Minimal residual disease in Myeloma: Application for clinical care and new drug registration

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow–based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy–based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid–based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes

Multiple myeloma epidemiology and survival: A unique malignancy

Multiple myeloma (MM), although a rare disease, is the second most common hematologic malignancy. It is found in the spectrum of plasma cell dyscrasias, which begins with monoclonal gammopathy of unknown significance (MGUS) to overt plasma cell leukemia and extramedullary myeloma. MM is associated with significant morbidity due to its end-organ destruction. It is a disease of the older population and its incidence in the African American population is twice that of the European American population. Improvements in the treatment of MM in the past couple of decades, beginning with the use of autologous stem cell transplantation followed by availability of novel treatments such as immunomodulatory drugs (ImIDs) and proteasome inhibitors (PIs) has transformed the natural history of the disease leading to longer survival times. Advancements in the diagnosis, monitoring, and treatment of MM are of the utmost importance as the general population lives longer due to other improvements in health care. The recent introduction of novel therapies has been paralleled by advancements in the monitoring of MM, namely, by the availability exquisitely sensitive techniques in detecting minimal residual disease. As drug development and technology continues to improve, it will be important to design rationale clinical trials enrolling patient populations that represent the overall population, including racial minorities and the elderly, so that trial results can be appropriately extrapolated. Herein, the changing epidemiology, improvements in survival, and the health disparity observed in important subgroups of MM are reviewed

T cell redirecting bispecific antibodies for multiple myeloma: emerging therapeutic strategies in a changing treatment landscape

In recent years, the treatment landscape of multiple myeloma has continued to evolve with the introduction of novel immunotherapies. This progress has translated to improved overall survival for patients, but an unmet need remains in the heavily pretreated and high-risk subsets of patients. Emerging immunotherapies in the form of CAR-T cell therapies have been approved for multiple myeloma. However, CAR-T cell therapy has logistical limitations and there is a need for immunotherapies that are readily available, safe, and effective in RRMM. Currently, pending approval, there are many "off the shelf" bispecific antibodies being developed that target BCMA, GPRC5D, FcRH5 and other cell surface proteins. Preliminary efficacy data has suggested that these bispecific antibody therapies have similar response rates (∼50-80%) in heavily pretreated patients. Similarly, to CAR-T cell therapy, cytokine release syndrome and immune effector cell associated neurotoxicity syndrome are adverse events of key interest and incidence range from ∼40 to 90% and 3 to 20%, respectively. In this review, we highlight the various bispecific immunotherapies under development in the treatment of multiple myeloma with a focus on the data from clinical phase I and II studies

A look backward and forward in the regulatory and treatment history of multiple myeloma: Approval of novel-novel agents, new drug development, and longer patient survival

The past decade has seen significant advances in our understanding and treatment of multiple myeloma (MM) and its precursor diseases. These advances include gains in knowledge of the underlying pathobiology including molecular and cellular prognostic factors for disease progression. In parallel we have witnessed the availability of novel therapeutics. Together these advances have translated into improvements in long-term clinical benefit and survival in MM. Indeed, it has been shown that patients diagnosed in the last decade have experienced almost doubling of median survival time. We aim to review and give further insight into drug development and novel drug approvals that have revolutionized the treatment of MM

Advance Multicenter Clinical Trial: MRD-Driven Therapy in Newly Diagnosed Multiple Myeloma Patients

Background and Significance: The use of modern combination therapy in newly diagnosed multiple myeloma patients delivers deep and durable treatment responses in large numbers of patients. Recently, the IFM 2009 and DFCI randomized studies for newly diagnosed patients have shown that MRD negativity 10^-6 translates into similar progression-free survival (PFS) and overall survival (OS) outcomes when comparing patients treated across treatment arms irrespective of receiving early transplant. Delayed transplant does not shorten OS. In the current ADVANCE study (NCT04268498), patients are randomly assigned to receive 8 cycles of carfilzomib-lenalidomide-dexamethasone with or without daratumumab (i.e. Dara-KRd versus KRd). High-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT) is only offered to patients who remain MRD positive after 8 cycles with all patients transitioning to maintenance lenalidomide. MRD negativity is the primary end-point. PFS, event-free survival (EFS), sustained MRD negativity, OS and correlative assays are part of the secondary endpoints. Unique features of this large study include the full integration of whole-genome sequencing, single cell sequencing, MRD tracking, and its multi-academic center design. Study Design and Methods: A total of 308 newly diagnosed multiple myeloma patients will be randomized between Dara-KRd or KRd. Enrolled patients are encouraged to collect peripheral stem cells after 4-6 cycles of therapy. For patients who collect stem cells, afterwards they will continue with combination therapy (total of 8 cycles). After completion of cycle 8, patients will be evaluated for MRD status (Adaptive ClonoSeq). HDM-ASCT is only offered to patients who are MRD positive after cycles 8. For patients who are MRD-negative, per study protocol, they transition to maintenance therapy with lenalidomide 10 mg daily days 1-21 on a 28-day cycle for a total of 2 years and thereafter continue per physician standard of care. Per protocol, sustained MRD status will be monitored annually while on maintenance. Patients will remain monitored long-term for PFS, EFS, and OS. Key eligibility includes confirmation of NDMM per the International Working Group Criteria (IMWG) diagnostic criteria with evaluable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, adequate organ function, <1 cycle of prior MM treatment; related malignancies, prior anti-CD38 treatment, significant comorbidities including severe asthma, COPD, hypertension, diabetes, hepatitis, HIV, and cardiac ejection fraction <40% are excluded. Assuming an MRD negativity rate of 34% (KRd) vs 50% (D-KRd), a total of 306 patients will be randomized 1:1 to each arm (153 per arm). The comparison will have 80% power using a two-sided alpha level of 0.05. Current Status: The ADVANCE trial (NCT04268498) is currently open to enrollment withover 57% of the planned patients have already been enrolled. In this multicenter investigator-initiated study, the Sylvester Myeloma Institute at the University of Miami is the Lead Investigator and Study Coordinating site with several other sites across the US already either enrolling or close to activation at this time. Early data confirm and expand our findings from the MANHATTAN trial (JAMA Onc, 2021). Detailed information on feasibility will be presented at the meeting. Conclusions: The large multicenter, randomized ADVANCE study is open for newly diagnosed multiple myeloma patients across the US. Using MRD testing after completed combination therapy, patients will only be offered HDM-ASCT if they remain MRD-positive after 8 cycles; else, they will keep the collected stem cells (delayed transplant) and move forward with maintenance therapy. The aim of this translational effort is to define the underlying biology of sustained MRD negativity in multiple myeloma patients

Diagnosed with myeloma before 40

In this issue of Blood, Caulier et al report clinical epidemiology data from a retrospective cohort of 214 patients diagnosed with multiple myeloma in France before the age of 40.1 The study describes baseline disease characteristics and prognostic factors of overall survival in these patients