Minimal Residual Disease (MRD) in Newly Diagnosed transplant ineligible MM patients treated with dara combinations in the Italian community population (Real MM study)

Rationale Multiple Myeloma (MM) is characterized by gradual progression of disease from Monoclonal Gammopathy of Undetermined Significance (MGUS), Smoldering Multiple Myeloma (SMM) to active MM and Plasma Cell Leukemia (PCL) and Extramedullary Disease (EMD). Increasingly specific treatments for disease stages will be developed and treatment choices will be made based on disease biology and patient-specific factors. Standard prognostic factors in multiple myeloma include (R-)ISS stage, cytogenetic abnormalities by FISH, molecular profile by GEP, and organ dysfunction. In addition, circulating tumor cells, mutational profile and (immune) microenvironment carry prognostic information. Different therapeutic modalities and novel drugs including immune therapy may confer specific prognostic impact. The exact role of most prognostic variables in different disease stages is not exactly known. A recently introduced prognostic factor for MM is achievement of Minimal Residual Disease (MRD) negativity in the bone marrow (BM). Two techniques are available to test MRD, namely next generation flow cytometry (NGF) and next generation sequencing (NGS). Both techniques can detect residual myeloma cells at a sensitivity up to 10-6. Concordance between these techniques is good, but so far only NGS has been taken into consideration by FDA. In order to allow for sequential testing of MRD by NGS, a BM sample, collected at the time of diagnosis, is required to characterize the patient specific MM clone. MRD-negativity after induction, as well as after High-Dose Therapy/Autologous Stem Cell Transplantation (HDT/ASCT) and after consolidation, has been shown to predict for Progression-Free Survival (PFS) and Overall Survival (OS) in several trials in Newly Diagnosed Multiple Myeloma patients (NDMM). Moreover, the best outcomes are associated with sustained-MRD negativity, defined as stable negativity for at least one year. With the introduction of novel treatment modalities, continuous monitoring of disease and response status becomes very relevant for early read-out of studies and for timely assessment of response and progression. In order to perform MRD measurements during each stage of the disease and at different phases of treatment, it will be necessary to collect a baseline tumor sample from the BM of MM patients. Collection of peripheral blood samples and extramedullary disease (EMD) tissues could allow the identification of spatial heterogeneity in the biology of MM cells and to explore new MRD measurement techniques. Comparison of biological disease characteristics at diagnosis or progression/relapse will also require the availability of upfront tumor specimens. In addition, samples obtained prior to any therapy are needed from patients who are referred for clinical trials for the purpose of identifying FISH and mutational profiles. Outside the context of clinical trials MRD assessment has not (yet) been widely implemented for various reasons, including the cost of NGS and the lack of uniform guidelines. The European Myeloma Network EMN is an international platform for clinical trials and consensus projects. EMN considers the need for a prospective biobank project for the following aims: - To create an EMN biobank of newly diagnosed MM samples obtained from patients in hospitals in countries that participate in EMN trials; these patients may be included in upfront trials or in maintenance or relapse trials later during their disease. - To collect, purify and store samples for the biobank in a proper way, such that all required diagnostic tests can be performed. Samples from bone marrow or peripheral blood will be isolated and stored, including cells, plasma, serum, DNA and RNA. The anticipated format and size of the biobank will be 6000 patients, to be collected over a period of 5 years per patient. Samples may be stored in the central laboratories of EMN or the individual EMN partners until use.