MULTIPLE MYELOMA
Pathophysiology
Male predominant, African Americans, average age 68 at diagnosis. Risk factors: toxins,
heredity
Immature B cells differentiate into plasma cells which secrete immunoglobulins.
Chromosomal alteration in plasma cells leads to monoclonal proliferation of myeloma
cells (IgG>A, usually heavy chains, 20% light chain, rarely nonsecretory).
Myeloma cells have low growth potential and are initially dependent on bone marrow
environment for survival=Bone- CA interaction. They can later become stromaindependent and have extramedullary spread=Malignant Melanoma. In the initial phases,
M cells bind to marrow cells which produce cytokines for Mcell growth and survival.
Cytokines include OAFs, which damage the marrow by increasing resorption and
decreasing bone formation, allowing M cell growth, and other cytokines which impair
immune function.
Clinical Presentation reflects presence of plasma cells in bone and Ig in serum/urine
Bone: hypercalcemia in 30%, osteoporosis, lytic lesions (pain, fracture) due to increased
osteoclasts. Not apparent on bone scan as process is destruction not formation.
Renal: 25%, impairment due to hypercalcemia /dehydration, or direct toxicity of light
chains; see increased creatnine and proteinuria. Often cause of death.
Hematologic: anemia of chronic disease/CRI in 80%, hyperviscosity in IgA disease,
abnormal platelet function
Infection: due to decrease in other circulating Ig, decreased APC function by cytokines.
Typically gm negative/polysaccharide encapsulated organisms. Cause of death.
Extramedullary: metastatic myeloma can go to pleura, blood, skin
Spectrum of Disease/Subtypes
MGUS: probably precursor to MM- first chromosomal hit causes MGUS, second causes
transformation to MM (transformation in 16% over about 10 years).
Dx=hypergammaglobulinemia (monoclonal, IgG or A usually) with <10% plasma cells
in marrow, no features of myeloma.
Smoldering: not quite myeloma, monoclonal gammopathy with abnormal marrow cells
Multiple Myeloma: 1 major and 1 minor criteria, or 3 minor criteria in patient with
symptoms and progressive (bone) disease
Other: plasma cell leukemia (>5x10^9 plasma cells in peripheral blood), solitary
plasmacytoma (solid tumor of monoclonal plasma cells on pathology), POEMS (bone
sclerosis, demyelinating neuropathy, HSM, endocrinopathy, skin disease)
Diagnosis
Plasma cells in marrow, monoclonal Ig protein peripherally
Criteria: Major- plasmacytoma, >30% plasma cells in marrow, monoclonal protein
(IgG>3.5, IgA>2, or Bence Jones proteins >1 g/24 hour)
Minor- lytic lesions, monoclonal hypergammaglobulinemia with others hypo,
10-30% plasmacytosis marrow
Evaluation
Laboratory: CBC, Calcium, Creatnine, 24hour urine protein (or ratio), LDH, U.A.,
CRP/ESR, beta2microglobulin (LMW protein HLA light chain, renally excreted)
Immunoglobulins in urine or serum
Peripheral smear
Immunoglobulin levels (one predominates), kappa to lambda ration
Immunofixation- monoclonal spike in paraprotein. Serum: IgG 53%, IgA20%, k/l
Immunofixation of urine: light chain disease- 20% bence jones proteins
Bone evaluation:
BMAspirate/bx- plasma cells, cytogenetics
Skeletal survey
BMD
Staging
Stage 1- low tumor mass (Hb>10, IgG<5, IgA<3, BJ<4g, normal calcium, <2 lytic bone)
Stage 2- int. tumor mass
Stage 3- high tumor mass (any: Hb<8.5, IgG>7, IgA>5, BJ>12g, Ca>12, multiple lytic)
Subclass by renal function (A if creatnine less than 2, B if greater)
Prognosis: poor if higher burden of tumor- LDH, UA, anemia, hypercalcemia,
Beta2microglobulin, also if older, cytogenetics, extramedullary, increase CRP/ESR
(cytokines)
Treatment
Supportive: radiotherapy to fracture, RRT, analgesia, hypercalcemia, Epo, infection px
Bisphosphonates: Supportive for bone disease (improved QOL), possibly directly
therapeutic. Indication= osteopenia, lytic lesion, fracture. Mechanism of action: inhibit
osteoclast function by decreasing recruitment/ inhibiting maturation, also decrease IL
production (OAF)- leads to decreased pain, fracture, and preservation of bone
structure/integrity. Rx Clodronate 2400 mg/day, or monthly IV
Pamidronate/Zolendronate. Duration uncertain, adjunct to chemotherapy as well.
Chemotherapy:
Goal is remission (IF negative at 6 weeks, <5% plasmacytosis, no evidence dz
progression). Median survival with conventional chemo 2-3 years, increased to 50% 5
year survival with high dose chemo and BMT. Drug resistance high.
Alkylating agents: Melphalan alone CR30%, Melph/Pred is standard. Combination
chemo (VAD or CVAMP) 3-5 cycles induces remission faster but not more effective.
Induce with combination chemo, then HIGH DOSE MELPHALAN myeloablation with
rescue autotransplantation of peripheral stem cells leads to 30-50% CR, 81% OR, 50% 5
year survival. OS is 6-9 years, in 21%. Tandem autotxp has 42%OS. Thalidomide if
relapse.
Biologic/immunologic: Interleukins; PEG IFN toxic, 4 mos increased survival; Steroids
to maintain remission also with side effects, Monoclonal Ab to B cells, Allogeneic
transplant high mortality.