Humoral immune reconstitution following therapy with daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara‐KRd), autologous hematopoietic cell transplantation, and measurable residual disease‐response‐adapted treatment cessation

Silbermann, Rebecca; Schmidt, Timothy; Bal, Susan; Dhakal, Binod; Dholaria, Bhagirathbhai; Biltibo, Eden; Chhabra, Saurabh; Giri, Smith; Godby, Kelly N.; Gowda, Sonia; Medvedova, Eva; Cornell, Robert F.; Callander, Natalie S.; Costa, Luciano J.

doi:10.1002/jha2.736

Cited by 3 publications

(3 citation statements)

References 9 publications

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“…We anticipate that results from the ongoing MRD2STOP study (NCT04108624), in which patients who achieve sustained MRD negativity at 10 −6 sensitivity level combined with undetectable M‐spike and no evidence of disease by positron emission tomography can discontinue maintenance treatment will further help to unravel the effect of not only de‐escalation but also a cessation of lenalidomide maintenance on humoral immunity. It will be particularly interesting in the context of recently published results documenting humoral immune reconstitution in patients who discontinued quadruplet, carfilzomib‐containing therapy after achieving MRD negativity, 27 with our data suggesting that this effect may be mostly driven by the discontinuation of the proteasome inhibitor.…”

Section: Discussionsupporting

confidence: 51%

Polyclonal immunoglobulin recovery in patients with newly diagnosed myeloma receiving maintenance therapy after autologous haematopoietic stem cell transplantation with either carfilzomib, lenalidomide and dexamethasone or lenalidomide alone: Subanalysis of the randomized phase 3 ATLAS trial

Kubicki,

Dytfeld,

Wróbel

et al. 2023

Br J Haematol

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SummaryPrevious studies suggest that postautologous stem cell transplant (ASCT) recovery of polyclonal immunoglobulin from immunoparesis in patients with multiple myeloma is a positive prognostic marker. We performed a longitudinal analysis of polyclonal immunoglobulin concentrations and unique B‐cell sequences in patients enrolled in the phase 3 ATLAS trial that randomized 180 subjects to either carfilzomib, lenalidomide, dexamethasone (KRd) or lenalidomide (R) maintenance. In the KRd arm, standard‐risk patients with minimal residual disease negativity after six cycles de‐escalated to R alone after cycle 8. One year from the initiation of maintenance at least partial recovery of polyclonal immunoglobulin was observed in more patients on the R arm (58/66, p < 0.001) and in those who de‐escalated from KRd to R (27/38, p < 0.001) compared to the KRd arm (9/36). In patients who switched from KRd to R, the concentrations of uninvolved immunoglobulin and the number of B‐cell unique sequences increased over time, approaching values observed in the R arm. There were no differences in progression‐free survival between the patients with at least partial immunoglobulin recovery and the remaining population. Our analysis indicates that patients receiving continuous therapy after ASCT experience prolonged immunoparesis, limiting prognostic significance of polyclonal immunoglobulin recovery in this setting.

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Section: Discussionsupporting

confidence: 51%

Polyclonal immunoglobulin recovery in patients with newly diagnosed myeloma receiving maintenance therapy after autologous haematopoietic stem cell transplantation with either carfilzomib, lenalidomide and dexamethasone or lenalidomide alone: Subanalysis of the randomized phase 3 ATLAS trial

Kubicki,

Dytfeld,

Wróbel

et al. 2023

Br J Haematol

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“…In our study, we set a cut‐off of 6 months to divide Dara and non‐Dara cohorts as some studies showed that there might be a marked recovery of immunoglobin and natural killer cells approximately 6 months after discontinuation of Dara‐based treatment. 36 , 37 The rates of severe COVID‐19 and COVID‐19‐related mortality were 25.6% and 7.7%, respectively, in the overall Dara cohort. In both univariate and multivariate analyses, the use of Dara within 6 months was a risk factor for severe COVID‐19.…”

Section: Discussionmentioning

confidence: 97%

“…However, the outcome of patients treated with anti‐38 Abs after COVID‐19 infection is not clear. In our study, we set a cut‐off of 6 months to divide Dara and non‐Dara cohorts as some studies showed that there might be a marked recovery of immunoglobin and natural killer cells approximately 6 months after discontinuation of Dara‐based treatment 36,37 . The rates of severe COVID‐19 and COVID‐19‐related mortality were 25.6% and 7.7%, respectively, in the overall Dara cohort.…”

