CBC, serum calcium & creatinine, serum protein electrophoresis or
UA, 24-hr urine protein & immunoglobulin electrophoresis, 24-hr urine
Bence-Jones protein collection.
Bone marrow biopsy & aspiration if IgG>2.5 g/dL or IgA>1.5 g/dL
or IgM>3 g/dL.
Skeletal x-ray survey for lytic lesions.
MM is uncommon in persons younger than 40 years; the incidence increases
rapidly after age 50, equally in men and women.
MM is characterized by
an accumulation of plasma cells in the bone marrow >10%
the overproduction of a monoclonal immunoglobulin. The frequency of
the various immunoglobulin types of MM parallels the serum concentrations
of those Igs: IgG in 60% to 70%, IgA in 20%, and light chain in only 15%;
few cases of IgD and IgE have been reported, and approximately 1% of patients
The plasma cell disorders are characterized by the secretion of
electrophoretically and immunologically homogeneous (monoclonal) proteins.
Each monoclonal protein (M-protein, myeloma protein, or paraprotein)
consists of two heavy (H) polypeptide chains of the same class and subclass
and two light (L) polypeptide chains of the same type. The heavy polypeptide
chains are IgG, IgA, IgM, IgD, and IgE. The light-chain types are kappa
(kappa) and lambda (lambda). A monoclonal protein (M-protein) is
usually seen as a narrow peak (like a church spire) in the densitometer tracing.
depressed levels of normal residual immunoglobulins.
Bence Jones proteins (urinary light chains) are detected in the urine
with antisera against light chains but without an anti-heavy-chain component.
Anemia: due mainly to decreased erythropoiesis; produces weakness and fatigue
Renal insufficiency: mainly due to "myeloma kidney" from light chains or
hypercalcemia; rarely from amyloidosis
Recurrent infections: respiratory and urinary tract infections or septicemia
due to gram-positive or gram-negative organisms
Bleeding diathesis: from thrombocytopenia or coating of platelets with M-protein
Amyloidosis: develops in 10 to 15%
Extramedullary plasmacytomas: occur late in the disease
Cryoglobulinemia type I: rarely symptomatic
Diagnostic Criteria for Various
Multiple Myeloma (MM)
The diagnosis of MM requires at least one of the following major
- bone marrow with at least 30% plasma cells; and
- M protein on serum electrophoresis showing levels of IgG >3.5 g/dl,
IgA >2.0 g/dl, or
- urine light-chain (Bence-Jones protein) excretion > 1 g/24 hr.
One or more of the following minor criteria are also required:
- bone marrow plasmacytosis greater than 10%;
- M protein in serum or urine but less than the levels listed above under
- lytic bone lesions; and decreased residual immunoglobulins.
Differentiation of MGUS from Multiple Myeloma and Macroglobulinemia
Differentiation of the patient with benign monoclonal gammopathy from one
in whom multiple myeloma, macroglobulinemia, or a related disorder eventually
develops is very difficult when the M-protein is first recognized. The size
of the M-protein is of some help--levels greater than 3 grams per deciliter
usually indicate overt multiple myeloma or macroglobulinemia, but some
exceptions, such as smoldering multiple myeloma (SMM), exist. Levels of
immunoglobulin classes not associated with the M-protein (normal polyclonal
or background immunoglobulins) are almost always reduced in multiple
myeloma or Waldenstrom's macroglobulinemia, but a reduction may also occur
in benign monoclonal gammopathy. The association of a monoclonal light
chain (Bence Jones proteinuria) with a serum monoclonal gammopathy suggests
multiple myeloma or macroglobulinemia, but in many patients with small amounts
of monoclonal light chain in the urine, the M-protein in the serum remains
stable for many years. The presence of more than 10% plasma cells in the
bone marrow suggests multiple myeloma, but some patients with more plasma
cells have remained stable for long periods. The presence of osteolytic
lesions strongly suggests multiple myeloma, but metastatic carcinoma
may produce lytic lesions as well as plasmacytosis and may be associated
with an unrelated monoclonal gammopathy.
Anemia is present in 70% of the patients at the time of diagnosis. Nearly
all patients will develop anemia as the disease progresses.
Peripheral blood smear - rouleaux formation
Serum protein electrophoresis - usually shows a spike or a localized band
(M spike in approximately 80% of patients). Of these, 50% are IgG protein,
20% IgA, and 17% free monoclonal light chains (Bence Jones protein).
Urine electrophoresis - positive about 70% of the time for light chains,
but inconsistencies hinder diagnosis
Elevated sedimentation rate
Elevated creatinine and BUN
Major Criteria for Multiple Myeloma:
Monoclonal protein spike on electrophoresis: IgG>3.5 g/dL or IgA>2
g/dL or Bence Jones proteinuria >1 g/24 hr
Bone marrow plasma cells at least > 10%
Lytic bony lesions
Possible Associated Features:
Cytopenias as frequent anemia, renal failure, & hypercalcemia (in
10-20% of MM patients).
Signs and symptoms of hyperviscosity, such as shortness of breath, confusion,
and chest pain, are uncommon in patients with IgG MM but may occur at extremely
high serum protein concentrations. Hyperviscosity occurs more often in patients
with IgA MM because of greater polymerization of the paraprotein.
Commonly used: Levels of other immunoglobulins, serum beta2-microglobulin
Investigational: plasma cell labeling index, serum Interleukin-6 levels,
cytogenetics or oncogene studies, etc.
Treatment of Multiple
Indications for therapy include the development of significant anemia,
hypercalcemia, or renal insufficiency; the occurrence of lytic bone lesions;
and the finding of extramedullary plasmacytomas.
