BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of ...resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.
The treatment paradigms for multiple myeloma and amyloidosis have been transformed by novel therapies and continue to be modified in the face of new immunologic agents. In this How I Treat series on ...plasma cell dyscrasias edited by Associate Editor Hervé Avet-Loiseau, experts in the field discuss the rapidly changing treatment landscape for multiple myeloma and light-chain amyloidosis. Using illustrative cases, they review the role of autologous transplant, novel combination therapies, and the impact of new immunotherapy approaches to these complex and heterogeneous diseases.
Our knowledge of myeloma genetics remained limited and lagged behind many other hematologic malignancies because of the inherent difficulties in generating metaphases within the malignant plasma cell ...clone. With the development of molecular techniques (microarrays and next-generation sequencing), our understanding has been highly improved in the past 5 years. These studies have not only confirmed the prevalence of wide heterogeneity in myeloma at the molecular level, but has also provided a much clearer picture of the disease pathogenesis and progression. Whether these data will enable improvements in the therapeutic approach is still a matter of debate. The next improvement will come from detailed analyses of these molecular features to try to move from a treatment fitted to every patient to individualized therapies, taking into account the complexity of the chromosomal changes, the mutation spectrum, and subclonality evolution.
In this trial, 700 patients with myeloma were randomly assigned to receive RVD therapy (lenalidomide, bortezomib, and dexamethasone) with or without autologous stem-cell transplantation. Patients who ...underwent transplantation had significantly longer progression-free survival.
For the past 20 years, high-dose chemotherapy plus autologous stem-cell transplantation has been the standard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age.
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However, this treatment requires hospitalization and can be associated with substantial toxic effects.
Over the past decade, immunomodulatory drugs
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and proteasome inhibitors
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have been shown to have substantial activity in patients with multiple myeloma. The use of combination therapy with immunomodulatory drugs, proteasome inhibitors, and dexamethasone has yielded increased rates of complete response and improved outcomes, both among patients who are eligible for transplantation and among those who . . .
Although therapeutic strategies have been adapted to age and comorbidities for a long time, almost all multiple myeloma (MM) patients currently receive similar treatment, whatever their disease risk ...category. However, high-risk MM patients still constitute an unmet medical need and should benefit from the most efficient drug combinations. Herein, we review and discuss how to optimally define risk and why a revision of the current definition is urgently needed.
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Patients with multiple myeloma (MM) seem to be at increased risk for more severe COVID-19 infection and associated complications due to their immunocompromised state, the older age and comorbidities. ...The European Myeloma Network has provided an expert consensus statement in order to guide therapeutic decisions in the era of the COVID-19 pandemic. Patient education for personal hygiene and social distancing measures, along with treatment individualization, telemedicine and continuous surveillance for early diagnosis of COVID-19 are essential. In countries or local communities where COVID-19 infection is widely spread, MM patients should have a PCR test of nasopharyngeal swab for SARS-CoV-2 before hospital admission, starting a new treatment line, cell apheresis or ASCT in order to avoid ward or community spread and infections. Oral agent-based regimens should be considered, especially for the elderly and frail patients with standard risk disease, whereas de-intensified regimens for dexamethasone, bortezomib, carfilzomib and daratumumab should be used based on patient risk and response. Treatment initiation should not be postponed for patients with end organ damage, myeloma emergencies and aggressive relapses. Autologous (and especially allogeneic) transplantation should be delayed and extended induction should be administered, especially in standard risk patients and those with adequate MM response to induction. Watchful waiting should be considered for standard risk relapsed patients with low tumor burden, and slow biochemical relapses. The conduction of clinical trials should continue with appropriate adaptations to the current circumstances. Patients with MM and symptomatic COVID-19 disease should interrupt anti-myeloma treatment until recovery. For patients with positive PCR test for SARS-CoV-2, but with no symptoms for COVID-19, a 14-day quarantine should be considered if myeloma-related events allow the delay of treatment. The need for surveillance for drug interactions due to polypharmacy is highlighted. The participation in international COVID-19 cancer registries is greatly encouraged.
Lenalidomide maintenance after stem-cell transplantation significantly prolonged progression-free and event-free survival in patients with multiple myeloma. At 4 years, overall survival was similar ...in the lenalidomide-treated and placebo-treated groups.
During the past decade, high-dose chemotherapy with autologous stem-cell transplantation has become the standard treatment for newly diagnosed myeloma in patients younger than 65 years of age. However, the median duration of response after this procedure does not exceed 3 years, and few patients remain free of the disease for more than 10 years.
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Relapses are due to the failure of high-dose chemotherapy to eradicate all myeloma cells. Maintenance treatments have been proposed to control the proliferation of residual malignant cells after transplantation. For many years, interferon with or without glucocorticoids was used,
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Multiple myeloma embodies the paradigm of the deeper the response, the longer the survival. However, results are conflicting regarding achievement of complete remission (CR) and ...minimal residual disease (MRD) negativity; some patients with persistent M protein have undetectable MRD. We reviewed the frequency of this discordance and outcomes of these patients. We spotlight possible explanations for and consequences of conflicting response criteria and suggest that MRD be assessed in patients achieving very good partial response or better in clinical trials.
It is established that in multiple myeloma, the depth of response to therapy predicts survival. However, the assessment of minimal residual disease (MRD) may be discordant with classical complete remission (CR) with patients having persistent M protein in the face of undetectable MRD. In this Blood Spotlight, Paiva et al review compelling evidence that survival is determined by MRD regardless of the presence or absence of CR.
Exosomes, secreted by several cell types, including cancer cells, can be isolated from the peripheral blood and have been shown to be powerful markers of disease progression in cancer. In this study, ...we examined the prognostic significance of circulating exosomal microRNAs (miRNAs) in multiple myeloma (MM). A cohort of 156 patients with newly diagnosed MM, uniformly treated and followed, was studied. Circulating exosomal miRNAs were isolated and used to perform a small RNA sequencing analysis on 10 samples and a quantitative reverse transcription polymerase chain reaction (qRT-PCR) array on 156 samples. We studied the relationship between miRNA levels and patient outcomes, including progression-free survival (PFS) and overall survival (OS). We identified miRNAs as the most predominant small RNAs present in exosomes isolated from the serum of patients with MM and healthy controls by small RNA sequencing of circulating exosomes. We then analyzed exosomes isolated from serum samples of 156 patients using a qRT-PCR array for 22 miRNAs. Two of these miRNAs, let-7b and miR-18a, were significantly associated with both PFS and OS in the univariate analysis and were still statistically significant after adjusting for the International Staging System and adverse cytogenetics in the multivariate analysis. Our findings support the use of circulating exosomal miRNAs to improve the identification of patients with newly diagnosed MM with poor outcomes. The results require further validation in other independent prospective MM cohorts.
•Two circulating exosomal microRNAs, let-7b and miR-18a, improved survival prediction in patients with MM.•Circulating exosomal miRNAs enhanced the stratification of patients with high-risk factors.
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