M
M
Nicholas Mitsiades, M.D. July 12 th , 2005
 Description
 Malignancy arising from clonal proliferation of plasma cells in the bone marrow.
 Plasma cells usually produce an immunoglobulin (referred to as a monoclonal protein or
M protein)
 Pathogenesis is poorly understood, but probably represents a sequential process with accumulation of oncogenic mutations. Putative factors contributing to malignant transformation include exposure to radiation, benzenes, organic solvents, herbicides, insecticides.
 Epidemiology
 2 nd most commonly diagnosed hematologic malignancy in the Western world. More than
15,000 new cases per year in the US.
 Affects older individuals (median age 65), although increasingly seen in younger ages.
 Slight male and African-American predominance.
 Clinical Features
 Classic clinical features are anemia, renal failure, bony lesions, hypercalcemia, and recurrent infections
 Skeletal
 Bone pain or pathologic fractures present in 2/3 of patients at time of dx
 Osteolytic, “punched out” bony lesions (skull and long bones especially affected)
 Generalized osteoporosis resulting from cytokine-stimulated osteoclastic activity
 Renal
 “Myeloma kidney” – cast nephropathy with intratubular cast formation (light chain +
Tamm-Horsfall protein aggregates)
 Hypercalcemia-induced renal dysfunction
 Light chain deposition disease and AL amyloid deposition (light chain fibrils) in glomeruli usually result in nephrosis
 Proximal tubule dysfunction (Fanconi syndrome) due to filtered light chains.
 Contrast nephropathy: Very important, especially in volume-depleted pts. Avoid IV contrast in myeloma pts.
 Hematologic
 Cytopenias, especially anemia (present in 2/3 of patients on dx) – secondary to bone marrow infiltration, renal insufficiency, or chronic disease
 Bleeding diathesis – secondary to impairment of coagulation by M protein or thrombocytopenia from bone marrow infiltration
 Hyperviscosity syndrome – visual changes, headaches, confusion, “sausage veins” seen on fundoscopy
 Neurologic
 Radiculopathy and cord compression – from plasmacytoma or vertebral collapse
 Altered mental status – hyperviscosity, hypercalcemia, or infection may contribute
 Peripheral neuropathy – resulting from M protein deposition or amyloidosis
 Metabolic
 Hypercalcemia – with symptoms of polyuria, polydipsia, weakness, fatigue, constipation, confusion
 Immunologic
 Immunosuppression – due to immunoglobulin dysfunction, leukopenia, and/or chemotherapy-induced neutropenia. Particularly prone to infections from encapsulated organisms.
 Cardiac : CHF, conduction abnormalities secondary to M protein amyloid
 Other : macroglossia, hepatomegaly secondary to amyloid deposition
Beth Israel
Deaconess Medical Center Residents’ Report

 Laboratory Features
 CBC with normocytic, normochromic anemia. Other cell lines may be reduced.
Peripheral smear with rouleaux formation (the visual equivalent of an elevated ESR).
 Hypercalcemia
 Renal insufficiency
 Elevated ESR
 M spike on serum protein electrophoresis
 M spike on urine protein electrophoresis / immunofixation (ideally send 24 hour urine)
 UA usually bland, but waxy casts may be seen and light chains (Bence-Jones protein) may detectable in urine with SSA
 Quantitative electrophoresis and immunofixation
 IgG most common subtype (60%)
 IgA (20%)
 Light chains alone (10%)
 IgD, IgE, and IgM comprise < 10%
 Reciprocal depression of the normal immunoglobulins common in myeloma
 In approximately 1% of patients, no serum or urine M protein detected despite bone marrow findings of multiple myeloma
 Elevated CRP, -2 microglobulin, and LDH associated with poorer prognosis
 Radiologic Studies
 Complete skeletal survey to identify lytic bone lesions or generalized osteopenia in >
80% of cases (N.B. bone scan is more sensitive for blastic lesions, thus not as helpful)
 CT or MRI for evaluation of suspected cord compression
 Diagnostic Criteria
 Bone marrow with >10% plasmacytosis + one of the following:
 Serum M protein spike (>3 g/dL).
 Urine M protein spike
 Lytic bone lesions or generalized osteoporosis on skeletal survey
 Presence of soft tissue plasmacytoma
 Spectrum of Plasma Cell Dyscrasia
 Smoldering myeloma
 M protein present and bone marrow plasmacytosis > 10% without bony lesions or other clinical manifestations of myeloma.
