ONCOLOGY

1. MANAGEMENT OF PLASMACYTOMA
AND MULTIPLE MYELOMA
Dr Dinesh Kumar Singh

2. • Plasma cell neoplasms represent a spectrum of
diseases characterized by clonal proliferation and
accumulation of immunoglobulin-producing
terminally differentiated B cells.
• IgG, IgA, IgM, IgD, and IgE

3. Clinical spectrum
• Monoclonal gammopathy of undetermined
significance (MGUS)
• Smoldering multiple myeloma (Asymptomatic
multiple myeloma)
• Multiple myeloma
• Waldenstrom’s macroglobulinemia
• Solitary plasmacytoma
• Systemic AL amyloidosis

4. Epidemiology
• 1% of all malignancies in whites and 2% in
African Americans- SEER
• 10% of all hematologic malignancies.
• Chinese and Japanese populations have a
lower incidence than whites.
• M>F
• Median age 70yrs.

5. Etiology
• Exposure to ionizing radiation is the strongest single
factor linked to an increased risk of multiple
myeloma( Atomic bomb survivors/People exposed to
low levels of radiation including radiologists, people
employed in the nuclear industry, or those handling
radioactive materials)
• Exposure to metals, especially nickel; agricultural
chemicals; benzene and petroleum products; agent
orange; and silicon.
• Hereditary and genetic factors
• MGUS has been considered a premalignant
condition.

6. Pathogenesis

7. 7
Pathogenesis
Adapted from Kuel WM, Bergsagel PL. Nat Rev Cancer. 2002;2:175-187.
Genetic Changes
MGUS
Smoldering
myeloma
Extramedullary
myeloma
Myeloma
cell line
Intramedullary
myeloma
Changes in BM Microenvironment Interaction
Bone Destruction
Germinal-
center B-cell
Increased DNA Labeling Index
Long-lived
plasma cell
IgH translocation Secondary Changes

8. Clinical features are due to
• Increased secretion of Ig
• Bone resorption
• Bone marow suppression
• Decreased Immunity

9. Clinical features
• Anemia
• Renal Failure
• Hypercalcemia and Bone Disease
• Infections
• Neurologic Symptoms
• Hyperviscosity
• Coagulopathy
• Extramedullary Disease

10. 10
Evaluation
• CBC, ESR, Peripheral smear
• Serum creatinine, uric acid, Cal/PO4
• Skeltal survey
• Bone marrow examination
• Electrophoresis (serum + urine)
– SPEP & SIFE
• Serum 2 Microglobulin, S. albumin,
• Serum IgG, IgA, IgM,
• Urine - 24 hour urine protein
• Serum LDH
• Cytogenetics

11. Bone lesions

12. Serum protein electrophoresis (SPEP)
and immunofixation (SIFE)

13. 13
Indications for MRI/PET scan
Situation
Recommended
examination
 Suspected cord compression
 Suspected solitary plasmacytoma
 Symptomatic Pt with negative X-rays
MRI
 As part of a trial PET-CT scan

14. Role of PET CT
• Helpful for detection of extraosseous soft tissue
masses and evaluation of rib and appendicular
bone lesions.
• Suspected extramedullary plasmacytoma.
• PET-CT obviates the need for a skeletal survey
• Independent predictive value of baseline
fluorodeoxyglucose-PET/CT and of
fluorodeoxyglucose suppression before high-dose
therapy

15. PET CT

16. Leukemia. 2009 January ; 23(1): 3–9. doi:10.1038/leu.2008.291

18. CRAB

19. Durie and Salmon Staging System
Stage I-
All of the following: Hemoglobin >10 g/dL
• Serum calcium normal
• Normal bone structure or solitary
plasmacytoma only
• Low M-component (IgG <5 g/dL, IgA <3 g/dL,
urine light chains <4 g/24 h)b

20. Stage II-
• Fitting neither stage I nor stage III
Stage III One or more of the following:
• Hemoglobin <8.5 g/dL
• Serum calcium >12 mg/dL
• Advanced lytic bone lesions
• High M-component (IgG >7 g/dL, IgA >3 g/dL,
urine light chains >12 g/24 h)

21. ISS

22. International Staging System

23. Mayo Risk Stratification
Abeloff

24. MANAGEMENT
• Multiple Myeloma
• Solitary Plasmacytoma

25. Newly Diagnosed MM
• Initial therapy depends on eligibility for SCT
and risk stratification.
• Eligibility for SCT is determined by age,
performance status, and coexisting
comorbidities.
• Risk stratification is based on presence or
absence of high-risk factors.

