Fig. 12.19 Multiplemyeloma.(A)Radiographoftheskull,lateralview.Thesharplypunched-outbonedefectsaremostobviousinthecalvaria.(B)Bonemarrowaspirate.Normalmarrowcellsarelargelyreplacedbyplasmacells,includingatypicalformswithmultiplenuclei,prominentnucleoli,andcyto-plasmicdropletscontainingimmunoglobulin.
Laboratory analyses typically show increased levels of immunoglobulins in the blood and/or Bence Jones proteins in the urine. Free light chains and an M protein component are observed together in 60% to 70% of cases, whereas in about 20% of patients only free light chains are present. Around 1% of myelomas are nonsecretory; hence, the absence of detectable M component does not completely exclude the diagnosis.
The diagnosis rests on radiologic and laboratory findings. It can be strongly suspected when imaging studies show typical bone lesions, but definitive diagnosis requires a bone marrow examination. Marrow involvement often gives rise to a normocytic normochromic anemia, sometimes accompanied by moderate leukopenia and thrombocytopenia.
The prognosis is variable. Patients with multiple bony lesions, if untreated, rarely survive for more than 6 to 12 months, whereas patients with “smoldering myeloma” may be asymptomatic for many years. The median survival is 4 to 7 years. Although cures have yet to be achieved, new therapies offer hope. Myeloma cells are sensitive to inhibitors of the proteasome, a cellular organelle that degrades unwanted and misfolded proteins. As discussed in Chapter 2, misfolded proteins activate apoptotic pathways, and myeloma cells are prone to the accumulation of misfolded, unpaired immunoglobulin chains. Proteasome inhibitors likely induce myeloma cell death by exacerbating this inherent tendency. The thalidomide-like compound lenalidomide also is effective in treating myeloma, but through a different mechanism that involves its ability to stimulate the degradation of specific proteins with oncogenic activities. Biphosphonates, drugs that inhibit bone resorption, reduce pathologic fractures and limit the hypercalcemia. Hematopoietic stem cell transplantation prolongs life but has not yet proven to be curative.
Lymphoplasmacytic lymphoma is a B cell neoplasm of older adults that usually presents in the sixth or seventh decade of life. Although bearing a superficial resemblance to CLL/SLL, it differs in that a substantial fraction of the tumor cells undergo terminal differentiation to plasma cells. Most commonly, the plasma cell component secretes monoclonal IgM, often in amounts sufficient to cause a hyperviscosity syndrome known as Waldenström macroglobulinemia. Unlike multiple myeloma, complications stemming from the secretion of free light chains (e.g., renal failure and amyloidosis) are relatively rare and bone destruction does not occur.
Virtually all cases of lymphoplasmacytic lymphoma are associated with acquired mutations in MYD88. The MYD88 gene encodes an adaptor protein that participates in signaling events that activate NF-κB and also augment signals downstream of the BCR (Ig) complex, both of which may promote the growth and survival of the tumor cells.