Updates on Multiple Myeloma Diagnosis and Treatment Strategies

Sonia Vallet, MD, and Klaus Podar, MD, PhD
Published: Tuesday, Aug 23, 2011


Multiple myeloma (MM) is a clonal plasma cell malignancy with a highly heterogeneous genetic background, characterized by bone marrow (BM) plasmacytosis, production of monoclonal proteins, osteolytic bone lesions, hypercalcemia, renal disease, anemia, and immunodeficiency. Several advances in diagnosis and treatment have been achieved during the past years. More sensitive imaging techniques, cytogenetic evaluations, and novel assays to measure paraprotein levels help to discern monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) from MM, and thereby enable the selection of patients who need treatment. Progress in our understanding of MM pathogenesis has led to the identification of new therapeutic targets. The introduction of derived agents, including thalidomide, bortezomib, and lenalidomide, into conventional chemotherapeutic regimens has fundamentally changed treatment strategies in MM during the last decade and steadily improved patient outcome.

Multiple myeloma (MM) is the second most common hematologic malignancy in the United States. Age-adjusted incidence and mortality rates of MM in the United States are 5.6 and 3.6 cases per 100,000 persons per year, respectively.1-3 MM is a disorder of terminally differentiated B lymphocytes, called plasma cells, that are preferentially located within the bone marrow and secrete monoclonal immunoglobulin (IgG in about 60%, and IgA in about 20%) or light chains (κ or λ). Deregulated tumor cell growth and paraprotein production induce myelosuppression, bone destruction and hypercalcemia, immunodeficiency, hyperviscosity, and renal failure. Other plasma cell disorders include monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and solitary plasmacytoma. MGUS and SMM, also referred to as indolent or asymptomatic MM, are characterized by the absence of symptoms and require regular follow-up but no treatment. The rare solitary plasmacytoma occurs as a single lesion and benefits from local therapies. Recent advances in the diagnostic workup helped to distinguish these forms of disease from symptomatic MM, and thereby helped to select patients who needed treatment. Improvements have been achieved also by the identification of tumor microenvironment-directed agents, including thalidomide, bortezomib, and lenalidomide. Their inclusion in current MM treatment regimens has extended median overall survival (OS) from 3 to at least 7 years, especially in the younger patient population.4 In addition, novel effective supportive therapies have improved patients’ quality of life.

Despite therapeutic advances, MM ultimately relapses and remains an incurable disease. Current research goals aim to further increase our knowledge, to identify additional targeted therapies, and to define patient-specific sequence and combination regimens in order to reduce adverse effects and improve response rates. Here, we summarize recent advances in both diagnosis and treatment strategies.

Table 1. Staging Systems in Multiple Myeloma
Durie-Salmon Staging
System 5
Stage I, all of the following:
- Hemoglobin value >10 g/dL
- Serum calcium value normal or ≤12 mg/dL
- Bone x-ray, normal bone structure, or solitary bone plasmacytoma only
- Low M-component production rate (IgG value <5 g/dL; IgA value <3 g/dL Bence Jones protein <4 g/24 h)
Stage II: Neither stage I nor stage III
Stage III: one or more of the following:
- Hemoglobin value <8.5 g/dL
- Serum calcium value >12 mg/dL
- Advanced lytic bone lesions (>3)
- High M-component production rate (IgG value >7 g/dL; IgA value >5 g/dL, Bence Jones protein >12 g/24 h).
Patients are further subclassified in either A or B:
A: Relatively normal renal function (serum creatinine value <2.0 mg/dL)
B: Abnormal renal function (serum creatinine value ≥2.0 mg/dL)
New International
Staging System (ISS)
for MM 6
Stage I: β-2 microglobulin <3.5 mg/L and albumin ≥3.5 g/dL
Stage II: Not stage I or III
Stage III: β-2 microglobulin ≥5.5 mg/L


Plasma cell disorders are characterized by bone marrow infiltrate of monoclonal tumor cells and paraprotein production. MGUS is defined by the absence of symptoms and a lower grade of bone marrow infiltration compared to SMM and MM (MGUS: <30g/L paraprotein, BM clonal plasma cells <10%). MM in contrast to SMM presents with symptoms related to calcium levels above 10.5 mg/dL, renal impairment with creatinine levels >2 mg/dL, anemia with Hb <10 g/dL, and/or bone disease (CRAB-criteria). MM requires prompt antitumor and supportive treatment. MGUS and SMM are managed by regular clinical follow-up and serum and/or urine paraprotein determination. In order to predict survival and choose the most appropriate treatment, patients are categorized according to the Durie-Salmon Staging System and the International Staging System (ISS) (Table 1).5,6 Advances in cytogenetic analysis pro-vides additional prognostic features. The recommended current diagnostic workup of MM patients is summarized in Table 2.7-9

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