26. Robert A. Kyle, M.D., and S. Vincent Rajkumar, M.D. :N Engl J Med 2004;351:1860-73.

28. Durie et al: Leukemia 2006;20:1467–1473.

29. Regimens for Transplant Eligible
Thalidomide-dexamethasone (Thal/Dex)-
Thalidomide 200 mg oral days 1–28
Dexamethasone 40 mg oral days 1, 8, 15, 22
Repeated every 4 weeks × 4 cycles as
pretransplant induction therapy or continued
until plateau or progression if used as primary
therapy.

31. Lenalidomide-dexamethasone (Rev/low-dose
Dex)
• Lenalidomide 25 mg oral days 1–21 every 28
days
• Dexamethasone 40 mg oral days 1, 8, 15, 22
every 28 days
• Repeated every 4 weeks × 4 cycles as
pretransplant induction therapy; or continued
until plateau or progression if used as primary
therapy.

32. Phase III trial of lenalidomide plus high-dose
dexamethasone versus lenalidomide plus lowdose
dexamethasone in newly diagnosed multiple
myeloma (E4A03): a trial coordinated by the
Eastern Cooperative Oncology Group
S. Vincent Rajkumar et al.
Conclusions
• Lenalidomide plus low-dose dexamethasone is
associated with significantly superior survival and
lower toxicity compared to lenalidomide plus highdose
dexamethasone
• High one-year survival rate with lenalidomide plus
low-dose dexamethasone
• DVT risk is 5-8% with lenalidomide plus low-dose
dexamethasone with routine aspirin prophylaxis

33. Bortezomib-dexamethasone (Vel/Dex)
• Bortezomib 1.3 mg/m2 intravenous days 1, 4,
8, 11
• Dexamethasone 40 mg oral days 1–4, 9–12
• Reduce dexamethasone to days 1–4 after first 2
cycles Repeated every 3 weeks × 4 cycles as
pretransplant induction therapy

34. Bortezomib plus dexamethasone as induction
treatment prior to autologous stem cell
transplantation in patients with newly diagnosed
multiple myeloma: results of an IFM phase II study.
Haematologica 2006; 91:1498-1505

35. Bortezomib-thalidomide-dexamethasone (VTD)
• Bortezomib 1.3 mg/m2 intravenous days 1, 4,
8, 11
• Thalidomide 100–200 mg oral days 1–21
• Dexamethasone 20 mg/m2 oral days 1–4, 9–
12, 17–20
• Reduce dexamethasone to days 1–4 after first
two cycles
• Repeated every 4 weeks × 4 cycles as
pretransplant induction therapy
PETHEMA/ GEM Study- Spanish Myeloma group

36. Guidelines for chosing regimen
• High risk Pts- Bortezomib based triplet therapy
• Pts with Peripheral Neuropathy(DM)- Bortezomib
and Thalidomide used carefully.
• Renal disease- Bortezomib based therapy
preferred. Dose modification in case of
Lenalidomide.

37. Initial Therapy in Standard-Risk Patients Who are not
Eligible for Transplantation
• Patients who are not transplant candidates are treated
with standard alkylating agent therapy. For decades
this has meant therapy with MP over the years, despite
better response rates, no survival benefit has been
reported with any of the more aggressive combination
chemotherapy regimens compared to MP.
• Recent randomized studies show that MPT (melphalan,
prednisone, and thalidomide) improves response and
event-free survival (EFS) compared to MP.

38. Melphalan-prednisone-thalidomide (MPT)
• Melphalan 0.25 mg/kg oral days 1–4
• Prednisone 2 mg/kg oral days 1–4
• Thalidomide 100–200 mg oral days 1–28
• Repeated every 6 weeks × 12 cycles

39. • Oral melphalan and prednisone chemotherapy plus
thalidomide compared with melphalan and prednisone
alone in elderly patients with multiple myeloma:
randomised controlled trial
Antonio Palumbo et al
• n=255
• oral MP for six 4-week cycles plus thalidomide (n=129; 100 mg
per day continuously until any sign of relapse or progressive
disease) or MP alone (n=126)
• Combined complete or partial response rates were 76·0% for
MPT and 47·6% for MP alone (absolute difference 28·3%, 95%
CI 16·5—39·1), and the near-complete or complete response
rates were 27·9% and 7·2%, respectively.
• Rates of grade 3 or 4 adverse events were 48% in MPT
patients and 25% in MP.

