Multiple Myeloma and Related Conditions

This heterogeneous group of conditions is associated with monoclonal immunoglobulin in serum or urine, and is characterized by disordered proliferation of monoclonal lymphocytes or plasma cells. The clinical phenotypes of these conditions are determined by the rate of accumulation, site and biological properties of both the ab- normal cells and the monoclonal protein.

Multiple myeloma

The incidence of myeloma is about 4 per 100 000 in the UK. Myeloma occurs over twice as frequently in African Americans than in white Americans and Europeans, but is much less common among Chinese and Japanese. Myeloma is extremely rare before the age of 40 years but its incidence increases to over 30 per 100 000 in indi- viduals over 80 years. The median age at diagnosis is 69 years, with slight male predominance.

Pathogenesis and clinical features

Myeloma arises in a post-germinal centre B lymphocyte in lymph node or in spleen. Neoplastic cells home into the bone marrow, where the environment facilitates plasma cell proliferation. Interactions between marrow stroma cells and myeloma cells are impor-

Figure 9.1  Osteoclast activation by myeloma cells. RANK-L, receptor activator of nuclear factor κB ligand (or TRANCE: TNF receptor  activation induced cytokine); OPG, osteoprotogerin

tant in disease pathogenesis. Stroma cells produce interleukin (IL)-6, a growth factor for plasma cells, which produce tumour necrosis factor α and IL-1β. These stimulate stroma cell production of the ligand of receptor activator of nuclear factor kappa B (RANK-L). RANK-L promotes osteoclast proliferation and differentiation (Fig.9.1). Osteoblasts are inhibited in myeloma, as is secretion of osteoprotogerin (OPG; an inhibitor of RANK-L binding and osteoclast formation). As a result, monoclonal plasma cells accumulate in the marrow, causing bone marrow failure and lytic bone destruction (Fig. 9.2).

Most patients have detectable monoclonal paraprotein, usually an intact immunoglobulin (Box 9.1). This is IgG in 60% of patients and IgA in 20–25%. In 15–20% of patients, only immunoglobulin light chains are produced. Free light chains are detectable in urine as Bence–Jones protein. IgD myeloma and non-secretory myeloma are rare. IgE and IgM myelomas are very rare (Fig. 9.3).

The paraprotein may cause hyperviscosity (especially IgA) or protein deposition in renal tubules, resulting in renal failure. Production of normal immunoglobulin is often depressed (immune paresis), which increases susceptibility to infection.

Bone destruction is a characteristic feature, and bone pain is a major cause of morbidity (Box 9.2). This is due to increased bone resorption by osteoclasts and inhibition of osteoblast bone formation causing pronounced bone loss and osteolytic lesions, predisposing

Figure 9.2  Radiograph showing multiple lytic lesions and pathological fractures of the humerus.

Figure 9.3  Protein electrophoresis strip showing (1) normal plasma, (2) polyclonal hypergammaglobulinaemia, (3) serum paraprotein and (4) Bence–Jones proteinuria  and albuminuria.

to pathological fracture. Widespread bone destruction may cause hypercalcaemia and resultant renal failure.

Complex cytogenetic abnormalities are frequently found in myeloma. Fluorescence in situ hybridization demonstrates aneuploidy in nearly all cases. These commonly involve chromosome 14q32 (IgH locus) and deletions of chromosome 13, which confer an unfavourable prognosis.

The commonest presentation is bone pain (60%). Symptoms of anaemia, renal failure or infection are frequent. Hyperviscosity (somnolence, impaired vision, purpura and haemorrhage), acute

hypercalcaemia, spinal cord compression, neuropathy or amyloidosis may occur. About 20% of patients are asymptomatic and diag- nosed by routine blood tests.

Investigations and diagnosis

Myeloma should be suspected in patients aged > 40 years with bone pain or fracture, osteoporosis, osteolytic lesions, lethargy, anaemia, red cell rouleaux, raised erythrocyte sedimentation rate (ESR) and plasma viscosity, hypercalcaemia, renal dysfunction, proteinuria, or recurrent infection. It is characterized by the triad of bone marrow plasmacytosis, lytic bone lesions on skeletal radiology, and the presence of M protein in the serum and/or urine (Box 9.3).

Investigation of a patient with suspected myeloma should include: a full blood count and film, measurement of ESR, plasma viscosity, urea and creatinine concentrations, calcium, phosphate, alkaline phosphatase, uric acid and serum immunoglobulins, serum protein electrophoresis, routine urine analysis, urine electrophoresis for Bence–Jones protein, skeletal survey, and bone marrow aspirate and biopsy (Box 9.4, Fig. 9.4).

