Cyclophosphamide etoposide dexamethasone as salvage and bridging therapy in relapsed refractory and extramedullary multiple myeloma.

Patients with relapsed refractory multiple myeloma (RRMM) that are triple-exposed to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies have a poor prognosis. Standard treatment for these patients has not been established. Patients with extramedullary disease or secondary plasma cell leukemia often display high tumor cell proliferation and might therefore be susceptible to chemotherapy. While current regimens are often platinum-based, we present single-center data on 70 patients with RRMM who were treated with cyclophosphamide, etoposide, and dexamethasone (CED) after a median of four lines of therapy. An overall response rate of 52% was achieved after 1-6 cycles, with 23% of patients having a very good partial response. Comparable response rates and survival were observed in patients with extramedullary disease and high-risk cytogenetics. Treatment resulted in non-hematological °III-IV adverse events in 31% of patients. No treatment-related deaths occurred. The median progression-free and overall survival were 6.2 and 10.9 months, respectively. 23% of patients were bridged to autologous stem cell transplantation (ASCT) or chimeric antigen receptor (CAR) T cell therapy. In summary, CED is an effective treatment regimen for RRMM cases with a tolerable safety profile and suitable as bridging therapy to CAR T cell treatment and ASCT.

IgE type multiple myeloma exhibits hypermutated phenotype and tumor reactive T cells.

Multiple myeloma (MM) is a hematological malignancy originating from malignant and clonally expanding plasma cells. MM can be molecularly stratified, and its clonal evolution deciphered based on the Ig heavy and light chains of the respective malignant plasma cell clone. Of all MM subtypes, IgE type MM accounts for only <0.1% of cases and is associated with an aggressive clinical course and consequentially dismal prognosis. In such malignancies, adoptive transfer of autologous lymphocytes specifically targeting presented (neo)epitopes encoded by either somatically mutated or specifically overexpressed genes has resulted in substantial objective clinical regressions even in relapsed/refractory disease. However, there are no data on the genetic and immunological characteristics of this rare and aggressive entity. Here, we comprehensively profiled IgE type kappa MM on a genomic and immune repertoire level by integrating DNA- and single-cell RNA sequencing and comparative profiling against non-IgE type MM samples. We demonstrate distinct pathophysiological mechanisms as well as novel opportunities for targeting IgE type MM. Our data further provides the rationale for patient-individualized neoepitope-targeting cell therapy in high tumor mutation burden MM.