40. Melphalan-prednisone-lenalidomide (MPR)
• Melphalan 0.18 mg/kg oral days 1–4
• Prednisone 2 mg/kg oral days 1–4
• Lenalidomide 10 mg oral days 1–28
• Repeated every 4–6 weeks × 9 cycles

41. Melphalan-prednisone-bortezomib (MPV)
• Melphalan 9 mg/m2 oral days 1–4
• Prednisone 60 mg/m2 oral days 1–4
• Bortezomib 1.3 mg/m2 intravenous days 1, 4, 8,
11, 22, 25, 29, 32
• Repeated every 42 days × 4 cycles followed by
maintenance therapy as given below:
• Melphalan 9 mg/m2 oral days 1–4
• Prednisone 60 mg/m2 oral days 1–4
• Bortezomib 1.3 mg/m2 intravenous days 1, 8, 15,
22
• Repeated every 35 days × 5 cycles
VISTA Trial

42. AUTOLOGOUS STEM CELL TRANSPLANTATION
• ASCT improves complete response rates and
prolongs median OS in myeloma by
approximately 12 months.
• The mortality rate is 1% to 2%.
• Preparative (conditioning)-
-Melphalan 200 mg/m2
-Melphalan 140 mg/m2 and 8 Gy total body
irradiation (TBI)
• Early Vs Delayed

44. TANDEM TRANSPLANTATION
• With tandem (double)ASCT, patients receive a
second planned ASCT after recovery from
the first procedure.
• Significantly better EFS and OS in recipients of
double ASCT versus single ASCT.
• Especially in patients who failed to achieve a
complete response or very good partial
response (>90% reduction in M protein level)
with the first procedure.

45. Maintenance Therapy
• Maintenance therapy with interferon-α is of
limited value and is seldom used.
• Prednisone might be useful.
• Clinical trials are currently evaluating
thalidomide, dendritic cell vaccination, and
other novel approaches as maintenance
therapy.

46. Treatment of Relapsed Multiple
Myeloma
• Almost all patients with myeloma eventually
relapse.
• If relapse occurs more than 6 months after
stopping therapy, the initial chemotherapy
regimen should be reinstituted
• Indolent relapse- single-agents or MP.
• Aggressive relapse-combination of active
agents

48. Treatment of Complications in
Multiple Myeloma

49. Myeloma bone disease
• Pamidronate or zoledronic acid in patients with
documented bone disease
• Encouragement of activity to prevent osteopenia and
deep-vein thrombosis
• Pain control with narcotic analgesics, if needed;
avoidance of nonsteroidal antiinflammatory agents
• Radiation to treat painful bony lesions refractory to
pain medication or cord compression
• Surgical intervention to prevent or treat pathologic
fractures
• Vertebroplasty or kyphoplasty for selected vertebral
lesions, to reduce pain and improve height

50. Anemia
• Treatment of reversible causes such as
deficiencies of iron, B12, or folate
• Erythropoietin for symptomatic anemia during
chemotherapy
• Transfusions as needed.

51. Infections
• Vaccination against Streptococcus pneumoniae,
Haemophilus influenzae, and influenza
• Consideration of prophylactic broad-spectrum
antibiotic therapy when corticosteroids are used
• Intravenous immune globulin for recurrent
serious infections associated with
hypogammaglobulinemia
• Consideration of prophylaxis against
Pneumocystis carinii when prolonged
corticosteroid therapy is used; avoidance of
trimethoprim–sulfamethoxazole when
thalidomide is used

52. Hypercalcemia
• Intravenous fluids and corticosteroids
• Bisphosphonates when hypercalcemia is
severe or unresponsive to hydration and
corticosteroids

53. Renal failure
• Correction of reversible causes such as
dehydration, hypercalcemia, and hyperuricemia
• Chemotherapy (e.g., vincristine, doxorubicin, and
dexamethasone; dexamethasone alone; or
thalidomide–dexamethasone) for rapid control of
disease
• Alkaline diuresis for acute renal failure due to cast
nephropathy; avoid alkalinization in patients with
hypercalcemia
• Trial of plasma exchange in acute evolving renal
failure

54. ROLE OF RADIOTHERAPY IN MULTIPLE
MYELOMA

55. • Multiple Myeloma (MM) is a chemo-
radiosensitive systemic disease.
• Most of the patients present with pain (70%)
• Ten percent of patients will have pathological
fractures at presentation.