Normochromic normocytic anaemia is often present; neutropenia and thrombocytopenia suggest advanced disease (Table 9.1). Rouleaux are usually seen in the blood film, and plasma cells may also be present in about 5% of cases. The ESR and plasma viscosity are usually elevated but are normal in 10% of patients. The serum calcium is increased in up to 20%. Serum alkaline phosphatase is invariably normal, reflecting suppressed osteoblast activity. Raised urea and creatinine occur in 20% and renal impairment, usually due to cast nephropathy, is common. Low serum albumin reflects ad- vanced disease.

Skeletal radiology is a critical investigation and shows lytic lesions, pathological fractures or generalized osteoporosis in 80% of cases.

Figure 9.4  Bone marrow aspirate showing infiltrate of abnormal  plasma cells

(medium power).

Osteoporosis alone is seen in 5–10%. Bone scans are typically negative despite extensive bone damage, and are of no value. Magnetic resonance imaging (MRI) is a sensitive imaging technique for myeloma and is valuable in suspected cord compression (Fig. 9.5).

Figure 9.5  Magnetic resonance image showing collapse of second cervical vertebra and narrowing  of spinal canal.

Approximately 10% of patients develop primary amyloid, which causes nephrotic syndrome, renal failure, cardiac failure or neuropa- thy. The extent of amyloid deposition is assessed using serum amyloid P scanning. 

The most important differential diagnosis is monoclonal gammopathy of undetermined significance (MGUS), for which no treat- ment is indicated. No single test differentiates the two conditions reliably. A serum IgG concentration > 30 g/L or IgA concentration > 20 g/L suggests a diagnosis of myeloma rather than MGUS. The diagnosis of ‘smouldering myeloma’ is applied to patients in whom paraprotein and bone marrow criteria exist for the diagnosis of myeloma, but no myeloma-related end-organ or tissue impairment occurs and, crucially, the paraprotein remains stable. These patients require close observation but no treatment. 

Several prognostic features have been recognized (Box 9.5). Deletion of chromosome 13q is an important adverse feature. Renal impairment is a risk factor, owing to its association with a high tu- mour burden. 

An International Staging System has been devised using serum β-2-microglobulin and albumin concentrations (Table 9.2).

Management and clinical course 

Without treatment, patients with multiple myeloma will experience progressive bone damage, anaemia and renal failure. Initial management should prioritize general aspects of care.

Initial treatment should consist of: (i) adequate analgesia – opi- ates are often necessary, and local radiotherapy to fractures or osteo- lytic lesions may have dramatic benefit; (ii) rehydration – patients are often dehydrated at presentation, even without hypercalcaemia or renal impairment; (iii) management of hypercalcaemia if present-rehydration, diuresis and bisphosphonate therapy; (iv) management of renal impairment – rehydration and treatment of any hypercalcaemia often have a pronounced effect on abnormal serum chemistry in myeloma, although, in some patients, plasmapheresis and/or dialysis is necessary; (v) treatment of infection – most infections at diagnosis are bacterial and respiratory, and respond to broad spectrum antibiotics; and (vi) chemotherapy (Box 9.6).

Conventional treatment for older patients (> 65 years) is oral melphalan and prednisolone administered at intervals of 4–6 weeks (Box 9.7). This produces > 50% reduction in paraprotein concentration in 50% of patients. It is well tolerated, but complete response (CR) is rare and maximum response requires 12 months of treatment. Most patients achieve ‘plateau phase’; the paraprotein remains

stable without further therapy for a median of 12–18 months. During plateau phase, clinical and laboratory parameters are regularly reviewed to identify progression. If a durable plateau is achieved, further treatment with melphalan may induce another plateau. Me- dian survival is about 3 years. Weekly cyclophosphamide is tolerated by most patients who fail to tolerate melphalan due to cytopenia.

Combination chemotherapeutic regimens produce higher re- sponse rates and may improve survival. These may be more effective in younger patients with high tumour loads, but are more toxic in elderly patients. The combination of vincristine, doxorubicin and dexamethasone produces a high response rate (80%), is well tolerated in renal impairment, requires 4–6 months of treatment to achieve maximum response and produces CR in more patients (up to 20%). This treatment is less toxic to haemopoietic progenitors than conventional melphalan or other alkylator-containing regimens and is widely used in patients aged < 65 years in whom autologous stem cell collection is planned.

Patients resistant to first line chemotherapy may respond to tha- lidomide, the response to which is increased by the addition of dexamethasone and/or cyclophosphamide.

High-dose melphalan and autologous stem cell transplantation after initial treatment with Vincristine, Adriamycin (Doxorobicine) and Dexamethasone (VAD) produces a CR in up to 75% of patients and prolongs survival, but is not curative. It has become standard therapy for patients aged < 65 years. CR is usually associated with prolonged survival. Median duration of CR is 2 years and median overall survival is 5 years.

