1. Miten R. Patel, MD Cancer Specialists of North Florida
Plasma Cell Dyscrasias
Miten R. Patel, MD
Cancer Specialists of North Florida

2. Disclosures
None

3. Objectives Review types of Plasma cell dyscrasias
Epidemiology and definitions
Presenting signs and symptoms
Myeloma staging
Couple of cases
Treatment overview

4. Plasma Cell Dyscrasias
Monoclonal Gammopathy of Unknown Significance (MGUS)
Smoldering Myeloma (SMM)
Multiple Myeloma (MM)
Waldenstroms Macroglobulinemia (WM)
Amyloidosis
Solitary plasmacytoma
POEMS syndrome

5. MGUS Mean age at diagnosis – 70yo
M>F, incidence increases with age, found in 1-2% of adults
African Americans 2-3x > Caucasians
Present in 3% of persons >50 and 5% of persons over the age of 70
Most cases sporadic but relatives of patients with MGUS/myeloma have an increased risk (RR 2-3)

6. MGUS
Definition
Serum monoclonal protein <3g/dL, bone marrow plasma cells <10%, and absence of end organ damage
Hypercalcemia
Renal Failure
Anemia/Thrombocytopenia
Lytic bone lesions

7. MGUS Non-IgM MGUS IgM MGUS Progresses to myeloma
Rarely, to AL amyloid, light chain disease or other lymphoproliferative disorder
IgM MGUS
Progresses to Waldenstroms macroglobulinemia
Rarely, to myeloma, AL amyloidosis or lymphoma

8. MGUS Part of the spectrum of smoldering myeloma and multiple myeloma
Characterized by a monoclonal protein level of <30 g/L (m spike of 3.0 g/dL), <10% plasma cells in the bone marrow
Progression to MM or related disorder is about 1% per year.
Clinically asymptomatic premalignant condition

9. MGUS
No symptoms?
Pts. identified when undergoing testing for other conditions such as neuropathy, vasculitis, hemolytic anemia, rashes, hypercalcemia, elevated ESR, elevated total protein
Likely had existed for years before diagnosis
Finding on labs - usually elevated total protein, immunoglobulin, abnormal SPEP/UPEP, positive IFE, or abnormal light chain ratio

10. MGUS – Workup
Labs - CBC + diff, BMP (Cr, Ca), SPEP + IFE, Quant Igs, 24 urine IFE, B2 microglobulin, albumin, serum free light chains
Imaging – Skeletal survey, Certain cases - MRI & PET scan
Bone Marrow biopsy & aspirate
Cytogenetics & FISH studies

11. MGUS
Once confirmed (Monoclonal protein <3 g/dL, <10% plasma cells, no CRAB symptoms) – no treatment
Serial followup, every 3-6 months, exam, assessment and labs, less often after 2 years.
Monitor for developing symptoms (bone pain, hypercalcemia, kidney dysfunction, anemia, etc)
SMM – every 3 months until progression
No treatment unless symptomatic MM

12. Smoldering Myeloma
Smoldering Myeloma (aka asymptomatic multiple myeloma)
Same as MM but without symptoms and
Hgb > 10.5,
Monoclonal Ig Peak (usually > 3g/dL and/or >10 but <60% clonal plasma cells)
Normal serum Ca and Cr levels
No lytic bone lesions
REQUIRES NO TREATMENT
>60% plasma cells or FLC ratio >100 even without end organ damage, best classified as multiple myeloma

13. Multiple Myeloma Presentation Weakness, Fatigue, Pallor (32%)
Weight Loss (24%)
Radiculopathy, cord compression
Bone pain (58%), fractures
Recurrent infections (dysfunctional immunoglobulin)
Labs – Anemia (73%), hypercalcemia (28%), elevated total protein, kidney dysfunction (48%)

14. Multiple Myeloma Rouleaux Formation Elevated Sed Rate
Elevated C Reactive Protein
Normocytic, normochromic anemia
Renal Disease, Cr > 2mg/dL in 19%
Renal insufficiency caused by cast nephropathy (myeloma kidney) or hypercalcemia
Altered mental status caused by hypercalcemia and hyperviscosity

15. Multiple Myeloma Monoclonal Ig
IgG 60%
IgA 20%
Light chain only 18% (K>L)
IgM, IgD, IgE, non-secretory < 1%
For nonsecretory myeloma (no M protein) or light chain only, diagnosis is often made with bony lesions and plasmacytosis by bone marrow

16. Myeloma Bone Marrow Aspirate

17. Myeloma Blood Smear

18. Myeloma Staging Durie Salmon
Stage 1
Ca <12, Hgb >10, Normal skeletal survey or solitary plasmacytoma, low M protein with IgG <5 g/dL or IgA <3 g/dL, Bence Jones protein <4g/24h
Stage 2
Neither stage 1 or 3
Stage 3
One of the following: Hgb <8.5, Ca >12, multiple lytic lesions, high M component (IgG >7, IgA >5 or Bence Jones >12gm)

