- Plasma cell neoplasms originate from terminally differentiated B cells and produce monoclonal immunoglobulins. They commonly affect people around age 70 and have a male predominance. - Risk factors include prior radiation exposure and certain chemical exposures. They are caused by genetic mutations that allow a clonal plasma cell population to proliferate in the bone marrow. - Presentations depend on the type but commonly include anemia, bone lesions, kidney dysfunction, and infections. Workup involves blood and urine tests and imaging like skeletal surveys and PET scans. - Treatment involves chemotherapy, radiation, stem cell transplants, surgery, and palliative care. Prognosis depends on the stage and type, ranging from potentially cur

1. Susheel Yeshala
Plasma cell neoplasms

2. Plasma cell tumours are derived from terminally differentiated B cells
B cells – Produce and secrete monoclonal immunoglobulins
Origins

3. Age: 70 years median age (rare in children and adults less than 30)
Incidence: 10-15% of hematopoietic malignancies
Mortality: 20% of deaths from hematopoietic malignancies
Race: Occurs in african americans twice as much as caucasians
Sex: male predominance
Survival: Stage I: 62 months median survival; Stage II: 44 months median survival; Stage III: 29 mont
hs median survival
Epidemiology

4. Unknown
Occupational exposures
Prior exposure to Radiations (Ionizing)
Chemical Solvents – Petroleum products
Etiology

5. Illegitimate switch recombination of partner oncogenes into the immunoglobulin heavy chain (IgH).
Cytogenetic hyperploidy and up-regulation of cell cycle control genes.
Development & propagation of a clonal population of B cells within the bone marrow additional events
Mutations of kinases, deletions of chromosomes, and up-regulation of enzymes such as c-myc
Pathophysiology

6. Malignant plasma cells begin to proliferate in the bone marrow microenvironment
Producing monoclonal proteins and causing osteolytic bone disease
The slow accumulation of these malignant cells gradually results in the characteristic clinical features
of myeloma: anemia, bone resorption, hypercalcemia, renal failure, and immunodeficiency.
Pathophysiology

7. Solitary Plasmacytoma – Solitary Bone Plasmacytoma (SBP)
Solitary Extraosseous Plasmacytoma (SEP)
Myeloma Spectrum – MGUS
Smoldering Myeloma
Multiple Myeloma
Plasma cell leukemia
Classification

8. Median age – 55 to 65 years,
10 years younger than Myeloma patients
Males to female ratio - 2:1.
Diagnosis - All the following criteria need to be satisfied
Single lesion
Histologically confirmed
Negative skeletal survey
Normal bone marrow biopsy (<10% monoclonal plasma cells)
No myeloma-related organ dysfunction.
Solitary Plasmacytoma

9. SBP VS SEP
Solitary
Bone
Plasmacytoma
Solitary
Extraosseous
Plasmacytoma
M/C Site Vertebral column H&N, UEDT
Secretory pattern Secretory No secretory
Presentation Bone pain
Neurologic compr
omise
Pathological #
Epistaxis,
nasal discharge
nasal obstruction
LN involvement Rare 30% - 40%
Progression to MM 50% - 80% 10% - 40%

10. Myeloma Spectrum
MGUS Smoldering Multiple Myeloma
Plasma cells <10% >10% >10%
Serum monoclonal
Proteins
<3g/dl >/= 3g/dl >3g/dl
End Organ damage No No Present
Risk of progression
to MM/ yr
1% 10% -
Management Monitor Close F/U Chemotherapy

11. End organ damage:
Anemia
Hypercalcemia
Renal dysfunction
Bone lesions
Frequent severe infections
Amyloidosis
Hyperviscosity syndrome
Multiple Myeloma

12. Very rare variant of multiple myeloma
Plasma cells is detected in the peripheral blood.
Very poor prognosis
Median survival <1 year
There is currently no standard therapy for this condition
Usually treated with high-dose, multiagent chemotherapeutic regimens
Plasma Cell Leukemia

13. Staging
Hb
Ca
Bone
M Prot

14. Staging

15. General
H&P.
CBC and differential with examination of peripheral smear
Chemistries, LFTs, albumin, calcium.
Work Up

16. Standard Laboratory tests
SPEP with immunofixation and quantitation of immunoglobulins (M Protein),
Twenty-four-hr UPEP and immunofixation.
24-hour urine for Bence-Jones proteins. (if no M protein detectable)
Serum viscosity if M-protein concentration >5 g/dL.
Beta-2 microglobulin, LDH, and C-reactive protein reflect tumor burden.
Work Up

17. Standard Laboratory tests
Unilateral bone marrow aspirate and biopsy.
Bone marrow immunohistochemistry and flow cytometry
Gene expression profiling is increasingly used for prognostic classification and to check for minimal
residual disease.
Cytogenetic/karyotype for hyper/hypodiploidy. Hyperdiploidy has better prognosis.
FISH [del 13, del 17, t(4;14), t(11;14), t(14;16)].
Work Up

