Risk Stratification in Multiple Myeloma

Review Article

Ann Hematol Oncol. 2015;2(6): 1046.

Risk Stratification in Multiple Myeloma

Rajshekhar C and Shaji K*

Division of Hematology, Mayo Clinic, USA

*Corresponding author: Shaji Kumar, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55906, USA

Received: March 30, 2015; Accepted: June 05, 2015; Published: June 10, 2015


Multiple myeloma (MM) is a malignant plasma cell disorder, characterized by bone marrow infiltration with clonal plasma cells (PCs), and affects nearly 20,000 patients in United States (US) each year. Revised International Myeloma Working Group (IMWG) diagnostic criteria for MM has included biomarkers, namely, clonal bone marrow PCs = 60%, serum free light chain ratio = 100 and = 1 focal lesion on magnetic resonance imaging (MRI) in addition to traditional CRAB (Hypercalcemia, Renal insufficiency, Anemia and Bone lesions) for defining MM. In the era of risk-adapted therapy with novel agents, importance of comprehensive risk stratification models, including a conglomerate of host factors, tumor factors and factors arising due to host-tumor interaction, is paramount. In this review, we have discussed host factors, including patient demographics and performance status, tumor factors including, albumin, C-reactive protein, lactate dehydrogenase, serum free light chain assay, complete blood count, bone marrow morphology, cytogenetics, gene expression profiling, immunophenotyping and proliferative capacity and factors related to tumor-host interaction, including β-2 microglobulin and renal function, which are important components of risk stratification. Furthermore, response to therapy, including impact of complete remission, early relapse and minimal residual disease after therapy have been shown to predict survival in MM. Clinical application of these components have been reflected in novel risk stratification models, including Mayo stratification of myeloma and risk adapted therapy (mSMART), IMWG and Intergroupe Francophone du Myélome (IFM), with further studies on identifying molecular characteristics of PCs in MM currently underway.

Keywords: Proteasome inhibition; Relapsed myeloma; Stratification


Multiple myeloma (MM) is a malignant plasma cell disorder, accounting for 10% of all hematologic malignancies [1]. The diagnosis of MM requires either 10% or more clonal plasma cells in bone marrow along with evidence of end-organ damage or 60% or more clonal plasma cells in the absence of end-organ damage [2]. Historically, the first case of MM was documented by Solly in 1844 in a 39 year old female presenting with fatigue and multiple fractures [3]. Cardinal clinical manifestations of MM attributable to the plasma cell clone are usually described using the acronym CRAB- Calcium elevation, Renal insufficiency, Anemia and Bone disease [4]. Estimated number of new cases of MM in 2014 in the United States (US) was 24,050 and estimated number of deaths being 11,090 [5]. The average ageadjusted incidence of MM in the US is approximately 4 per 100,000, with median age at diagnosis being 65 years [2]. The annual incidence in Europe is 4.5-6 per 100,000 with median age at diagnosis being 65-70 years [6]. In a study conducted in US on the incidence of MM in Olmsted County, Minnesota, the overall annual incidence rate was found to be pretty stable in the last 6 decades [7]. A population based study in Sweden has shown a temporal improvement in median Overall Survival (OS) from 24.3 to 56.3 months in younger (= 65 years) patients with MM diagnosed from 1950 to 2005 [8]. Another larger study using Surveillance, Epidemiology, and End Results (SEER) database showed improvement in five-year Relative Survival rate (RS) during the time period 2004-2011 compared to 1991-2002 in all age-groups, implicating improved survival after approval of novel proteasome inhibitor bortezomib in 2003 [9]. Among patients with relapsed MM after Stem Cell Transplantation (SCT), those relapsing after year 2000 were found to have better OS compared to those before 2000 [10]. All these studies point towards improving survival in MM with advent of novel therapeutic agents in recent decades. Since riskadapted therapy is the standard of care in MM currently [2], the need for a comprehensive risk stratification model for prognostication and assisting with therapeutic decision-making is paramount.

MM is characterized by clinical and biological heterogeneity, with recent genetic analyses identifying subgroups with predictable prognosis across different types of treatment [11]. Various immunoglobulin gene translocations and chromosomal anomalies have been identified in addition to traditional prognostic factors like β-2 microglobulin, which has necessitated chromosomal studies to be conducted for front-line risk stratification and therapeutic consideration in MM [12,13]. Furthermore, data show that novel therapeutic agents like proteasome inhibitors and immunomodulators are more effective than traditional chemotherapy in patients with high-risk cytogenetics [14], advocating the use of such agents for induction prior to SCT in high-risk transplant-eligible patients [2,6]. Due to such heterogeneity in pathogenesis and response to therapy, selection of a risk-stratification tool depends upon the context of host and tumor factors, host-tumor interactions and therapeutic considerations [15]. The future of myeloma therapy lies in precision medicine due to improved understanding of MM cell biology and will require utilization of new relevant prognostic factors [16].

This comprehensive review outlines prognostic markers inherent to patients (host factors), the tumor (myeloma-related factors) and host-tumor interaction (Figure 1). The clinical value of these markers in the era of novel therapeutic agents and transplantation has been described along with current clinical application of evidence-based strategies in prognostication and individualizing treatment.

Citation: Rajshekhar C and Shaji K. Risk Stratification in Multiple Myeloma. Ann Hematol Oncol. 2015;2(6): 1046. ISSN : 2375-7965