56. Indications of radiotherapy in Multiple
Myeloma
• Pain Relief
• Spinal Cord Compression
• Dose of radiotherapy in Multiple Myeloma
• Various dose range of RT have been used, ranging
from 3.0Gy to 60Gy depending upon institution’s
practice .
• Leigh reported the minimum dose of 10Gy for
durable pain relief.
• Bosch et al used dose of 30Gy in 10 to 15 fractions
for local sites of radiation.

57. • Optimal Radiotherapy portal-
• Include 2 vertebra above and 2 vertebra
below the involved vertebra
• 2 cm margin beyond the symptomatic lesion
• Incorporation of the entire length of
medullary cavity in the RT portal was not
mandatory
Catle et al

58. • Total Body Irradiation as Conditioning Regimen
for Bone Marrow Transplantation-
• The French intergroup Phase III study-
-melphalan, 200 mg/m2 alone (M200) vs.
melphalan 140 mg/m2 with TBI, 8 Gy in four
fractions (M140/TBI)
-TBI-containing arm suffered more grade 3 or 4
mucosal toxicity, higher transfusion requirement,
and longer hospitalization stay. There was a higher
toxic death rate in the M140/TBI arm.
• Tomotherapy- reduced toxicity

59. Hemi Body Irradiation in Multiple
Myeloma
• Palliation of pain in patients with widespread
symptomatic bony lesions- 5-8Gy
• Sequential HBI can be effectively used in
patients with disseminated and symptomatic
chemo-refractory disease.

60. PLASMACYTOMA

61. • < 10%
• Two types
-Solitary Bone Plasmacytoma:
-Solitary Extramedullary Plasmacytoma
Definitive RT is Mainstay of Rx

62. • SBP-
Common site- spine/ centroaxial skeleton.
Higher risk of subsequent development of
myeloma with a 10-year rate of 76%
• EMP-
Common site- head & neck region
Subsequent development of myeloma 10-
year rate is approx 36%

63. Portals
• Based on patterns of relapse data from
retrospective reviews of case series.
– CT and MRI for delineation of GTV
– CTV to encompass probable routes of microscopic
spread.
– Conformal radiotherapy techniques like 3D-CRT &
IMRT to spare adjacent critical structures thereby
improving the therapeutic ratio.

65. Role of Prophylactic Nodal Irradiation in
Extramedullary Plasmacytoma
• SBP- 0-4%
• EMP- 10-20%
Routine?
Bulky Disease?
Involved nodes?

66. Optimal Dose of Radiotherapy
• Multiple retrospective series have treated
patients with doses ranging from 30Gy to
60Gy.
• Minimum dose of 40 Gy- Mendenhall et al.
• local control rate of 100% with doses ≥ 50Gy-
Kilcikiz et al
• Above 45Gy- Rangeard et al

67. Clinical and prognostic features
of plasmacytomas
A multicenter study of Turkish Oncology Group-
Sarcoma Working Party- Kilciksiz et al
Am J Hematol. 2008 Sep;83(9):702-7. doi:
10.1002/ajh.21211.
• The favorable factors were radiotherapy dose
of > or =50 Gy and RT + S for PFS and younger
age for MMFS

68. Int. J. Radiation Oncology Biol. Phys., Vol. 64, No. 4, pp. 1013–1017, 2006

69. Role of Surgery
• For SPB which predominantly present in axial skeleton,
surgery may be required in cases presenting with bone
instability and rapidly deteriorating neurological
symptoms eg. spinal cord compression. Destruction of
bone requires an early orthopedic/ neurosurgical
referral for surgical stabilization.
• Small lesions amenable to complete surgical resection
without significant morbidity may be considered for
surgical resection.
• Adjuvant radiotherapy should be administered to
patients with very large lesions and with close/ positive
surgical margins.

70. conclusion
• Plasma cell dyscrasia is a spectrum of disease
• Thorough workup is mandatory before
embarking upon management
• Proper management of systemic disorder due
to monoclonal gammopathy
• Regular follow-up with proper investigations

71. THANK YOU