Multiple myeloma is a malignant disease of the BM characterized by clonal expansion of plasma cells. Current guidelines recommend that newly diagnosed transplant-eligible patients with multiple myeloma (NDMMTE) shall undergo several cycles of induction, followed by one or two cycles high-dose melphalan followed by autologous stem cell transfusion (ASCT). With the introduction of new drugs, the prognosis of multiple myeloma patients has considerably improved over time. Currently, induction therapy schemes usually consist of an immunomodulator (thalidomide or lenalidomide), a CD38 targeting antibody, a proteasome inhibitor, and dexamethasone. The induction therapy is then followed by stem cell mobilization and subsequently one or two cycles of high-dose melphalan-chemotherapy based on the initial cytogenetic findings of the malignant plasma cells and the initial stage of the disease. Current guidelines recommend two cycles of high-dose melphalan therapy followed by autologous stem cell transplantation in case of the following initial findings: presence of cytogenetic: (4;14), (14;16), (14;20) translocations or deletion 17p (del 17p), determined by fluorescence in situ hybridization (FISH). In addition, initial stage of R-ISS stage III leads also to the recommendation of two rounds of high-dose melphalan. Furthermore, if the patient does not achieve partial response as described by International Myeloma Working Group (IMWG) recommendations after the first cycles of high-dose melphalan, a second cycle of high-dose melphalan therapy should be administered. Later, patients treated outside clinical trials receive either 2-3 cycles of consolidation therapy and finally take lenalidomide (usually 10 or 15 mg on a daily basis) or proceed directly to a lenalidomide based maintenance therapy till progression or intolerable toxicity. Essentially, all NDMMTE patients undergo at least one cycle of high-dose chemotherapy, which is associated with high morbidity including acute toxicities like cytopenia, infection, and long-term effects such as myelodysplastic disease (MDS) and secondary malignancies and rarely death.

Based on preliminary data and published reports, exposure to high-doses of the genotoxic agent melphalan might render the residual malignant myeloma cells into more aggressive clones, accelerating relapse by potentially altering stroma. Finally, exposure to melphalan is well known to increase the possibility of secondary malignant disease development. In MM patients, high-dose melphalan therapy improves OS and PFS if patients from all risk groups are taken in consideration. Yet, it remains to be answered, whether also low risk patients have an additional benefit from high-dose melphalan therapy or whether for these patients, a less toxic regime would be similarly sufficient with regard to PFS and OS. The challenging question will be whether the effect of melphalan on initial disease control might be outpaced by the negative effects as described above. Hence, the sponsor will explore whether treatment with high-dose melphalan might represent an overtreatment for certain subpopulation myeloma patients. These patients might be adequately treated without need of high-dose melphalan as part of the first line treatment. We, therefore, propose to use a personalized approach to evaluate whether patients with a low-risk profile (R-ISS stage I, characterized by low tumor burden and absence of adverse cytogenetic findings or elevated LDH) and with a gene expression profile indicating a standard risk of relapse (please see below) might be sufficiently treated with an intensified induction course without subsequent upfront high-dose melphalan chemotherapy.

Personalized therapy can be achieved by considering gene expression analysis of the malignant BM cells together with the diagnostic work-up. We have a standardized CE-certified gene expression array, the MMprofilerTM, allowing accurate prediction of high-risk disease based on the SKY92 risk signature, calculating a risk score based on the expression of 92 genes from the malignant plasma cells. Its prognostic superiority has been analyzed in multiple retrospective analyses, totaling over 3,000 MM patients. This enables us to better define the aggressiveness of the disease and NDMMTE patient's 'individual' risk for disease progression within this research initiative and to define appropriate clinical strategies.

As an ultimate goal of this study, the sponsor aims to combine the outcome of gene expression array with the revised international staging system (R-ISS) to achieve a more personalized treatment. For patients with R-ISS stage I and the absence of high-risk disease as determined by the SKY92 signature (GEP-SR), the sponsor proposes a therapeutic approach without a requirement for high-dose chemotherapy as part of first-line therapy. This study would provide personalized treatment for myeloma patients, which could dramatically reduce toxicity, cost of therapy and lower the probability to develop a malignant clone (by about 25%) in all NDMMTE, and simultaneously improving the outcome of overall survival (OS) and progression-free survival (PFS).