognostic indicator.

28. CR •Noserum/urineMproteinbyimmunofixationelectrophoresisfor≥6weeks
•<5%plasmacellsinbonemarrowaspirate
•Noincreaseinthesizeornumberoflyticbonelesions
•Disappearanceofsoft-tissueplasmacytomas.
PR •≥50%reductioninserumMprotein>6weeks
•≥90%reductionin24-hrurinarylight-chainexcretion
•≥50%reductioninsoft-tissueplasmacytomas
MR •≥25%reductioninserumMproteinfor>6weeks
•≥50%–89%reductionin24-hoururinarylight-chainexcretion
•Noincreaseinthesizeornumberoflyticbonelesions
Treatment response criteria
(CIBMTR/EBMTR)

29. International Myeloma Working Group
Response Criteria
 Complete
Response(CR)
 stringent CR
 Immunophenotype CR
 Molecular CR
 VGPR
 Partial Response
 Minimal Response
 Stable Disease
 Progressive Disease
 Clinical Relapse
 Relapse from CR

32. MANAGEMENT

33. 1)MGUS
 Benign or a premalignant condition .
 The risk of transformation has been estimated at 1% per
year
 The long period of stability supports annual monitoring
with serum electrophoresis and blood counts.
 Recent studies indicate that the diagnosis of
symptomatic multiple myeloma is typically preceded by
monoclonal gammopathy for 2 or more years.

34. 2)Smoldering Myeloma
Smoldering myeloma generally progresses to
multiple myeloma at the rate of 10% per year for
the first 5 years, 3% per year for the next 5 years,
and then 1% for the next 10 years.

35. 3)Management of Solitary Plasmacytoma
 Consists of radiation therapy (at least 45 Gy).
 Surgery should be considered for structural instability of
bone or rapidly progressive neurologic compromise such
as spinal cord compression.
 RT is still indicated due to a high likelihood of
microscopic residual disease. Surgery alone without RT
leads to an unacceptably high local recurrence rate.

36. Management..RT
 For the spine, inclusion of two vertebral bodies
above and below the grossly involved vertebra(e)
is a common practice.
 Prophylactic regional nodal coverage is not
necessary in solitary plasmacytoma of bone as
multiple studies have found a very low risk of
regional nodal failure.

37. Follow-up
 Over 60-75% of patients with solitary bone tumor
progressed to myeloma in 10 yrs , at a median of 2
to 3 years after treatment.
 The M-protein is measured every 3 to 6 months as
indicated.
 Radiologic skeletal survey is performed annually
or when symptoms develop.

38. 4)Solitary extramedullary plasmacytoma
 Of all solitary extramedullary plasmacytomas, 90%
occur in the head and neck,and produce local
compressive symptoms.
 If complete surgical excision can be achieved with
minimal morbidity, it may be curative, and postoperative
RT is not recommended(Soutar et al., 2004).
Incomplete excision is an indication for radical RT. Local
lymph nodes are only included in the target volume if they
are clinically involved.

39. 5)Multiple MyelomaTreatment
The main options for therapy include:
 Chemotherapy.
 Immune modulating treatments such as
thalidomide (Thalomid®),lenalidomide (Revlmid®),
and bortezomib (Velcade®).
 Corticosteroids such as prednisone or
dexamethasone.
 Stem cell (bone marrow) transplantation.

40. When to start treatment?
Once symptoms develop,
treatment with one or more of the
options discussed above is
recommended for almost all
patients

41. Choice of initial therapy
The choice of initial therapy
depends on eligibility for high-dose
therapy (HDT) and autologous
stem cell transplantation (ASCT).

42. Is stem cell transplantation an option?
 Because of the risk of toxic and even fatal
complications related to stem cell
transplantation, not everyone with multiple
myeloma is a candidate for stem cell
transplantation.
 Eligibility varies across countries and across
institutions

43. Eligibility Criteria For Stem cell
transplantation
 In most European countries
<65 years of age.
 In most centers in the United States,
Patients with following factors are NOT considered eligible for transplantation:
Age >77 years
Direct bilirubin >2.0 mg/dL
Serum creatinine >2.5 mg/dL
ECOG performance status 3 or 4 unless due to
bone pain
NewYork Heart Association functional status
Class III or IV

44. Eligibility Criteria For Stem cell
transplantation
 However, these factors are guidelines; the
decision regarding transplant eligibility
should be made by the patient and physician
after discussing the potential risks, benefits,
and the needs and wishes of the patient

45. Types ofTransplant
 Autologous transplantation: the stem cells are obtained from the
individual with multiple myeloma. Most commonly recommended.
 Allogeneic transplantation: the stem cells or bone marrow are obtained
from a donor with a tissue type matching that of the patient. This type
of transplantation carries very high risks and is not recommended for
most individuals with multiple myeloma.40% mortality rate.
 Syngeneic transplantation: the stem cells or bone marrow are obtained
from an identical twin of the individual. This is the optimal form of
transplantation although few people with multiple myeloma have an
identical twin who can serve as a donor.

