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

Abstract

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.

The Development of IgE Multiple Myeloma Following Treatment for Locally Advanced Prostate Cancer

“…Additionally, 16% of MM cases are characterized by the secretion of FLC, either kappa or lambda, with a subset being non-secretory. Among these, IgE-type MM is particularly rare, accounting for only 0.1% of cases, and is associated with aggressive clinical behavior and a poor prognosis [ 4 ]. Diagnostic protocols typically involve the measurement of IgG, IgA, and IgM, often overlooking IgE and IgD.…”

“…Characteristically, both malignancies present with bone involvement, and although rare, simultaneous diagnosis of prostate cancer and MM has been reported [ 3 ]. IgE MM is particularly rare, accounting for only 0.1% of cases, and has a poor prognosis [ 4 ]. The presence of renal involvement in MM is a poor prognostic factor [ 5 ].…”

Immunoglobulin E (IgE)-Mediated Multiple Myeloma Presenting as Pleural Effusion

“…Similarly, serum free light chain levels and electrophoresis with immunofixation are vital for determining the extent of immunoglobulins involved. Full-body skeletal imaging with CT, PET, or MRI is required for evaluation of the lytic lesions spread throughout the body [ 3 - 5 ]. In our case, the patient underwent extensive investigations, which revealed low hemoglobin levels, deranged serum calcium, and creatinine.…”

“…Since then, only 63 cases have been added to the literature [ 4 ]. As with any other myeloma, IgE-mediated MM can present with symptoms of renal insufficiency and hematological and bone complications [ 5 ]. However, myelomas leading to pleural infiltrations are a rare occurrence (1%) [ 6 ].…”

Development of a Cytotoxic Antibody–Drug Conjugate Targeting Membrane Immunoglobulin E-Positive Cells

“…This may be related to its unique clinical features, such as the potent expansion of plasma cells (plasma cell leukemia, PCL) occurring more commonly than in other types of multiple myeloma (MM) [23] and the presence of cytogenetic abnormalities, such as t (11;14) [24]. Due to the high mutational rate, this condition has been classified as one with a high tumor mutational burden (TMB) [25]. Chemotherapy with immunomodulatory imide drugs, proteasome inhibitors, and immunotherapy using anti-CD38 antibodies were not successful [21].…”