19. Myeloma Staging ISS Stage 1 Stage 2 Stage 3 B2M ≤3.5 and albumin ≥3.5
B2M > 3.5 but <5.5 or albumin >3.5
Stage 3
B2M ≥5.5

20. Case Presentation
41yo WF with no symptoms goes to annual physical at office based clinic.
No symptoms other than mild fatigue
Routine annual labs drawn

21. Lab draw #1

22. Lab draw #2

23. Lab draw #3

24. Lab draw #4

25. Bone Marrow Biopsy

26. Myeloma Treatment Determine eligibility for HDT and SCT
Age, overall health, psychological evaluation
Avoid alkylating agents (marrow toxic)
Chemotherapy to induce remission
Refer for stem cell collection and transplant
Maintenance therapy
Regular monitoring
ASCT improves median OS by >12 months

27. Myeloma Treatment Transplant ineligible
Immunomodulators (Thalidomide, Revlimid, Pomalyst)
DVT risk
Proteosome inhibitors (Velcade, Kyprolis)
Chemotherapy (MP, VAD, Doxil, HyperCVAD)
Supportive care
Bisphosphonates

28. Myeloma Treatment

29. Solitary Plasmacytoma
Approx 3% of myeloma patients
No or very low myeloma protein in serum or urine
MR must be done to evaluate patient as it may detect other bone lesions (upstage the patient to myeloma)
Presence of monoclonal protein >1yr after irradiation denotes progression to myeloma
Treat with XRT (at least 45 Gy).
MM manifests overtime, only 20% remain disease free at 10 yrs
Median time to progression is 2 yrs

30. Waldenstrom’s Lymphoplasmacytic bone marrow infiltration
Malignant B lymphocytes producing monoclonal IgM
Median age 65; Whites > Blacks; M>F
1500 cases in the US per year
Hyperviscosity syndromes
neurologic complaints including vision change, headache, vertigo, nystagmus, dizziness, deafness, diplopia and ataxia
10-20% of pts. Have a cryoglobulin (Type I) which precipitates at high T >22C on cold exposure may cause symptoms such as Raynauds phenomenon, urticaria, purpura and acral cyanosis.
Diarrhea and Steatorrhea (IgM infiltration into GI tract)

31. Waldenstrom’s

32. Waldenstrom’s Treatment
Goal to reduce hyperviscosity (IgM is a pentamer!) and lymphoproliferation
Pheresis if symptoms from the hyperviscosity causing severe neurologic deficits
Chemotherapy
Chlorambucil, other CCU, Cladribine and Fludarabine, Rituxan, IFN, Thalidomide, Ibrutinib, Velcade

33. Case #2
73yo WF presenting with neuropathy, dizziness, 40lb weight loss, IgM 5454, immediately hospitalized due to neurologic symptoms, started plasma exchange

34. Case #2
Bone Marrow
Bone marrow, flow cytometric immunophenotypic analysis: Monoclonal plasma cells and lymphocytes identified, consistent with Waldenstrom's macroglobulinemia.

35. Case #2
Dramatic decline in IgM (>5000 to <2000) after plasma exchange
Symptoms have improved
Treated with Rituxan and Velcade, IgM started rising again.
Changed to Ibrutinib, symptoms remain improved, IgM stabilized below 1500
IgM stable for > 2 years now

36. Amyloidosis Occurs in 10% of patients with MM
Infiltrative process resulting from amyloid fibril deposition in organs
Fibril is made from the terminal amino acid residue (NH2) of the variable portion of the light chain Ig molecule
Produced by clonal plasma cells

37. Amyloidosis
Renal disease - asymptomatic proteinuria to nephrotic syndrome
Cardiomyopathy
Hepatomegaly
Neuropathy
Pseudohypertrophy of muscles
Bleeding problems (Factor X def, Liver dz)
Lung and Skin infiltration

38. Amyloidosis

39. Amyloidosis
AL should be suspected in patients with plasma cell dyscrasia history
Biopsy results as shown
SPEP/UPEP - confirms monoclonal protein (plasma cell population)
Treatment - treat underlying plasma cell dyscrasia

40. Summary MGUS, SMM and MM are a spectrum of the same disease process
MGUS and SMM patients need close observation
WM patients present with hyperviscosity symptoms and very high IgM, total protein
Amyloidosis (AL) is characterized by fibril deposition in organs with damage (most commonly heart/liver/kidney)
Treatment is dependant on the disease process

41. Questions Miten R. Patel, MD Office 904-516-3737
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