Palliative radiation in a dose of 20 to 30 Gy should be limited to patients
who have multiple myeloma with disabling pain and a well-defined focal process
that has not responded to chemotherapy. Analgesics in combination with
chemotherapy usually can control the pain.
Autologous Stem Cell or Bone Marrow Transplantation for patients younger
than 70 years old
- the median survival was longer with transplantation than with chemotherapy.
Chemotherapy is the preferred initial treatment for overt, symptomatic multiple
myeloma in patients older than 70 years or in younger patients in whom
transplantation is not feasible.
The oral administration of melphalan and prednisone produces objective
response in 50 to 60% of patients.
Melphalan 0.15 mg/kg /day for 7 days (8-10 mg/day), with prednisone 20 mg
three times daily for the same 7 days.
The chemotherapy course is repeated every 6 weeks for at least 3 courses,
and usually is for one year.
Almost all patients with multiple myeloma will eventually relapse.
Treatment for Refractory Multiple Myeloma:
VBAP (vincristine, carmustine
[BCNU], doxorubicin [Adriamycin]) on day 1 and prednisone
daily for 5 days every 3 to 4 weeks benefits 30% of patients. It is well
tolerated. If the patient's leukocyte and platelet levels are satisfactory,
cyclophosphamide, 600 mg/m2 /day intravenously for 4 days (days 1-4), plus
prednisone, 50 mg twice a day for the same 4-day period, followed by granulocyte
colony-stimulating factor, has been helpful in patients with refractory advanced
Thalidomide given orally at a dose of
200 mg/d for 2 weeks, then increased by 200 mg/d every 2 weeks, up to a maximal
dose of 800 mg/d. Four (25%) achieved a partial response to therapy, with
a greater than 50% reduction in the serum or urine M protein level. Responses
lasted 2, 4+, 8, and 10+ months. Major adverse effects included constipation,
sedation, rash, and peripheral neuropathy. CONCLUSION: Thalidomide is an
active agent in the treatment of patients with advanced myeloma. (Mayo
Clin Proc 2000 Sep;75(9):897-901)
Multiple myeloma has a progressive course, and the median survival is
approximately 3 years.
Meets myeloma criteria except minimal or no bony lesions, no compression
Possible Associated Features:
Usually asymptomatic; no anemia, hypercalcemia or renal failure
MGUS (Monoclonal Gammopathy of Undetermined
Monoclonal protein spike on electrophoresis: IgG<3.5 g/dL, IgA<2 g/dL;
Bence Jones proteinuria <1 g/24 hr
Bone marrow plasma cells <10%
No lytic bony lesions & Other immunoglobulins normal
Possible Associated Features:
Should be asymptomatiac; no anemia, hypercalcemia, or renal failure. NO
underlying disease associated with paraproteinemia (eg. lymphoma, amyloidosis)
Ancillary investigations: Related to level of paraproteinemia
present & Requires periodic follow-up testing.
It occurs in about 1% of the general population and 3% of normal persons
older than 70 years; IgG is most commonly increased. Features of MM that
distinguish it from MGUS include greater concentrations of serum and urine
M proteins, increased percentage of bone marrow plasma cells, higher plasma
cell label-ing index, the presence of lytic bone lesions, and the presence
of circulating plasma cells in the peripheral blood. After prolonged follow-up,
four groups of patients with MGUS can be identified:
(1) those with a contained monoclonal gammopathy (19%);
(2) those whose serum immunoglobulin level increases to more than 3 g/dl
but do not require any therapy (10%); (3) those who die without multiple
myeloma or another related disease developing (47%); and
(4) those in whom myeloma, amyloidosis, macroglobulinemia, or another
lymphoproliferative disorder develops (24%, two thirds of which are myeloma).
Progression to a malignancy occurs at 8 to 10 years. Unfortunately, there
are no laboratory studies that reliably predict which patients with MGUS
will progress to MM.
Biclonal gammopathies occur in 2 to 3% of patients with monoclonal gammopathies.
Biclonal gammopathy of undetermined significance accounts for about two thirds
of patients. The remainder have multiple myeloma, macroglobulinemia, or other
lymphoproliferative diseases. Triclonal gammopathies may also occur.
Biopsy-proven monoclonal plasma cell tumore; absence of other major criteria
Possible Associated Features: Frequently symptomatic (eg, bone
Ancillary investigations: Requires periodic follow-up testing.
Serum or urine paraprotein should disappear after local Rx.
Monoclonal IgM paraprotein with IgM > 3 g/dL
Waldenstrom's macroglobulinemia, characterized by an IgM gammopathy,
lymphadenopathy, and hepatosplenomegaly, was formerly included with these
disorders but is now more appropriately classified as a lymphoplasmacytoid,
indolent non-Hodgkin's lymphoma
is characterized by the deposition of amyloid fibrils in various tissues.
Amyloidosis may occur either
secondary to a chronic inflammatory condition (amyloid A, or AA) or as
primary condition (amyloid light chain-related, or AL) in the setting
of a B cell malignancy. In AL, the fibrils are made up of fragments
of light chains of immunoglobulins, with a clonal proliferation of bone marrow
plasma cells, and Bence Jones proteinuria is present.
The diagnosis is made by a biopsy of the affected organ or a urine sample
stained with Congo red.
Idiopathic Bence Jones Proteinuria
Bence Jones proteinuria is a recognized feature of multiple myeloma, primary
amyloidosis, Waldenstrom's macroglobulinemia, and other malignant
lymphoproliferative disorders. A benign Bence Jones proteinuria may also
occur. Patients have been documented to have a stable serum level of M-protein
and Bence Jones proteinuria for more than 15 years without developing multiple
myeloma or related disorders.