Section: Discussionmentioning

confidence: 99%

Outcomes of COVID‐19 in multiple myeloma patients treated with daratumumab

Jin,

He,

et al. 2023

Cancer Science

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Despite concerns about an increased risk of adverse outcomes following coronavirus disease (COVID‐19) in multiple myeloma patients treated with anti‐CD38 Abs, the impact of COVID‐19 on this group of patients is unclear. We tried to evaluate the clinical outcomes of these patients. We collected data from 1036 patients with multiple myeloma and enrolled 509 cases with COVID‐19. We divided enrolled patients into daratumumab or nondaratumumab cohorts based on whether they had received daratumumab‐based treatment within 6 months of COVID‐19 infection. We applied a propensity score matching method to reduce the bias of baseline characteristics, and then compared the incidence of adverse outcomes between these two cohorts. A total of 117 patients were enrolled in the daratumumab cohort, and 392 patients in the nondaratumumab cohort. After propensity score matching, 204 patients were matched. The proportions of patients who developed COVID‐19 pneumonia (59.8% vs. 34.3%, p < 0.001), were hospitalized (33.3% vs. 11.8%, p < 0.001) and developed severe disease (23.5% vs. 6.9%, p = 0.001) were higher in the matched daratumumab cohort. By multivariate analysis, daratumumab exposure was an independent risk factor for severe disease. An ECOG performance status >2 and history of chronic kidney disease were independent risk factors for COVID‐19‐related mortality among patients who received daratumumab‐based therapy. This study suggested that multiple myeloma patients exposed to daratumumab were at a higher risk of adverse outcomes from COVID‐19.

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Impaired SARS-CoV-2-Specific CD8+ T Cells After Infection or Vaccination but Robust Hybrid T Cell Immunity in Patients with Multiple Myeloma

Shoumariyeh,

Csernalabics,

Salimi Alizei

et al. 2024

Vaccines

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Background: Multiple myeloma (MM) patients are at high risk of severe infections including COVID-19 due to an immune dysregulation affecting both innate and adaptive immune responses. However, our understanding of the immune responses to infection and vaccination in MM patients is limited. To gain more detailed insights into infection- and vaccine-elicited T cell immunity in MM, we studied the CD8+ T cell response on the single-epitope level in SARS-CoV-2 convalescent and mRNA-vaccinated MM patients. Methods: We compared peptide/MHC class I tetramer-enriched SARS-CoV-2-specific CD8+ T cells and antibody responses in MM patients (convalescent: n = 16, fully vaccinated: n = 5, vaccinated convalescent: n = 5) and healthy controls (HCs) (convalescent: n = 58, fully vaccinated: n = 7) either after infection with SARS-CoV-2 alone, complete mRNA vaccination or SARS-CoV-2 infection and single-shot mRNA vaccination (hybrid immunity). Results: MM patients have lower frequencies and a lower proportion of fully functional virus-specific CD8+ T cells compared to HCs, after both SARS-CoV-2 infection and vaccination. CD8+ T cell memory subset distribution in MM patients is skewed towards reduced frequencies of central memory (TCM) T cells and higher frequencies of effector memory 1 (TEM1) T cells. In contrast, the humoral immune response was comparable in both cohorts after viral clearance. Notably, CD8+ T cell frequencies as well as the humoral immune response were improved by a single dose of mRNA vaccine in convalescent MM patients. Conclusions: MM patients have relative immunological deficiencies in SARS-CoV-2 immunity but benefit from hybrid immunity. These findings underline the relevance of vaccinations in this vulnerable patient group.

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Humoral immune reconstitution following therapy with daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara‐KRd), autologous hematopoietic cell transplantation, and measurable residual disease‐response‐adapted treatment cessation

Cited by 3 publications

References 9 publications

Polyclonal immunoglobulin recovery in patients with newly diagnosed myeloma receiving maintenance therapy after autologous haematopoietic stem cell transplantation with either carfilzomib, lenalidomide and dexamethasone or lenalidomide alone: Subanalysis of the randomized phase 3 ATLAS trial

Polyclonal immunoglobulin recovery in patients with newly diagnosed myeloma receiving maintenance therapy after autologous haematopoietic stem cell transplantation with either carfilzomib, lenalidomide and dexamethasone or lenalidomide alone: Subanalysis of the randomized phase 3 ATLAS trial

Outcomes of COVID‐19 in multiple myeloma patients treated with daratumumab

Impaired SARS-CoV-2-Specific CD8+ T Cells After Infection or Vaccination but Robust Hybrid T Cell Immunity in Patients with Multiple Myeloma

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