Multiple Myeloma

Multiple Myeloma
• Definition: Malignant proliferation of plasma cells
derived from a single clone
• Etiology: radiation;mutations in oncogenes;
familial causes;role of IL 6
• Incidence/Prevalence: 14,400 cases in 1996;
incidence 30/1,00,000
• Incidence increases with age
• Males> females ; Blacks > Whites
 Clinical Manifestations
• Common
– bone pain and pathological fractures
– anemia and bone marrow failure
– infection due to immune-paresis and neutropenia
– renal impairment
• Less common
– acute hypercalcemia
– symptomatic hyperviscosity
– neuropathy
– amyloidosis
– coagulopathy
 Clinical Manifestations
• Bone Pain:
– 70%,Precipitated by movement
– Pathological fractures
– Activation of Osteoclasts by OAF produced by
myeloma cells
• Susceptibility to infections:
– Diffuse hypogammaglob. If the M spike is excluded
– Poor Antibody responses ,Neutrophil dysfunction
– Pneumococcus,S.aureus,GN aerobes-
Pneumonia,Pyelonephrits
 Clinical Manifestations
• Renal failure: 25%
– Multiple contributory factors
– Hypercalcemia,Hyperuricemia,recuurent Infections
– Tubular damage produced by Light chains
– type 2 proximal RTA,Non selective proteinuria
• Anemia: 80%
– Normochromic/Normocytic
– Myelophthisis;Inhibition by cytokines produced by
plasma cells.
– Leukopenia/thrombocytopenia only in advanced cases.
 Bone Disease

• Lytic Lesions – 60%

• Osteoporosis, Fx, Compression Fx – 20%
• Myeloma Cells Produce Cytokines that:
– Stimulate Osteoclastic Activity
– Inhibit Osteoblastic Activity
• Can be Detected by Plain Xray
Lytic lesions(Punched out lesions) on X Ray.
 Vertebral collapse secondary to
osteoporosis/pathological fracture
 Normal bone

Lesion

Multiple myeloma: lesion in rib – Lab 11

Multiple myeloma: multiple lesions in skull – Lab 11
 Renal Disease
• Serum Cr Elevated in 50% and >2 in 20% at
Diagnosis
• Cast Nephropathy (Myeloma Kidney)
– Large, Waxy Casts in Distal Tubules composed of
Precipitated Light Chains
• Not detected on Dipstick
– SSA Test – Positive detected as the degree of turbidity
when SSA added to urine suggests presence of non-
albumin proteins
• Hypercalcemia
• Amyloidosis
 Case Report of Myeloma
nephropathy
• Bone marrow biopsy: 70% cellularity,
increased atypical plasma cells comprising
60% of cellularity, c/w multiple myeloma
 Epidemiology of Myeloma
nephropathy

• In two large multiple myeloma studies, 43%

(of 998 pts) had a creatinine > 1.5 and 22%
(of 423 pts) had a Cr > 2.0
• The one-year survival was 80% in pts with
Cr < 1.5 compared to 50% in pts with a Cr
> 2.3
• Prognosis is especially poor in pts who
require dialysis
 Causes of renal failure in MM

• Cast nephropathy
• Light chain deposition disease
• Primary amyloidosis
• Hypercalcemia
• Renal tubular dysfunction
• Volume depletion
• IV contrast dye, nephrotoxic meds
 Myeloma Kidney
• Two main pathogenetic mechanisms:
– Intracellular cast formation
– Direct tubular toxicity by light chains

• Contributing factors to presence of renal failure

due to multiple myeloma:
– High rate of light chain excretion (tumor load)
– Biochemical characteristics of light chain
– Concurrent volume depletion
 Cast Nephropathy
• Most common pathological diagnosis on renal
biopsy in multiple myeloma
• Due to light chains binding with Tamm-Horsfall
mucoprotein, which is secreted by tubular cells in
ascending loop of Henle, forming casts
• Multinucleated giant cells surround the casts
• Dehydration worsens cast nephropathy due to
decreased flow in tubules, increased concentration
of light chains
Cast Nephropathy
Cast Nephropathy
Cast Nephropathy
Minimal diagnostic criteria for myeloma

• >10% Plasma cells in bone marrow or

plasmacytoma on biopsy
• Clinical features of myeloma
• Plus at least one of:
– Serum M band (IgG >30 g/l; IgA >20 g/l)
– Urine M band (Bence Jones proteinuria)
– Osteolytic lesions on skeletal survey
 Initial Work-up
• CBC w/diff – peripheral smear
– Normocytic, Normochromic Anemia most common
– Rouleaux Formation >50% of patients
• Chemistry (ca, alb, cr, LD, CRP, B2M)
• SPEP – Monoclonal Protein
• Serum Viscosity (if M-protein conc. Is high,
>5g/dL) or sx of hyperviscosity are present
• UA and UPEP
• Metastatic bone Survey
• Bone Marrow Biopsy
Rouleaux formation
 M protein
• Amount of the M protein -marker of tumor load
• Nature variable:
– May be an intact molecule or a fragment
– Extramedullary / Solitary plasmacytomas <1/3
have M spike
– 20% of Myelomas _ only Light Chains
produced
– Non Secretory Myelomas_rare
– frequency of myelomas : Ig G> IgA > IgD
1.Normal Plasma 2.Polyclonal Hyperglobulinemia
3.Monoclonal Spike4.Bence Jones proteins in urine
Plasmapheresis in MM
 Diagnostic Criteria

