Drug resistance and minimal residual disease in multiple myeloma.

Great progress has been made in improving survival in multiple myeloma (MM) patients over the last 30 years. New drugs have been introduced and complete responses are frequently seen. However, the majority of MM patients do experience a relapse at a variable time after treatment, and ultimately the disease becomes drug-resistant following therapies. Recently, minimal residual disease (MRD) detection has been introduced in clinical trials utilizing novel therapeutic agents to measure the depth of response. MRD can be considered as a surrogate for both progression-free and overall survival. In this perspective, the persistence of a residual therapy-resistant myeloma plasma cell clone can be associated with inferior survivals. The present review gives an overview of drug resistance in MM, i.e., mutation of ß5 subunit of the proteasome; upregulation of pumps of efflux; heat shock protein induction for proteasome inhibitors; downregulation of CRBN expression; deregulation of IRF4 expression; mutation of CRBN, IKZF1, and IKZF3 for immunomodulatory drugs and decreased target expression; complement protein increase; sBCMA increase; and BCMA down expression for monoclonal antibodies. Multicolor flow cytometry, or next-generation flow, and next-generation sequencing are currently the techniques available to measure MRD with sensitivity at 10-5. Sustained MRD negativity is related to prolonged survival, and it is evaluated in all recent clinical trials as a surrogate of drug efficacy.

Long-term CR Multiple Myeloma Patients Show Cured or MGUS-like Minimal Residual Disease Pattern by Next Generation Flow.

BACKGROUND: In the era of novel agents, many multiple myeloma patients can achieve a complete remission, but most of them relapse, and minimal residual disease detection can play a crucial role. Next-generation flow (NGF) can detect monoclonal plasma cells with a sensitivity of 10-6. Little is known about long-term remission patients (> 2 years) and in particular, if more sensitive techniques such as NGF can still detect minimal disease in those patients. OBJECTIVE: Aim of the study was to analyze patients with MM in response to NGF at > 2 years of sustained remission after several treatments. METHODS: MRD was studied by NGF in bone marrow aspirates according to Euroflow Consortium indications. RESULTS: 62 patients with sustained CR at >2 years were studied, MRD+ status was detected at a threshold cut-off of 10-6 in 32/62 (52%); 4/15 (27%) patients were MRD positive at >5 years of remission and they displayed a prevalence of normal vs abnormal monoclonal plasma cell immune-phenotype (MGUS-like). CONCLUSION: NGF is a powerful technique to detect MRD. Myeloma patients in prolonged sustained complete remission can show in high percentage an MRD negative status or MGUS like.

Minimal Residual Disease in Multiple Myeloma: State of the Art and Applications in Clinical Practice.

Novel drugs have revolutionized multiple myeloma therapy in the last 20 years, with median survival that has doubled to up to 8-10 years. The introduction of therapeutic strategies, such as consolidation and maintenance after autologous stem cell transplants, has also ameliorated clinical results. The goal of modern therapies is becoming not only complete remission, but also the deepest possible remission. In this context, the evaluation of minimal residual disease by techniques such as next-generation sequencing (NGS) and next-generation flow (NGF) is becoming part of all new clinical trials that test drug efficacy. This review focuses on minimal residual disease approaches in clinical trials, with particular attention to real-world practices.