47. DelayedTransplantation.
Alternatively, after stem cell collection standard
chemotherapy with melphalan (or similar drugs)
given to achieve a plateau phase.
At the time of relapse, high doses of melphalan (or
similar drugs) are given.
The previously collected stem cells are returned to
the patient.

48. TandemTransplant
 Double autologous transplantation (two
consecutive autologous transplantations)
may be more effective than single autologous
transplantation if the first transplant has
not produced a complete or near complete
response. The second transplantation is
usually performed within six months of the
first.

49. Effectiveness
 About 1 to 2 percent of individuals die from
complications related to transplantation.
However, compared with chemotherapy
alone, autologous stem cell transplantation is
more likely to produce a response, and is
associated with 12-month longer survival
compared to chemotherapy alone.
(approximately 57 versus 44 months)

50. Treatment Regimens
 Primary Induction Therapy for Transplant
Candidates
 Primary Induction Therapy for Non-
Transplant Candidates
 MaintenanceTherapy
 SalvageTherapy

53. Bor/Dexa
• IFMTrial
• Bor/Dexa vs
VAD
• n=482
• ORR 78 v 62%
• CR 14 v 6 %
• VGPR 37 v 15
%
Bor/Thali/Dexa
• GIMEMATrial
• Bor/Th/Dex vs
Th/Dex
• n =480
• ORR 94 %
• CR 31 vs 11 %
Lena/Dexa
• SWOGTrial
SO232
• ECOG E4A03
• ORR 82-85 %
• CR 4-22 %
Primary InductionTherapy forTransplant Candidates

54. The dose-limiting side effects
 Thalidomide:VTE,peripheral neuropathy,somnolence .
 Lenalidomide ..VTE and thrombocytopenia.
 bortezomib..Increased risk of Herpez Virus Infection,neuropathy
and hematosuppression

56. MPV
• Most Efficacious
• VISTATrial
• MP vs MPB
• n=682
• 13% reduced risk of
death
• Median OS 56 vs 43
months
MPT and MPL
• IFM01-01
• MP vs MPT
• n =232
• Median OS 44 vs 29
months
• Median PFS 24 vs 18
months
• E1A06
• MPT vs MPL
• No difference in
RR,PFS and OS
Lena/Dexa
• FIRSTTrial
• Lena/Dexa vs MPT
• n = 1623
• 28 % reduction in risk
of progression or death
Primary InductionTherapy for Non-Transplant Candidates

57. Follow-up
Re-evaluation after 2 cycles with
labs,bone survey,bone marrow
aspirate and biopsy.

58. High-dose therapy following induction
therapy
 Consolidation with high-dose therapy after induction therapy
improves the response rate as well as event-free and overall
survival, especially in good-risk patients.
 In a randomized trial reported from Italy, induction with VTD,
followed by tandem transplantation and then consolidation with
VTD followed by steroid maintenance, resulted in a very high
complete response rate of 58%, 3-year progression-free survival of
68%, and overall survival of 86%, with clear superiority to
thalidomide and dexamethasone (TD) as a comparator.

59. Consolidation Regimen
 A high-dose alkylating agent, most commonly
melphalan at 200 mg/m2 with peripheral blood stem
cell support, is a standard conditioning regimen.
 Addition of total-body irradiation (TBI) does not
improve the outcome.
 Interestingly, in a randomized study, Fermand et al
have confirmed an equivalent survival benefit
between up-front high-dose therapy vs high-dose
therapy as a salvage regimen at relapse following
initial induction therapy.

60. Promising second-generation novel
agents.
 Pomalidomide
 Carfilzomib (Kyprolis)
 Histone deacetylase inhibitors
vorinostat (Zolinza)
panobinostat (LBH589)
 Perifosine
 Elotuzumab,

61. Plateau phase
 Chemotherapy is usually continued until multiple
myeloma enters a stable (plateau) phase.
 The plateau phase is reached when the myeloma becomes
stable and shows no signs of progressing.
 Although this phase is usually temporary, it typically lasts
six months or longer.
 Occurs in about one half of individuals after
chemotherapy.
 Achieving this phase usually requires at least six or more
cycles of treatment.