18. Imaging
Skeletal survey - Purely osteolytic lesions have low isotope uptake, compared to osteoblastic lesions
that typically have more uptake.
MRI or PET is indicated if no abnormality found on plain radiograph in a symptomatic area (Terpos et
al. JCO 2013).
MRI - extent of vertebral disease and the presence of spinal cord or nerve root compression
Consider CT (avoid contrast if renal dysfunction) if painful weight-bearing areas.
Consider PET/CT scan for suspicion of plasmacytoma of bone.
Work Up

23. Solitary Bone plasmacytoma
RT is the standard of treatment.
Surgery for structural instability of bone or cord compression
Involved field RT (≥30 Gy).
LC ~90%,
MS ~10 year,
~70% progress to MM.
Whole body MRI to look for additional sites of disease
Management

24. Solitary Extraosseous plasmacytoma
Surgery for small lesion
Surgery + PORT (For incompletly excised tumors)
Involved field RT (≥45 Gy) alone, surgery alone, or surgery + RT.
LC >90%,
MS >10 years,
~30% progress to MM
10 yr survival rates 0f 72% - 78%
Management

25. MGUS
Typically, patients with MGUS require no therapy.
Smoldering Myeloma
Close observation
Intervention - disease progression or the appearance of end organ damage,
(bone lesions or anemia).
Management

26. Management - MM
Patients Eligible for Autologous Stem Cell Transplantation
Autologous stem cell transplantation (ASCT) - standard of care for eligible patients
Various regimens to induce response prior to stem cell collection.
Steroid based, either with high dose dexamethasone alone or with vincristine, Adriamycin(doxorubicin
), and dexamethasone (VAD).
Newer agents that have been validated in the relapse setting are now being used as initial therapy wit
h superior results, including bortezomib and lenalidomide.

27. Management
Bortezomib
First proteasome inhibitor to be used in clinical trials and
Has demonstrated efficacy and safety in frontline therapy
Response rates improved when compared with VAD or dexamethasone alone
It is often the preferred agent in patients with renal insufficiency and high-risk disease
Neuropathy, occurring in 13% to 15% of patients at ≥grade 3; this may be reduced, however, with wee
kly use80 or when given subcutaneously.

28. Management
Lenalidomide
Immunomodulatory drug derived from thalidomide
Effective- both as upfront therapy and in relapsed disease.
Most commonly used in combination with low-dose dexamethasone.
Lenalidomide has also been used in combination with conventional chemotherapy and most recently
with bortezomib.
This has resulted in even higher response rates and complete remission rates of >50%.

29. Management
Thalidomide
Alternative to VAD induction is the combination of thalidomide and dexamethasone (TD).
Preferred initial regimens include bortezomib or lenalidomide, but alternatives include thalidomide or
doxorubicin prior to ASCT.

30. Management
Patients Not Eligible for Autologous Stem Cell Transplantation
Melphalan and Prednisone (MP),
Thalidomide to melphalan and prednisone (MPT)
MPT increases response rates and overall survival, but with increased toxicity such as thrombosis and
somnolence

31. Management
Autologous Stem Cell Transplantation
Standard of care for eligible patients
Improve complete response, prolong disease-free survival, and extend overall survival.
Melphalan 200 mg/m2 is the most commonly used conditioning regimen
Allogeneic Stem Cell Transplantation
Myeloablative stem cell transplant is perhaps the only current potential cure for patients with myeloma
may produce a profound graft versus myeloma effect
Its use is very limited due to the lack of donors, age restriction, high treatment-related mortality,
and graft versus host disease

32. Management
Maintenance Therapy
post-ASCT to prolong remission and survival.
controversial, and most guidelines do not recommend its use unless the patient is at high risk of rapid
recurrence.
Relapse After Autologous Stem Cell Transplantation
Patients will relapse after a median of 2 years after the first ASCT
Thalidomide, bortezomib, and lenalidomide.
Carfilzomib (PI) and pomalidomide (IMD)
Can confer prolonged progression-free and overall survival

33. Management
Total Body Irradiation (TBI)

34. IFM [Intergroupe Francophone du Mye’lome]
trial 9502
Melphalan, 200 mg/m2
alone
Toxic death rate 0%
The event-free survival: No
Difference
45m OS - 65.8%, P = .05
M200
Melphalan 140 mg/m2 +
TBI (8 Gy in 4 #)
Toxic death rate in the 3.6%
The event-free survival: No
Difference
45m OS - 45.5%; P = .05
grade 3/4 mucosal toxicity,
heavier transfusion
longer hospitalization stay
M140/TBI
EFS: The length of time after primary tretment the patient remains free of certain complication or
events that the treament was intended to prevent or delay