Allogeneic bone marrow transplantation may cure some patients with myeloma, but carries significant treatment-related morbidity and mortality. It is generally restricted to patients aged < 50 years with a compatible sibling. This treatment offers a 33% chance of durable remission and possible cure, 33% chance of survival with recurrence, and 33% risk of transplant-related mortality.

Plateau phase

Most patients achieve a stable partial response with conventional melphalan therapy, with > 50% reduction in the paraprotein (Fig.9.6). In plateau phase, cessation of chemotherapy is not followed by a rise in the paraprotein or further signs of progression for many months (median 12–18 months). After high-dose therapy, the plateau phase may be associated with undetectable paraprotein (CR). Maintenance interferon-α may prolong plateau phase by 6 months, but does not improve survival. Maintenance thalidomide may pro-

Figure 9.6  Natural history of multiple myeloma after melphalan treatment

long response in a significant proportion of patients. Bisphosphonate treatment reduces the rate of further bone damage and may have an additive analgesic effect. 

Disease progression With regular follow-up, serological detection of disease allows therapy to be restarted before new bone damage develops. In many patients, several responses may be re-induced by therapy. Inevitably, myeloma becomes resistant to conventional melphalan. Thalido- mide and/or dexamethasone may achieve further disease control. Low-dose cyclophosphamide can be effective palliative treatment in patients unresponsive to or unable to tolerate thalidomide. Local radiotherapy is useful for sites of bone pain (Fig. 9.7). Thalidomide controls myeloma in over 20% of patients with advanced myeloma and, in combination with dexamethasone, in up to 70% of patients previously treated with chemotherapy. The new agents bortezomib

Figure 9.7  Bone pain from mechanical effects of myeloma damage (as in spine shown here) often requires long-term  treatment with strong analgesia despite response  to chemotherapy

and Revlimid® can achieve further responses as single agents and in combination with chemotherapy or dexamethasone in patients resistant to other agents. Infection is the most common cause of death.

Conditions related to multiple myeloma 

Monoclonal gammopathy of undetermined significance 

MGUS is defined by the presence of a paraprotein in a patient without multiple myeloma (Box 9.8), Waldenström’s macroglobulinaemia (Box 9.9), amyloidosis, lymphoma, or other related disease (Box 9.10). The prevalence of MGUS is 20 times greater than that of multiple myeloma, and the incidence increases with age (1% over 50 years; 3% over 70 years). 

Multiple myeloma, macroglobulinaemia, amyloidosis, or lymphoma ultimately develops in 26% of patients with MGUS, with a cumulative risk of 1–2% per year of follow up (actuarial rate 16% at 10 years). 

Solitary plasmacytoma of bone and extramedullary plasmacytoma 

About 5% of patients have a single bone or soft tissue (extramedullary) lesion with no evidence of disseminated bone marrow involvement. Generally intact paraprotein is undetectable (up to 70% of cases) or present in low concentration. The serum free light chain

assay is abnormal in most patients. Some patients may be cured by radiotherapy (40 cGy). Long-term disease-free survival is achieved in 30% of patients with solitary plasmacytoma of bone and in 60% with extramedullary plasmacytoma. Both should be monitored longterm. Further plasmacytoma or myeloma may develop. MRI may identify bone lesions undetectable by X-ray. Median survival is over 10 years.

Waldenström’s macroglobulinaemia

Waldenström’s macroglobulinaemia is caused by proliferation of lymphoid cells that produce monoclonal IgM. The median age at presentation is 63 years, and over 60% are men. Many clinical features are due to hyperviscosity. Weakness, fatigue and bleeding are common, followed by visual upset, weight loss, recurrent infection, dyspnoea, heart failure and neurological symptoms. Bone pain is rare.

The ESR is greatly elevated. If the plasma viscosity exceeds 4 centipoise (cP), symptoms of hyperviscosity are frequent. All patients have an IgM paraprotein. Monoclonal light chains may be present in the urine. Trephine biopsy often shows extensive infiltration with plasmacytoid lymphocytes.

Symptomatic hyperviscosity requires urgent plasmapheresis. Chlorambucil for 7–14 days every 4 weeks usually reduces bone marrow lymphocytosis, serum IgM concentration and plasma viscosity, and improves symptoms. Median survival is about 5 years. Fludarabine is an effective alternative and is good second line therapy. Rituximab induces responses in up to 75%.

Other related conditions

Chronic lymphocytic leukaemia and low grade non-Hodgkin’s lymphomas may produce small amounts of monoclonal IgG or IgM. This has no prognostic importance. Primary amyloidosis is associated with a low level paraprotein in 85% of cases and abnormal serum free light chains. The ‘heavy chain diseases’ are rare lymphoproliferative disor- ders in which abnormal cells excrete only parts of immunoglobulin heavy chains (γ, α, or µ).