 Monoclonal gammopathy of uncertain significance (MGUS)
 M protein concentration < 3 gm/dL, <10% bone marrow plasmacytosis, and no other clinical manifestations of myeloma. It is an asymptomatic pre-myeloma condition, present in 1% and 3% of individuals age >50 and >70, respectively.
 Progresses to myeloma with ~1% annual risk and 25% cumulative probability of progression over 20 years.
 Solitary myeloma – Isolated intra- or extra-medullary plasmacytoma.
 Staging and Prognosis
 Clinical staging systems (such as Salmon-Durie system) less reliable than objective prognostic testing
 -2 microglobulin, and LDH are associated with poorer prognosis
 Bone marrow cytogenetics, especially deletion of 13q, may predict poorer prognosis
 Therapy
 No curative treatment available. Goal of care is to induce remission and then go for auto-
BMT, if the pt eligible.
 High dose chemotherapy with autologous BMT (“auto-BMT”)
 Standard of care in patients with symptomatic myeloma who are younger than 65
(age limit may vary slightly by treatment center).
 Induction with non-alkylating agents (thalidomide+dexamethasone), stem cell collection, then high dose chemotherapy with melphalan, followed by stem cell reinfusion, is most common approach.
Beth Israel
Deaconess Medical Center Residents’ Report

 Improved overall survival at 5 years (52% vs 12%), but most patients will continue to have evidence of disease, and all will eventually relapse.
 Allogeneic BMT is associated with high mortality (up to 50%) due to infections and
GVHD. Nonmyeloablative (“mini-allo”) BMT is under investigation as a possibly less toxic approach.
 Conventional Chemotherapy
 Oral melphalan and prednisone (MP regimen) have been standard therapy if pt not a candidate for auto-BMT. Response rates of 40-60%, but <5% complete remission.
Alkylating agents, such as melphalan, destroy stem cells, so should be avoided in any pt who is considered for autologous BMT.
 Vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD regimen) has been used, but its effectiveness is largely attributed to the dexamethasone component.
Vincristine is falling out of favor because of toxicity (neuropathy).
 Treatment is usually continued until M protein levels decline to a plateau.
 Disease often recurs within 1 to 2 years of discontinuation of therapy.
 Newer therapies:
 Thalidomide: Inhibits myeloma cell growth, suppresses angiogenesis and blocks production of growth factors in the myeloma microenvironment. Standard of care for myeloma. Side-effects: Somnolence, severe constipation, DVT/PE.
 Bortezomib: Inhibits an intracellular proteolytic complex (proteasome) and triggers death (apoptosis) of the myeloma cells. Approved in 2003 by FDA.
 Lenalidomide: A thalidomide analog with higher activity and better toxicity profile (but can still cause DVT/PE), just finished clinical trials. Expected to become available later this year.
 Adjunctive therapies :
 Interferoneffects (chronic “flu-like” symptoms, depression, autoimmunity, thyroid abnormalities).
 EPO.
 Bisphosphonates: Significant benefit in reducing the number of fractures. Two options: pamidronate (one 90 mg IV infusion given over two hours) or zoledronate
(one 4 mg IV infusion given over 15 minutes), both given q3-4 weeks. The only documented advantage of zoledronate is the shorter infusion time, so for inpatients we give pamidronate (much cheaper). The “new” side-effect of all bisphosphonates is osteonecrosis of the jaw , usually after a dental procedure.
 Management of complications : renal failure, hypercalcemia, anemia, hyperviscosity, bone pain and fractures, spinal cord or nerve root compression.
Remember:
- The diagnostic study of choice is a complete skeletal survey, not a bone scan (because the bone lesions are lytic ).
- NEVER give IV contrast to a pt with myeloma.
- Because the circulating immunoglobulin is positively charged, myeloma is one of the two conditions that can give a LOW anion gap (the other is hypoalbuminemia ). So a “normal” gap in a myeloma patient is not necessarily reassuring.
Clinical scenario:
A pt with multiple myeloma, on thalidomide treatment, comes to the ED and you suspect PE.
What is the imaging study of choice?
Beth Israel
Deaconess Medical Center Residents’ Report