Learning from Cancer Precursors

A bone marrow biopsy confirmed a case of smoldering myeloma: Hematoxylin-eosin staining showed 30% to 50% marrow cellularity (A); immunostaining for CD138 showed 40% CD138 positive cells (B);  Immunostaining for free kappa  light chains (C) and free lambda light chains (D) showed a kappa light chain restriction pattern with almost no lambda-positive plasma cells. (100X magnification)

A bone marrow biopsy confirmed a case of smoldering myeloma: Hematoxylin-eosin staining showed 30% to 50% marrow cellularity (A) ; immunostaining for CD138 showed 40% CD138 positive cells (B); Immunostaining for free kappa light chains (C) and free lambda light chains (D) showed a kappa light chain restriction pattern with almost no lambda-positive plasma cells. (100X magnification)

Cancers that are preceded by distinct nonmalignant lesions provide an opportunity to study cancer progression and develop early detection and intervention strategies. Multiple myeloma—a cancer of the bone marrow that originates in a type of white blood cell called plasma cells—is consistently preceded by one of two nonmalignant precursor diseases: monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma. Ola Landgren, M.D., Ph.D., and Adam Waxman, B.A., of the CCR Medical Oncology Branch recently published a case presentation and review in JAMA that discusses current understanding of myeloma precursor diseases and future opportunities for improving personalized management of patients with these conditions.

The authors present the case of an otherwise healthy 72-year-old man who was diagnosed with MGUS 11 years ago. A recent interim checkup revealed that the disease had progressed to smoldering myeloma. Within a few months of this diagnosis, the patient began experiencing bone pain—a common symptom of multiple myeloma—and the presence of this cancer was confirmed and treatment was begun. This case study illustrates the importance of closely monitoring patients with myeloma precursor diseases; however, management strategies must take into account the fact that the majority of MGUS or smoldering myeloma patients never develop multiple myeloma. Ideally, intensive monitoring would be reserved for high-risk patients while lower-risk patients would undergo a less-intensive monitoring regimen, but this approach depends on the ability to assess risk of individual patients. Enabled by the results of clinical research, recently released guidelines for the first time call for differential monitoring and management of MGUS and smoldering myeloma patients based on laboratory and clinical measurements that are indicative of risk. While this represents a step forward, additional research is needed to further stratify patients so they can be optimally monitored and managed.

Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) showed metabolically active and anatomically visible lesions (arrowheads) in the sacrum and the iliac bone.
Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) showed metabolically active and anatomically visible lesions (arrowheads) in the sacrum and the iliac bone.

Researchers are also working to uncover the molecular events that lead to MGUS and smoldering myeloma and the progression of these precursor diseases to myeloma. Such knowledge may help with risk stratification of patients and identify potential therapeutic targets. It appears that these diseases are the result of several overlapping oncogenetic events within plasma cells and the bone marrow microenvironment. One early event that seems to occur in virtually all precursor and multiple myeloma lesions is dysregulation of a cyclin D gene, a member of a family of genes that controls cell proliferation. Subsequent aberrant changes vary among individuals but several commonly affected genes have been identified. The interaction between plasma cells and their bone marrow microenvironment plays an important role in myeloma and the bone lesions characteristic of the disease. One area of active research is the development of new imaging agents and techniques to facilitate earlier detection of these lesions.

The authors urge prospective research on patients with precursor diseases and extensive molecular analysis in order to address the ongoing challenge of developing individualized risk profiles for these patients. The ability to identify the highest-risk MGUS and smoldering myeloma patients and/or to detect myeloma in its earliest stages, possibly through imaging, could lead to opportunities for earlier intervention.

Summary Posted: 12/2010

Reference

JAMA. 2010 Dec 1;304(21):2397-404 PubMed Link