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Serum Protein Markers of Early Oncogenic Events: A Pre-Diagnostic Study of Multiple Myeloma

Principal Investigator
Name
Ola Landgren
Degrees
-
Institution
NCI, DCEG, GEB
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2005-0017
Initial CDAS Request Approval
Jun 7, 2006
Title
Serum Protein Markers of Early Oncogenic Events: A Pre-Diagnostic Study of Multiple Myeloma
Summary
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder that has a prevalence of 1-3% in the general population. Long-term follow-up of MGUS cases reveals ~1% annual risk of developing multiple myeloma (MM) or related malignancy. The annual incidence of MM is 16,000 cases in the U.S. with a median survival of 3-4 years. It is yet unknown whether MGUS precedes all cases of MM, or if MM can arise de novo without preceding MGUS. Since MM has poor prognosis, delaying/preventing the progression of MGUS assumes great significance. However, given the absence of effective drugs with low long-term toxicity it is currently not possible to launch a MM prevention study among MGUS patients. We also lack understanding of precise features of high-risk MGUS cases for MM progression. The amount and type of the serum monoclonal (M) protein at baseline (i.e. at MGUS diagnosis) are the only known risk-factors for MM progression. Recently, kappa and lambda free light chain (FLC) levels in serum at baseline were found to be independent predictors of MM progression. Importantly, the size and type of the M protein and the serum FLC kappa/lambda ratio at baseline could be combined to predict MM: a low-risk (only 5% risk of MM over 20 years of follow-up) and a high-risk group (58% risk of MM over 20 years of follow-up) were observed. Using pre-diagnostic serum obtained at baseline from MM cases, we will determine the occurrence/absence and pattern of M protein and FLC prior to the diagnosis of MM. The prospective design with availability of repeated biospecimens during the disease free period permits an evaluation of the relationship of MM to abnormal M protein and FLC levels, to their joint effects, and to the trajectory of change over time. No previous study has been able to study these issues. EEMS offers a unique opportunity to examine protein expression patterns involved in the pathogenesis/etiology of MM
Aims

Aims of our study: 1. Determine whether there are MM cases who do not exhibit MGUS prior to the diagnosis of MM. 2. Determine the prevalence and pattern of M protein in serum prior to the diagnosis of MM, based on analyses of pre-diagnostic serum among MM cases. 3. Determine the prevalence and pattern of FLC in serum prior the diagnosis of MM, based on analyses of pre-diagnostic serum among MM cases. 4. Define the proportion of MM that exhibit prior abnormalities in occurrence and pattern of i) M protein, ii) FLC, and iii) models including both M protein and FLC, based on analyses of pre-diagnostic serum among MM cases. Hypotheses to be tested: Does MGUS precede all cases of MM (Type 1) or does MM arise de novo without preceding MGUS (Type 2)? Do <5% of MM patients have an absent MGUS stage (Type 2) prior to MM diagnosis? Does the pattern of M protein in MGUS cases in pre-MM-diagnostic serum predict MM development? Is there an accelerated rise in M protein amount of approximately 1 g/dL per year in the 2-3 years preceding diagnosis of MM? Is the pattern of monoclonal FLC in pre-MM-diagnostic serum a marker of clonal evolution in the neoplastic plasma cell in MGUS, and thus a predictor of MM? Does the FLC ratio exhibit increasingly abnormal values in the 2-3 years preceding diagnosis of MM? Is the combined pattern of M protein and monoclonal FLC in pre-MM-diagnostic serum a marker of clonal evolution in the neoplastic plasma cell in MGUS, and thus a predictor of MM?

Collaborators

Dalsu Baris (NCI)
Neil Caporaso (NCI)
Lynn Goldin (NCI)
Robert Hoover (NCI)
Jerry Katzmann (Mayo Clinic)
Robert Kyle (Mayo Clinic)
Ola Landgren (NCI, DCEG)
S. Vincent Rajkumar (Mayo Clinic)

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