62. Thalidomide
• Cat 1
• IFM 99-06
• n =597
• Thal vs
Thal/Pamidria vs
Observation after
ASCT
• Superior EFS and
OS
Lenalidomide
• Cat 1
• CALGB 100104
• n =460
• Lena vs Placebo
• TTP 46 vs 27
months
• MM-015
• n -459
• Improved PFS 66
% compared to
placebo
Bortezomib
• Cat 2a
• UPFRONT study
Remission maintenanceTherapy

63. Refractory and relapsed disease
 Approximately 10% to 15% of patients with
newly diagnosed multiple myeloma are
unresponsive to induction therapy.
 Moreover, virtually all patients who respond
initially will relapse.

64. Treatment Options
 Conventional chemotherapy
Alkylating agents, alone or in combination, have
been effective in approximately one-third of patients
withVAD-refractory disease.
 Thalidomide
Thalidomide has an established role in therapy for
refractory/relapsed multiple myeloma, with 30% of
patients achieving at least 50% reduction in
paraprotein levels. Remissions obtained are durable

65. Treatment Options
 High-dose chemotherapy
High-dose melphalan and stem cell rescue should be
offered to patients who have deferred the transplant
initially.
Novel agents
 Lenalidomide
Lenalidomide has greater potency than does
thalidomide.
 Bortezomib

66. FDA Approvals
 In February 2012, pomalidomide (Pomalyst) was approved by
the FDA to treat patients with relapsed or refractory multiple
myeloma who have received at least two prior therapies,
including lenalidomide and bortezomib.
 The phase II clinical trial that led to the approval showed a
7.4% ORR in patients treated with pomalidomide alone, and a
29.2% ORR in patients treated with pomalidomide plus low-
dose dexamethasone.

67. SUPPORTIVE
TREATMENT

68. SupportiveTherapies

69. Supportive care
 Bedrest
 Bisphosphonates
(Pamidronate, 90 mg IV over >2 hours, or Zoledronic acid, 4 mg IV over 15
minutes) given monthly are indicated for all patients with stage II or III MM (and
perhaps stage I as well)
 Hydration Patients must be repeatedly reminded to drink 2 to 3 L of liquids
daily to promote urinary excretion of light chains, calcium, and uric acid.
 Infections are the foremost cause of death in patients with MM(Due to lack of
opsonization). Infections must be investigated and treated urgently. IVIG therapy
should be considered in cases of recurrent, life-threatening infections

70. PalliativeTreatment:Role of EBRT
 The most common use of RT in the
management of plasma cell tumors is for
palliative treatment of bony disease (relief of
compression of spinal cord cranial nerves, or
peripheral nerves).
 It has been estimated that approximately 40%
of patients with multiple myeloma will require
palliative RT for bone pain at some time
during the course of their disease

71. Role of EBRT
 When RT is given for pain due to disease
involving a long bone, a local field suffices. It
is unnecessary to treat the entire bone .
 Doses of 10 to 20 Gy (in five to 10 fractions)
are effective, although the pain relief is often
partial .

73. Corrected Calcium
[4 - plasma albumin in g/dL] X 0.8 + serum Ca
For every 1-g/dL drop in serum albumin below 4 g/dL,
measured serum calcium decreases by 0.8 mg/dL. Therefore, to
correct for an albumin level of less than 4 g/dL, one should add
0.8 to the measured value of calcium for each 1-g/dL decrease
in albumin. Without this correction, an abnormally high serum
calcium level may appear to be normal.

74. Management in Renal Failure
 The treatment of impaired kidney function is aimed at the specific
underlying cause.
 Treatment usually includes:
 intravenous fluids
 Prednisone can indirectly lower blood calcium levels.
 Allopurinol, a drug that can lower blood levels of uric acid.
 Adequate Hydration
 They should also avoid using NSAIDs and contrast media
 Some patients may be candidates for hemodialysis treatment

75. Regimes Used In Renal Failure
 Thalidomide/Dexa
 VAD
 Valcade /Dexa
 Linilidamide/Dexa

78.  A multicenter study suggested that a longer
fractionated regimen (30 Gy in 10 fractions or
higher) was associated with better neurologic
recovery than 20 Gy in five fractions or a
single 8 Gy fraction

79.  For the spine, inclusion of two vertebral
bodies above and below the grossly involved
vertebra(e) is a common practice. As this is
based on relapse patterns seen following RT
for spinal metastases for solid tumors rather
than plasmacytomas, it may not be directly
applicable to solitary plasmacytoma.

80.  Several studies have demonstrated durable
local control in >85% of tumors <5 cm with 35
to 40 Gy, and there is little evidence that
higher doses are necessary for small tumors,
regardless of bone or EMP locations. In
contrast, plasmacytomas >5 cm have worse
local control (90,117), and doses of 45 to 50
Gy are recommended in these bulkier
tumors, which also tend to be EMPs