CRO Perspectives: Driving Innovation, Consistency and Reliability in Multiple Myeloma Clinical Trials

Despite advances in treatment options, multiple myeloma incidence rates have increased since 1990. Drug development for this complex disease requires a unique combination of technology and expertise. In this short series of blog posts, we will share perspectives on multiple myeloma testing, technique and innovation that can reduce variability and improve clinical trial data quality.

This is the first of the four-part series that will be published over the next two months, and sets the stage for understanding the current landscape in multiple myeloma clinical trials. Future posts will address the potential benefits of partnering with a centralized multiple myeloma services team, the role of CD138 plasma cell enrichment, and multiple myeloma MRD by flow cytometry, moving from exploratory use to primary and secondary endpoints.

Multiple myeloma: a complex and dynamic disease

Multiple myeloma accounts for approximately 10% of all hematological malignancies, with more than 32,000 new cases diagnosed annually in the United States and 13,000 patients dying of the disease per year.¹ In 2018, almost 160,000 new multiple myeloma cases were recorded globally, consisting of around 90,000 in men and 70,000 in women.² While incidence rates have increased uniformly across the world since 1990, they remain highly variable, with the highest recorded rates in Australasia, North America and Western Europe.³

Multiple myeloma is a complex and dynamic disease, with changes in patients’ cytogenic profiles influencing the disease course. As the profile patterns evolve from the characteristic early trisomic and IgH translocations to secondary changes including gain(1q), del(1p), del(17p), del(13), RAS mutations, and translocations involving MYC, the disease typically becomes more aggressive.^4,5 Thus, it is important for clinicians and researchers to be able to test effectively for these and to be able to understand any predictive and prognostic consequences. Importantly, the incidence of chromosomal abnormalities varies depending on the method of detection.

There are several potential challenges for sponsors conducting multiple myeloma clinical trials, including the production of statistically objective and defensible data and in their alignment with the evolving testing capabilities and associated technological landscape. Furthermore, access to combinable datasets within clinical studies is important to ensure high consistency, efficient reproducibility of testing, and optimized monitoring. These attributes are pivotal to generating reliable insights about the clinical efficacy of a potential new therapy. Our Central Laboratory Services (CLS) has established a dedicated multiple myeloma service and global processes to provide consistency and reduce variability.

Evolution of testing for disease biomarkers

In patients with multiple myeloma, neoplastic plasma cells usually secrete abnormal immunoglobulin (Ig) or Ig fragments in serum and urine.⁶

Key tests in the diagnostic process are serum and/or urine electrophoresis, serum free light chain assay, tissue diagnosis based on either bone marrow or plasmacytoma biopsy, and, although not relevant to the laboratory perspective, skeletal surveys.⁶ Testing of biopsy tissue with fluorescence in situ hybridization (FISH) and other cytogenetic tests, including multiparameter ﬂow cytometry, are required to stratify patient risk and inform patient management.^1,6

This has been reflected in the latest International Myeloma Working Group (IMWG) diagnostic criteria in which the definition of multiple myeloma has evolved from being a disease defined by symptoms to one defined by biomarkers (Fig. 1).⁷ Technologies that help us to gain a better understanding of potential predictive and prognostic biomarkers in multiple myeloma are essential to progressing disease management. Our CLS team offers a comprehensive test menu to support IMWG testing recommendations.

Evolving risk stratification, as tests tell us more

Currently, multiple myeloma patients are generally categorized as having high- or standard- (lower) risk disease.¹³ Those with high-risk disease typically have an overall survival of two years or less, despite the use of novel agents, while low-risk disease is associated with a survival of ten years or more.¹³ This risk stratiﬁcation provides a framework for the testing of therapeutic strategies within clinical trials, including the identification of new and more effective treatment options for high-risk patients.¹³ Treatment of symptomatic, newly diagnosed multiple myeloma (NDMM) is dictated by eligibility for autologous stem cell transplant (ASCT) and risk stratification.¹ Although a large number of prognostic markers have been described in multiple myeloma, none of these completely explains the heterogeneity seen in this disease and attempts have been made to develop systems using several of the prognostic markers to risk stratify patients better.¹³

FISH panels remain the most commonly used test in diagnosing multiple myeloma.⁵ While FISH provides essential information on molecular abnormalities driving the disease, testing has evolved for patients with newly diagnosed disease to have the International Staging System (ISS) stage completed by lactate dehydrogenase (LDH) levels and FISH analysis of del(17p), t(4;14) and t(14;16) in plasma cells, so as to assess risk more accurately (Revised ISS, R-ISS).¹⁴

Multiparameter ﬂow cytometry (MFC) immunophenotyping is also a mainstay technique in the diagnosis and monitoring of most hematological malignancies.¹⁵ Together with the patient’s clinical history, analytic results and morphological evaluation of blood smears, MFC is part of the initial diagnostic work-up, mainly because of its capacity to generally provide conclusive results within a few hours.¹⁵ MFC provides much useful information in multiple myeloma, including in informing predictive and prognostic outcomes, response assessment, and in making a differential diagnosis.

