When we think of advancements in oncology, new and less toxic therapies are what we tend to focus on, for it is these new chemotherapies or drugs that extend and improve patient lives. But laboratory testing also plays a key role in oncology patient management. Without a means to detect biomarkers, pharmaceutical companies would have difficulty proving the efficacy of new drugs. As diagnostic testing improves and becomes more sensitive, pharmaceutical companies can create novel drugs that are more targeted to eliminate “bad” cells, deliver deeper responses than before, reduce toxicity and extend life. At the same time, clinicians can use these diagnostic tests in patient management to improve diagnosis and monitoring of a patient’s disease.
One cancer that has seen a drastic improvement in treatment outcomes over the last two decades is Multiple Myeloma, a cancer of the plasma cells. Patients with Myeloma often present first to their primary care physician with vague symptoms such as unexplained fatigue, bone pain and anemia. An acronym used to remember these non-specific symptoms is CRAB: C - Hypercalcemia, R – Renal involvement, A – Anemia and B- Bone lesions.
Identifying a Multiple Myeloma patient only after the onset of CRAB symptoms essentially means waiting for end-organ damage to take place, which is what produces these symptoms. Twenty years ago, doctors had to make a trade-off: wait for a patient to experience organ damage before treatment or subject the patient earlier to toxic chemotherapy regimens with questionable clinical benefits from early intervention. The advent of new diagnostic tests and techniques such as serum free light chain (sFLC) assays, flow cytometry and imaging have provided additional and more sensitive methods to measure the efficacy of new drug therapies for Myeloma.
What is Myeloma?
Multiple Myeloma is a malignant disease of plasma cells. The plasma cells reside in our bone marrow and are normally responsible for producing antibodies or immunoglobulins that fight against pathogens that enter our body. Antibody molecules are composed of two identical heavy chains and two identical light chains. There are five types of heavy chains: G, A, M, D and E and two types of light chains: kappa and lambda. As with most cancers, the cell grows and divides at an abnormal rate, creating a mass of cells that originate from one plasma cell. Patients who are diagnosed with Multiple Myeloma have their disease typed, e.g. IgA kappa Multiple Myeloma or IgG lambda Multiple Myeloma.
Diagnostic testing for Multiple Myeloma
What tests should doctors order when they suspect Myeloma? Up until the beginning of this century, doctors would usually order Serum Protein Electrophoresis (SPE) to detect Myeloma and Immunofixation Electrophoresis (IFE) to type Myeloma. However, these tests are not very sensitive for detecting disease, and about 12 percent of patients with a malignant plasma cell disease are missed when only these two tests are performed.
This is where sFLC assays come in. These assays are very sensitive and specific tests that measure free antibody light chains in serum. sFLC assays allow performing of serum free light chain testing with SPE and IFE, which is part of the national and international guidelines for the initial diagnostic workup of Myeloma. This combination of tests increases the clinical sensitivity from 88 percent (for SPE alone) to 100 percent for diagnosing Myeloma.1
What are sFLC assays?
The sFLC assays are a pair of automated tests that measure the concentration of antibody light chains in serum that are not bound to the heavy chains. The tests are run separately to detect free kappa and free lambda antibody light chains. Two numeric values are obtained, as well as a ratio of kappa/lambda. Each of the three values is important to clinicians.
Healthy plasma cells produce 40 percent more light chains than we need to make intact antibodies, thus even normal individuals have a small concentration of excess free light chains circulating in the bloodstream (i.e. serum). It is the ability to measure antibody sFLC concentrations not only at abnormal levels but also at normal levels that make sFLC assays valuable biomarkers for monitoring patients with malignant plasma cell disease. sFLC assays can provide clinicians with an indication of how the cancer is responding to therapy, if it is progressing or if it is in remission.
Evolution of Myeloma testing
Twenty years ago, when a patient was diagnosed with Myeloma the treatment options were so toxic that early detection was not advantageous. When Freelite* assays from Binding Site were FDA cleared in 2001, they were the first tests of their kind with improved sensitivity and specificity that traditional tests did not offer.
In 2009 the International Myeloma Working Group (IMWG) and National Comprehensive Cancer Network (NCCN) updated their guidelines to include sFLC testing in the initial diagnostic workup of Myeloma.2 The IMWG mentioned the assays by Binding Site by name in these guidelines.3
In 2014, a further update to the guidelines was made. This time CRAB symptoms were no longer required to make a Myeloma diagnosis if an individual had ≥10 percent clonal plasma cells detected in the bone marrow and at least one Myeloma Defining Event (MDE). An MDE was defined as an involved: uninvolved sFLC ratio ≥00 as defined by a Freelite test; evidence of end-stage organ damage that can be attributed to the underlying plasma cell disorder (i.e. CRAB symptoms); clonal bone marrow plasma cell percentage ≥60 percent; or >1 focal lesions on MRI studies.4
Also, with the recent advent of better and less toxic therapies, it became advantageous to pick up Myeloma earlier – before CRAB symptoms.4 Now with much less toxic treatment options, early detection of Myeloma can improve outcomes of patients.
Today’s opportunities for improved patient care
Myeloma can present with non-specific symptoms such as unexplained back or bone pain, anemia, fatigue, or recurring infections, which make it difficult to diagnose early. Patients typically visit their primary care or internal medicine clinicians when they experience such symptoms. Running sFLC assays with SPE and IFE will pick up 100 percent of Myeloma diagnoses,1 and help ensure that patients are referred to a hematologist expeditiously.
However, in 2018, Genzen et al. published a study that showed only 6 percent of the initial diagnostic workups for monoclonal gammopathies followed the NCCN guidelines.5 When the appropriate tests are not run upfront, it can take six months or longer for patients to be diagnosed; by this time, patients are usually experiencing more severe symptoms such as kidney issues or bone fractures. Laboratories can take a leadership role in improving patient care by educating clinicians on which tests to order to be compliant with existing guidelines.
The future of testing for Multiple Myeloma
As Myeloma patients go into deeper remissions from the use of improved therapies, they need to continue to be monitored to ensure that the cancer does not come back. It is important that diagnostic tests with improved sensitivity be available to detect even small levels of minimal residual disease (MRD). As diagnostic testing continues to advance and as new technology becomes available, this depth of response can be measured more accurately.
Binding Site is developing novel tests to improve the identification and accurate measurement of monoclonal proteins using mass spectrometry. The new assay is designed to allow the monitoring of monoclonal proteins with increased sensitivity and to enable clinicians to monitor their patients’ depth of response even more closely. It is these types of innovations that will continue to extend patient lives.
References:
- Katzmann et al. Clin Chem 2009; 55: 1517-22
- Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Multiple Myeloma V.2.2020, 2019. © National Comprehensive Cancer Network, Inc 2020. All rights reserved. Accessed February 2, 2020.
- Dispenzieri et al. Leukemia 2009; 23: 215-24
- Rajkumar et al. Lancet Oncol 2014; 15: e538-49
- Genzen et al. Arch Pathol Lab Med 2018; 142: 5-15
- Freelite * Serum assays from Binding Site
*Freelite® is a registered trademark of The Binding Site Group Ltd (Birmingham, UK) in certain countries.
