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Accelerated single cell seeding in relapsed multiple myeloma.

ABSTRACT: Multiple myeloma (MM) progression is characterized by the seeding of cancer cells in different anatomic sites. To characterize this evolutionary process, we interrogated, by whole genome sequencing, 25 samples collected at autopsy from 4 patients with relapsed MM and an additional set of 125 whole exomes collected from 51 patients. Mutational signatures analysis showed how cytotoxic agents introduce hundreds of unique mutations in each surviving cancer cell, detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature. Thus, a unique, single-cell genomic barcode can link chemotherapy exposure to a discrete time window in a patient's life. We leveraged this concept to show that MM systemic seeding is accelerated at relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell following treatment with high-dose melphalan therapy and autologous stem cell transplant.

SUBMITTER: Landau HJ

PROVIDER: S-EPMC7368016 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Accelerated single cell seeding in relapsed multiple myeloma.

Landau Heather J HJ Yellapantula Venkata V Diamond Benjamin T BT Rustad Even H EH Maclachlan Kylee H KH Gundem Gunes G Medina-Martinez Juan J Ossa Juan Arango JA Levine Max F MF Zhou Yangyu Y Kappagantula Rajya R Baez Priscilla P Attiyeh Marc M Makohon-Moore Alvin A Zhang Lance L Boyle Eileen M EM Ashby Cody C Blaney Patrick P Patel Minal M Zhang Yanming Y Dogan Ahmet A Chung David J DJ Giralt Sergio S Lahoud Oscar B OB Peled Jonathan U JU Scordo Michael M Shah Gunjan G Hassoun Hani H Korde Neha S NS Lesokhin Alexander M AM Lu Sydney S Mailankody Sham S Shah Urvi U Smith Eric E Hultcrantz Malin L ML Ulaner Gary A GA van Rhee Frits F Morgan Gareth J GJ Landgren Ola O Papaemmanuil Elli E Iacobuzio-Donahue Christine C Maura Francesco F

Nature communications 20200717 1

Multiple myeloma (MM) progression is characterized by the seeding of cancer cells in different anatomic sites. To characterize this evolutionary process, we interrogated, by whole genome sequencing, 25 samples collected at autopsy from 4 patients with relapsed MM and an additional set of 125 whole exomes collected from 51 patients. Mutational signatures analysis showed how cytotoxic agents introduce hundreds of unique mutations in each surviving cancer cell, detectable by bulk sequencing only in ...[more]

PMID: 32680998

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Project description:The present study aimed to study the efficacy and adverse effects of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in relapsed or refractory multiple myeloma. Patients were divided into three dose groups based on cell therapy concentration. After CAR-T cell therapy for 10 patients with recurrent or refractory multiple myeloma, the patients were monitored and evaluated regularly to observe the efficacy and adverse reactions of CAR-T cell therapy. At a median follow-up of 337 (253-504) days, one patient succumbed 24 days due to rapidly progressing disease. The overall response rate of nine patients was 88.9%, including 77.8% (7/9) with minimal residual disease negative complete remission (CR) and 11.1% (1/9) with partial remission. A total of three patients were maintained in remission state for more than a year and eight were maintained for more than six months. Among the three patients with extramedullary invasion, two extramedullary lesions disappeared and one was stable. The highest copy number of CAR-T cells in seven patients with CR was >1x105 copies/µl gDNA, and the best therapeutic effect can be achieved within 30 (7-30) days after the copy number of CAR-T cells reached 1x105 copies/µl genomic DNA. The median onset time in the nine patients was 43 (22-169) days, and the median progression-free survival was 337 (253-504). Among the 10 patients, nine (90%) had cytokine release syndrome, all of which were below grade II. There were nine (90%) patients with hematological adverse reactions, six (60%) patients with severe anemia, five (50%) patients with grade III and above leukopenia, five (50%) patients with granulocytopenia, four (40%) patients with grade III and above thrombocytopenia, and three (30%) patients with grade III and above pancytopenia. It was concluded that anti-BCMA CAR-T cell therapy is a promising treatment method for relapsed or refractory multiple myeloma and extramedullary invasion, with stable efficacy and controllable adverse effects.

Dataset Information

Accelerated single cell seeding in relapsed multiple myeloma.

Publications

Accelerated single cell seeding in relapsed multiple myeloma.

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