ESH MM 2018 | Assessment of response in multiple myeloma

The MM Hub attended the 4^th International Conference in Multiple Myeloma, organized by the European School of Haematology (ESH), which took place at the beginning of October in Mandelieu, France. During the meeting, world experts in the field of multiple myeloma (MM) covered diverse topics during a session focused on the methods available for assessing the response to treatment.

The session was chaired by Shaji Kumar from the Mayo Clinic in Rochester, US who talked about the use of flow cytometry (FC) as an assessment response tool.¹ Although FC is a poor technique for quantitating plasma cell percentage in the bone marrow, it is a very reliable tool for characterizing these cells. FC is more sensitive than conventional methods and allows precise measurement of residual plasma cells, also known as minimal residual disease (MRD), which in the future may be used as a surrogate end-point for progression-free survival (PFS). FC is a common technology available in many laboratories worldwide with several advantages: there are many experienced users; it can potentially become less expensive; it provides a fast turn-around, which is valuable during clinical trial enrolment. However, FC has some drawbacks, which include: variability, mainly due to the time interval between sample collection and processing; sensitivity, it usually detects residual plasma cells at 10^-5 while next generation sequencing detects plasma cells at 10^-6; subjectivity of the observer. FC provides the additional advantage that not only can be used to evaluate tumorous cells but also to assess the non-tumor environment, which may provide useful information about disease progression.

Nikhil C. Munshi from the Dana Farber Cancer Institute, Boston, US talked about new (rather than next) generation sequencing (NGS) as an assessment method in MM.² The current status of NGS allows targeted sequencing (seq), which is quick, easy, requires small amounts of starting material, and is less expensive than in the past. NGS provides insight into the heterogeneity of the MM genome and can be applied for:

• Targeted seq
• Deep seq of specific genes such as IgH and Igkappa
• UTR (untranslated region) sequencing
• Cell-free DNA and single circulating cell seq
• Seq of myeloma-specific chromatin signatures
• RNA-seq
• Single-cell RNA-seq
• Drop seq

Drop seq offers the possibility of sequencing mRNA transcripts from droplets of single cells. Each cell compartmentalizes in a tube-like microfluidic device where it is being coded with unique barcoded primers. The method allows seq of around 10,000 cells per day.

Elena Zamagni from the University of Bologna, Bologna, Italy, talked about the importance of evaluating the metabolic response to treatment outside the bone marrow (BM) and the use of ¹⁸F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with low dose computed tomography (CT) (PET/CT).³ She highlighted that imaging is essential because it assists detection of morphological abnormalities that reside outside the bone marrow. As well as a temporal heterogeneity, which is reflected by gradual changes in the genome, MM presents with a spatial heterogeneity that can be detected with imaging techniques. Although 65-80% of patients achieve complete suppression of ¹⁸F-FDG uptake after first-line treatment, there is a group of patients with risk of persistence after treatment who present with extramedullary disease (EMD). PET/CT is a powerful technique for assessing tumor metabolic activity and evaluating response to treatment; however, both false-positive and false-negative results have been described. False-negative results are observed in cases of hyperglycemia or recent administration of high-dose steroids and have been recently described in patients with mutations in hexokinase-2. To overcome sensitivity and specificity caveats, new biomarkers are being generated, including ¹¹C-choline and ¹¹C-methionine. These biomarkers are not approved yet and there are no available trials showing their clinical value in MM. Efforts are currently taking place to standardize the ¹⁸F-FDG-PET/CT scans using a descriptive platform, which is based on the Deauville criteria applied in lymphoma, and a thorough analysis of results from prospective clinical trials.

Evangelos Terpos from the University of Athens Medical School, Athens, Greece, finalized the session with a talk on magnetic resonance imaging (MRI) as an additional imaging tool for assessing response to treatment in MM.⁴ MRI has the advantage over PET/CT scan that it detects both focal and diffuse lesions, while PET/CT has low sensitivity for identifying diffuse lesions. However, the IMAJEM trial revealed that although both MRI and PET/CT are equally valid tools for detecting bone lesions at diagnosis, only PET/CT has strong prognostic power before maintenance. An imaging technique that derives from MRI is the diffusion-weighted imaging (DWI). DWI relies on measuring the random motion of water molecules in biological tissues using a parameter known as apparent diffusion co-efficient (ADC). The value of ADC increases in necrotic focal lesions and decreases in fatty marrow conversion. Different studies suggest that this new imaging technique can improve the results of MRI and become a strong prognostic tool for MM. Finally, whole-body MRI (WBMRI) is a powerful imaging technique but there are very few available data that provide direct comparison with PET/CT scan. In contrast to a PET/CT scan, WBMRI is not a radioactive technique; interpretation of results relies on accurate assessment by radiologists.