IMW 2019 | Diagnostic work-up and treatment decisions in multiple myeloma

At the 17^th International Myeloma Workshop, Boston, MA, US, Prof. Shaji Kumar and Prof. Pieter Sonneveld presented the current diagnostic work-up¹ and how prognostic factors can guide treatment² for multiple myeloma (MM), respectively.

The majority of MM cases start from an asymptomatic pre-malignant stage known as monoclonal gammopathy of undetermined significance (MGUS). The intermediate stage between MGUS and clinical progression to MM is referred to as smoldering MM (SMM).

Clinically it is crucial to correctly identify patients in different stages of the disease as this will determine their risk of progression and guide their treatment. To make the right diagnosis, clinicians need to be familiar with the different definitions and criteria for each disease stage.

The current definition of active MM is clonal bone marrow plasma cell (BMPC) percentage ≥10% or biopsy-proven plasmacytoma plus either at least one myeloma defining event or an early progression biomarker. The following are considered as myeloma defining events, which are absent in MGUS and SMM:¹

• C. Hypercalcemia: serum calcium >1 mg/dL higher than the upper limit of normal or >11 mg/dL
• R. Renal insufficiency: creatinine clearance <40mL/min or serum creatinine >2 mg/dL
• A. Anemia: hemoglobin >20 g/L below the lower limit of normal or hemoglobin <100g/L
• B. Bone lesions: osteolytic lesions on x-ray, CT or PET-CT

While biomarkers of early disease progression for patients with active MM are considered as follows:

• Clonal BMPC percentage ≥60%
• Involved: uninvolved serum free light chain ratio ≥100
• ≥1 focal lesion on MRI

With the incorporation of these early relapse biomarkers to the definition of MM, it is now possible to identify patients with a risk of progression ≥80% in a two-year period. According to Prof. Kumar “The change in myeloma diagnostic criteria was probably the most important change in the past 20–30 years in myeloma research because it fundamentally changed the way we think about myeloma”.¹

SMM is defined as an asymptomatic disease with absence of myeloma defining events or amyloidosis and with one of the following diagnostic criteria:¹

• Serum monoclonal protein (IgG or IgA) ≥3 g/dL
• Urinary monoclonal protein ≥ 500 mg/24h
• Clonal BMPC percentage 10-60%

MGUS is defined as an asymptomatic pre-malignant disease matching the following criteria¹:

• Serum monoclonal protein <3 g/dL
• BMPC percentage <10%
• Urinary monoclonal protein <500 mg/24h
• Absence of myeloma defining events or amyloidosis

As can be seen from the above definitions, the progression from MGUS to SMM and into MM is followed by a quantitative increase in the levels of monoclonal protein, BMPCs and end organ damage. Thus, the detection of monoclonal protein and BMPCs, as well as peripheral clonal cells is crucial in the correct diagnosis of the myeloma stage.

But how can clinicians apply all these diagnostic criteria in the clinic?

According to Prof. Kumar, upon clinical suspicion of a patient having monoclonal gammopathy the first step is to screen for a potential ongoing clonal process. The best technique for clonal identification and quantification in 85–90% of patients is serum protein electrophoresis with immunofixation (IFE). In the remaining 10–15% of patients who produce little or incomplete monoclonal protein (immunoglobulin; Ig), the use of a serum-free light chain assay will be able to detect any clonal presence through the κ:λ Ig light chain ratio. Together these two tests can identify approximately 99.5% of patients with underlying clinical gammopathy. If a patient is also suspected to have amyloidosis, an additional test that assesses the levels of monoclonal protein in the urine over 24 hours in combination with IFE should be performed.

Figure 1. Myeloma diagnosis workup steps upon clinical suspicion of monoclonal gammopathy. Based on Prof. Kumar’s and Prof. Sonneveld’s presentations at the 17^th International Myeloma Workshop, Boston, MA, US.

Once an ongoing clonal process has been identified the next step is assessing for end organ damage with complete blood counts, serum creatinine and calcium levels, metabolic panel and/or imaging (PET, CT, MRI). Following that, and upon the diagnosis of MM, the patient needs to be stratified according to their risk of relapse. To date, risk stratification for patients with MM is performed mainly with the help of serum β2 microglobulin/albumin levels, serum lactate dehydrogenase (LDH) levels, and fluorescent in situ hybridization (FISH) on BMPC. From these tests, alone clinicians should be able to assess the revised International Staging System (ISS) stage of the patient.^1,2 Other useful tests for risk stratification include plasma cell proliferation rates and gene expression profiling. For more details in risk stratification models for MM please refer to our comprehensive article here.

With the help of FISH and gene expression profiling genetic abnormalities that are associated with poor patient outcomes can be identified. The most common of those in MM are: t(14;16), t(4;14), t(6;14), t(14;20), del(1p32), gain(1q21), del(17p13) and the TP53 mutation.² Such genetic abnormalities along with certain baseline characteristics (i.e. age, frailty, risk stratification stage etc.) and disease presentation/heterogeneity make up some of the prognostic factors that have been identified in the MM setting and aid in outcome prediction prior to treatment. These in combination with prognostic markers that can be assessed during treatment, like minimal residual disease (MRD), complete response rate, disease transformation, and clonal evolution help clinicians decide on strategies to pursue.

These prognostic factors are fundamental for guiding treatment strategies in patients with MM. This has been validated by multiple clinical trials, including the IFM-2009 study which showed that patients achieving MRD negativity had similar prognosis and response to treatment, regardless of their cytogenetic risk (high versus standard). Another example of this was provided by the EMN02 study, which reported that patients with high-risk cytogenetics or revised ISS II-III have better outcomes with tandem rather than single autologous stem cell transplant. These results were further validated by other phase III trials. To date, due to the use of prognostic markers and risk stratification models, clinicians have been able to identify the treatments that work best for patients with different progression risk. For example, we know that in patients with t(1;14) translocations (high-risk cytogenetics) proteasome inhibitors improve outcomes while thalidomide-, lenalidomide- or pomalidomide-based therapies do not.²

It is evident that by following a good diagnostic work-up (Figure 1) and having a flexible prognostic marker-guided treatment approach, the notion of high-risk MM could be abrogated and the outcomes of patients with myeloma can greatly improve.