• Presence of an M-Protein in serum and/or

urine
• Presence of clonal bone marrow plasma
cells or plasmacytoma
• Presence of Related Organ/Tissue
involvement
– Hypercalcemia, renal insufficiency, anemia,
lytic bone lesions
 Screening and Diagnosis

• Blood and urine tests

• X-rays
• Magnetic Resonance Imaging (MRI)
• Computerized Tomography (CT)
• Bone marrow examination
Normal Cell (5%)
Myeloma Cells (10%)
Plasma Cell
Bone Marrow Aspirate
 Bone Marrow Aspirate

• Usually >10% plasma Cells, but can be

from 5-100%
– ≥ 50% involvement – worse prognosis
• Immunoperoxidase staining detects either
kappa or lambda light chains, NOT both
(confirming proliferation is monoclonal)
• Immunophenotyping – Malignant Plasma
Cells stain positive for CD38, CD56, and
CD138
Bone Marrow Biopsy
 Staging

• Stage 1
– Low amount of myeloma
• Stage 2
– Medium amount of myeloma
• Stage 3
– High amount of myeloma
• A
– Normal kidney function
• B
– Abnormal kidney function
 International Staging System

• Stage I – B2M <3.5 mg/L and serum alb ≥

3.5 g/dL
• Stage II – neither stage I nor Stage III
• Stage III – B2M ≥ 5.5 mg/L
 Staging 1.
• Hb/Serum Ca/M component level/radiology
– Stage I: Hb >10;Serum Ca < 12;Normal Bone
survey;Low M component levels
– Stage III: HB < 8.5, Serum Ca >12;Lytic
lesions+;High M component levels
– Stage II : Intermediate
• Divided into A or B depending on Serum
Creatinine level < or > than 2 mg/dl.
 Staging 2
• Serum b2 microglobulin levels.
• If < 0.004 g/L : Stage 1; Median survival 43
months
• If >0.004 g/L: Stage II; Median survival 12
months
 Prognostic Factors

• Performance status 3 0r 4
• Serum albumin < 3 g/dL
• Serum Cr ≥ 2.0 mg/dL
• Platelet Count <150,000
• Age ≥ 70 years
• Beta-2-microglobulin >4 mg/L
• Serum Calcium ≥ 11 mg/dL
• Hemoglobin <10 g/dL
 Treatment
• Options:
– melphalan with or without prednisone
– Infusional chemotherapy - vincristine and
adriamycin infusion plus either dexamethasone
all methylprednisolone
– combination therapy - for example, adriamycin,
carmustine, cyclophosphamide, and melphalan
– weekly cyclophosphamide (“C weekly”)
 Treatment
• Prompt reduction in bone
pain,anemia,hypercalcemia.
• M component lags behind -4-6 weeks to fall
• 60% of patients will acieve a 75% reduction in
tumor mass.
• Treat q 4-6 weeks for 1-2 years.
• Leads to a plateau phase- relapse within a year.
• Maintenance: alpha Interferon ???
 Treatment
• Supportive therapy
– analgesia
– rehydration
– treatment and any hypercalcemia
– treatment of any renal impairment
– treatment of any infection
– local radiotherapy if required
– chemotherapy
– prevention of further bone damage
 Treatment
• Melphalan and Prednisone (Oral)
– Preferred Tx in pts NOT going for BMT
– 7 day course repeated q 6weeks (x 3)
– Objective response in 50-60%, MS of 2-3 yrs
• Melphalan, prednisone, and Thalidomide
– RR of 93% with 26% CR
– When compared to above regimen, had better CR and
RR; however, more toxicity
• Thalidomide with or w/o Dexamethasone
– Preferred in Candidates for BMT
– For pts with Relapsed or Resistent Disease
• VAD (Vincristine, Dex, and Adriamycin)
• Radiation – Reserved for pts with focal process
that has not responded to chemo
 Treatment Outcomes

• Cure – Not yet been Achieved

• Molecular Complete Response
– No evidence of Disease
• Complete Response
– No detectable M protein AND nml % of Plasma
cells in Bone Marrow
• Progressive Disease
– >25% increase in M Protein, new bony lesions,
or a new plasmacytoma
MGUS: Monoclonal gammopathy of
undetermined significance

• No explained symptoms suggestive of myeloma

• Serum M protein concentration < 30 g/l
• < 5 percent plasma cells in bone marrow
• Little or no M protein in urine
• No bone lesions
• No anemia, hypercalcemia, or renal impairment
• M protein concentration and other results stable on
prolonged observation