35. IFM trial
Melphalan, 200 mg/m2
M200
M140 for the first, M140/TBI
for the second
No benefit with TBI
Increased toxicity
M140->M140/TBI
All subsequent IFM trials abandoned the use of TBI

36. Management
Hemibody Irradiation
Diffuse bone pain involving wide areas of the skeleton
Single doses of 5-8Gy
The main toxicity is myelosuppression.
The sequential hemibody radiation phase II and phase III trials
As “systemic” treatment to control myeloma, in patients with or without skeletal pain
SWOG
CR to Sequential HBI vs Further chemotherapy
Poorer OS in HBI
No standard role for sequential hemibody radiation

37. Management
Local External Beam for Palliation
For palliative treatment
Relief of compression of spinal cord, cranial nerves, or peripheral nerves
40% of patients – require – palliative radiation therapy for bone pain
Reduces the incidence of future vertebral fractures or the appearance of new lesions
Palliative RT to Bone
a local field suffices
10 to 20 Gy (in 5 to 10 fractions) are effective
response rate of 97% (CR/PR)

38. Management
Local External Beam for Palliation
Palliative RT for cord compression
Motor improvement is expected in approximately 50% of irradiated patients
30 Gy in 10 fractions or higher was associated with better neurologic recovery[1] than 20 Gy in 5 fractio
ns or a single 8 Gy.
Rades D, Stalpers LJ, Veninga T, et al. Evaluation of five radiation schedules and prognostic factors for metastatic spina
l cord compression. J Clin Oncol 2005; 23(15):3366–3375.

39. RADIATION TECHNIQUES
SIMULATION AND FIELD DESIGN
Solitary Plasmacytoma –
Involved field RT including involved portion of bone +2–3 cm margin.
For the spine, inclusion of two vertebral bodies above and below the grossly involved vertebra(e) is a
common practice.
CTV should encompass probable routes of microscopic spread
For extramedullary plasmacytoma, nodal involvement at presentation is observed in 10% to 20%, and
occasional nodal failure
RT coverage to the draining lymph node region.

40. RADIATION TECHNIQUES
SIMULATION AND FIELD DESIGN
Solitary Plasmacytoma –
PTV should account for day-to-day setup variation and will typically add 5 to 10 mm around CT
CT-based planning and the use of conformal techniques, including intensity-modulated
radiation therapy, should be employed when needed to treat the PTV adjacent to critical structures.
Particularly important in extramedullary disease involving the paranasal sinuses, where avoidance of
the optic structures and salivary glands is desirable.

41. RADIATION TECHNIQUES
SIMULATION AND FIELD DESIGN
Multiple Myeloma
Main indication is for palliation.
For symptomatic bony lesions, consider including entire bone
If treating vertebral column, include involved vertebrae +2 vertebrae above and below.
Consider balloon kyphoplasty or vertebroplasty for painful spinal compression fractures.

42. RADIATION TECHNIQUES
DOSE PRESCRIPTIONS
Solitary Plasmacytoma –
Usual recommended doses 40-45Gy
<5cm - 35-40Gy
>5cm - 45-50 Gy over 3–5 weeks, 2 Gy/fx..
Multiple Myeloma
low-dose RT (10–30 Gy) in 1.5–2 Gy fractions vs. 8 Gy × 1 can be used as palliative treatment for
uncontrolled pain, for impending pathologic fracture, or impending cord compression.
May increase dose to 30–36 Gy for cord compression, bulky soft tissue component, and incomplete
palliation

43. Management
Supportive Care
Erythropoietic agents
Bisphosphonates
Vertebroplasty
kyphoplasty

44. Response assesment
MRI, should be done approximately 6 to 8 weeks following completion of treatment.
It is common for a residual soft tissue abnormality to persist on follow-up imaging
Periodic reimaging may be required every 4 to 6 months until any residual mass disappears or remain
s stable on consecutive scans

45. Follow Up
Multiple myeloma:
Most patients continued on maintenance therapy.
Quantitative immunoglobulins + M-protein every 3 months.
Follow CBC, serum BUN, Cr, Ca, serum
FLC bone survey annually or for symptoms.
MRI/PET CT as clinically indicated.
Bone marrow biopsy to assess response, minimal residual disease.

46. Follow Up
Smoldering multiple myeloma:
Quantitative immunoglobulins + M-protein every 3 months.
CBC, serum BUN, Cr, Ca every 3–4 months,
skeletal survey annually.
SP osseous/extraosseous:
M-protein every 3 months × 1 year, then annually.
Bone survey, PET CT/MRI every 6 months × 1 year, then as clinically indicated.

47. THANK YOU