Identifying predictive and prognostic markers

To move beyond the broadly defined clinical category of ‘high-risk multiple myeloma’, which refers to approximately 25% of all newly diagnosed patients, there is a need to understand tumor biology more fully and to rationalize therapy according to the patient’s tumor subtype.¹⁶

FISH can detect deletions, insertions and translocations, but not mutations, and is ideal for use with a low number of probes. Therefore, the amount of information that can be obtained from the complex genome of multiple myeloma using FISH is limited.⁵ New sequencing technologies (next generation sequencing; NGS) that have been introduced and developed in the last decade have the ability to return detailed information on the genome of each patient’s tumor.⁵ Data shows that minimal residual disease (MRD)-negative status, as estimated by flow cytometry or NGS, confers around a 50% relative reduction in the risk of both multiple myeloma progression and mortality.¹⁷ While the IMWG diagnostic criteria in 2016 include MRD as the deepest level of treatment response in multiple myeloma, current studies are ongoing to determine if treatment should be adjusted to reflect MRD status.^1,7 Furthermore, there is a need to determine if MRD negativity can be used as a surrogate endpoint for regulatory approval.¹⁶ Going forward, technological developments are required before the number of tumor genomes sequenced are maximized and provide increased sensitivity, as well as support the identification of novel predictive markers that may guide treatment.¹⁶ For example, ‘liquid biopsy’ approaches detecting circulating cell-free DNA (cfDNA) and/or circulating tumor cells (CTCs) hold promise for further accuracy to progression-free survival (PFS) prediction by defining MRD negativity. Using a combination of techniques is key in describing the main clonal gene lesions in the majority of NDMM patients.⁵

A centralized, consistent, and reliable testing approach

Central Laboratory Services offers a dedicated multiple myeloma team that performs all protein electrophoresis (PEP), immunofixation electrophoresis (IFE), immunoglobulin and free light chain testing using the same instruments and assays throughout its global network of central labs. This allows samples to be processed and tested within prescribed turnaround times. For consistency and reliability, interpretations are provided by a team of highly experienced pathologists located in Indianapolis. This team averages 7,000 interpretations per month. All PEP and IFE reports follow the same format, which is easily fit for data transfer.

To further support pre-analytical requirements, the company has developed a comprehensive and nimble supply chain that efficiently moves specimens from the point of collection to the testing laboratory and provides uniformity in specimen collection, tube type, preservatives and sample storage.

This approach to reducing the variability in multiple myeloma testing is just one example of how a central lab can help assure globally combinable data and high-quality results. The IMWG 2016 criteria state that MRD negativity can be defined by either MFC-based or NGS assay with a complete response plus sensitivity of at least 1 in 100,000 cells.⁷ Our multiple myeloma MRD flow cytometry assay, now available to use for primary and secondary endpoints, has reached IMWG sensitivity requirements. Its results will also be centrally interpreted.

Advances in immunotherapeutics have required further innovations. The HYDRASHIFT 2/4 daratumumab assay (in vitro diagnostic, IVD FDA-approved) is available to help determine whether assay results reflect residual drug antibodies or residual myeloma antibodies. The test allows for in vitro removal of potential IgG Κ M-protein interference to the serum IFE assay due to daratumumab drug administration and quantification of immunoglobulins IgA, IgG and IgM together with IFE interpretation of heavy- and light-chain patterns in serum samples. We are proud to have supported the FDA 510(k) filing for this assay.

As science continues to advance new testing technologies will emerge. We are committed to investing in advanced testing capabilities, so that we can continue to support investigators and remain at the forefront of clinical trial laboratory services.

Key Takeaways:

Challenges for sponsors conducting multiple myeloma clinical trials include developing statistically objective and defensible data, alignment with evolving testing capabilities and gaining access to combinable datasets. These attributes are pivotal to generating reliable insights about the clinical efficacy of a potential new therapy.
Our dedicated myeloma service combines global processes with centralized interpretation to provide consistent and combinable data.
We offer a comprehensive test menu to support IMWG testing recommendations for multiple myeloma.
Our multiple myeloma MRD assay using flow cytometry has reached IMWG sensitivity requirements for primary and secondary endpoints.
Additional technological developments like “liquid biopsy” hold promise for further accuracy to progression-free survival (PFS) prediction

As you navigate the challenging landscape of multiple myeloma clinical trials, you need a trusted partner who can provide consistency and reduce variability. Our Centralized Multiple Myeloma Service can help you set or keep your laboratory testing strategy on the right path.

Connect with us today.

Abbreviations

ASCT: autologous stem cell transplant

cfDNA: cell-free DNA

CTC: circulating tumor cells

DNA: deoxyribonucleic acid

FDA: U.S. Food and Drug Administration

FISH: fluorescence in situ hybridization

IFE: immunofixation electrophoresis

ISS: International Staging System

IVD: in vitro diagnostic

IWMG: International Myeloma Working Group

LDL: low-density lipoprotein

MFC: multiparameter ﬂow cytometry

MRD: minimal residual disease

NDMM: newly diagnosed multiple myeloma

NGS: next generation sequencing

PEP: protein electrophoresis

PFS: progression-free survival

R-ISS: Revised International Staging System

References

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