Expression-linked and R-ISS-adapted Stratification for First Line Therapy in Multiple Myeloma Patients

Multiple myeloma is a malignant disease of the BM characterized by clonal expansion ofplasma cells. Current guidelines recommend that newly diagnosed transplant‐eligiblepatients with multiple myeloma (NDMMTE) shall undergo several cycles of induction,followed by one or two cycles high‐dose melphalan followed by autologous stem celltransfusion (ASCT). With the introduction of new drugs, the prognosis of multiple myelomapatients has considerably improved over time. Currently, induction therapy schemesusually consist of an immunomodulator (thalidomide or lenalidomide), a CD38 targetingantibody, a proteasome inhibitor, and dexamethasone. The induction therapy is thenfollowed by stem cell mobilization and subsequently one or two cycles of high‐dosemelphalan‐chemotherapy based on the initial cytogenetic findings of the malignant plasmacells and the initial stage of the disease. Current guidelines recommend two cycles ofhigh‐dose melphalan therapy followed by autologous stem cell transplantation in case ofthe following initial findings: presence of cytogenetic: (4;14), (14;16), (14;20)translocations or deletion 17p (del 17p), determined by fluorescence in situhybridization (FISH). In addition, initial stage of R‐ISS stage III leads also to therecommendation of two rounds of high‐dose melphalan. Furthermore, if the patient does notachieve partial response as described by International Myeloma Working Group (IMWG)recommendations after the first cycles of high‐dose melphalan, a second cycle ofhigh‐dose melphalan therapy should be administered. Later, patients treated outsideclinical trials receive either 2‐3 cycles of consolidation therapy and finally takelenalidomide (usually 10 or 15 mg on a daily basis) or proceed directly to a lenalidomidebased maintenance therapy till progression or intolerable toxicity. Essentially, allNDMMTE patients undergo at least one cycle of high‐dose chemotherapy, which is associatedwith high morbidity including acute toxicities like cytopenia, infection, and long‐termeffects such as myelodysplastic disease (MDS) and secondary malignancies and rarelydeath.Based on preliminary data and published reports, exposure to high‐doses of the genotoxicagent melphalan might render the residual malignant myeloma cells into more aggressiveclones, accelerating relapse by potentially altering stroma. Finally, exposure tomelphalan is well known to increase the possibility of secondary malignant diseasedevelopment. In MM patients, high‐dose melphalan therapy improves OS and PFS if patientsfrom all risk groups are taken in consideration. Yet, it remains to be answered, whetheralso low risk patients have an additional benefit from high‐dose melphalan therapy orwhether for these patients, a less toxic regime would be similarly sufficient with regardto PFS and OS. The challenging question will be whether the effect of melphalan oninitial disease control might be outpaced by the negative effects as described above.Hence, the sponsor will explore whether treatment with high‐dose melphalan mightrepresent an overtreatment for certain subpopulation myeloma patients. These patientsmight be adequately treated without need of high‐dose melphalan as part of the first linetreatment. We, therefore, propose to use a personalized approach to evaluate whetherpatients with a low‐risk profile (R‐ISS stage I, characterized by low tumor burden andabsence of adverse cytogenetic findings or elevated LDH) and with a gene expressionprofile indicating a standard risk of relapse (please see below) might be sufficientlytreated with an intensified induction course without subsequent upfront high‐dosemelphalan chemotherapy.Personalized therapy can be achieved by considering gene expression analysis of themalignant BM cells together with the diagnostic work‐up. We have a standardizedCE‐certified gene expression array, the MMprofilerTM, allowing accurate prediction ofhigh‐risk disease based on the SKY92 risk signature, calculating a risk score based onthe expression of 92 genes from the malignant plasma cells. Its prognostic superiorityhas 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 defineappropriate clinical strategies.As an ultimate goal of this study, the sponsor aims to combine the outcome of geneexpression array with the revised international staging system (R‐ISS) to achieve a morepersonalized treatment. For patients with R‐ISS stage I and the absence of high‐riskdisease as determined by the SKY92 signature (GEP‐SR), the sponsor proposes a therapeuticapproach without a requirement for high‐dose chemotherapy as part of first‐line therapy.This study would provide personalized treatment for myeloma patients, which coulddramatically reduce toxicity, cost of therapy and lower the probability to develop amalignant clone (by about 25%) in all NDMMTE, and simultaneously improving the outcome ofoverall survival (OS) and progression‐free survival (PFS).