Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets

Sehgal, Kartik; Das, Rituparna; Zhang, Lin; Verma, Rakesh; Deng, Yanhong; Kocoglu, Mehmet H.; Vasquez, Juan C.; Koduru, Srinivas; Ren, Yan; Wang, Maria; Couto, Suzana; Breider, M A; Hansel, Donna E.; Seropian, Stuart; Cooper, Dennis; Thakurta, Anjan; Yao, Xiaopan; Dhodapkar, Kavita M.; Dhodapkar, Madhav V.

doi:10.1182/blood-2014-11-611426

Cited by 108 publications

(121 citation statements)

References 45 publications

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“…To analyze the effect of pomalidomide on ILCs in vivo, samples obtained from MM patients treated with pomalidomide as a single agent in the context of a prior clinical trial 18 were analyzed. For these studies, samples obtained before therapy and at 4 hours after the first dose were compared for the expression of Ikzf1 in ILCs as well as cytokine production after in vitro activation.…”

Section: In Vitro and In Vivo Effect Of Pomalidomide On Human Ilcsmentioning

confidence: 99%

Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy

Bailur¹,

Mehta

Zhang³

et al. 2017

Blood Advances

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Section: In Vitro and In Vivo Effect Of Pomalidomide On Human Ilcsmentioning

confidence: 99%

Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy

Bailur¹,

Mehta

Zhang³

et al. 2017

Blood Advances

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“…RNA from sorted human SP CD4 + and CD8 + T cells was amplified, labeled, and hybridized on the Affymetrix Human Genome U133 Plus 2.0 microarray chips. The data were analyzed with Gene Spring GX12.5 (Agilent Technologies) and Partek Genomics Suite (6.6) software, as previously described (44,45). All original microarray data were deposited in the NCBI's Gene Expression Omnibus (GEO GSE85074).…”

Section: Discussionmentioning

confidence: 99%

ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cells

Boddupalli¹,

Nair²,

Gray³

et al. 2016

Journal of Clinical Investigation

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“…13 In addition, single-agent pomalidomide has been shown to upregulate CD38 expression on MM cell lines, 14 and pretreatment of patientderived effector cells with an IMiD (lenalidomide) has been shown to synergistically enhance daratumumab-mediated antibody-dependent cell-mediated cytotoxicity. 15 Finally, pom-dex has demonstrated immune modulation, via activation of T cells, that correlated with clinical response, 16 which could potentially complement the immunomodulatory effects demonstrated by daratumumab. 9 For all of these reasons, pomalidomide paired with daratumumab is a rational choice for a combination regimen.…”

Section: Introductionmentioning

confidence: 99%

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma

Chari

Suvannasankha

Fay

et al. 2017

Blood

405

311

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• No new safety signals were observed with daratumumab plus pomalidomide and dexamethasone, except for increased neutropenia.• Daratumumab plus pomalidomide and dexamethasone induced rapid, deep, and durable responses in heavily treated patients with multiple myeloma.Daratumumab plus pomalidomide and dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with ‡2 prior lines of therapy who were refractory to their last treatment. Patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly. Safety was the primary end point. Overall response rate (ORR) and minimal residual disease (MRD) by next-generation sequencing were secondary end points. Patients (N 5 103) received a median (range) of 4 (1-13) prior therapies; 76% received ‡3 prior therapies. The safety profile of daratumumab plus pomdex was similar to that of pom-dex alone, with the exception of daratumumab-specific infusion-related reactions (50%) and a higher incidence of neutropenia, although without an increase in infection rate. Common grade ‡3 adverse events were neutropenia (78%), anemia (28%), and leukopenia (24%). ORR was 60% and was generally consistent across subgroups (58% in double-refractory patients). Among patients with a complete response or better, 29% were MRD negative at a threshold of 10 25 . Among the 62 responders, median duration of response was not estimable (NE; 95% confidence interval [CI], 13.6-NE). At a median follow-up of 13.1 months, the median progression-free survival was 8.8 (95% CI, 4.6-15.4) months and median overall survival was 17.5 (95% CI, 13.3-NE) months. The estimated 12-month survival rate was 66% (95% CI, 55.6-74.8). Aside from increased neutropenia, the safety profile of daratumumab plus pom-dex was consistent with that of the individual therapies. Deep, durable responses were observed in heavily treated patients. The study was registered at www.clinicaltrials.gov as #NCT01998971. (Blood. 2017;130(8):974-981)

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Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets

Abstract: Key Points Pomalidomide leads to rapid immune activation in vivo correlating with clinical outcome in relapsed myeloma. Baseline expression of ikaros/aiolos protein in tumor cells is not predictive of outcome.

Cited by 108 publications

References 45 publications

Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy

Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy

ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cells

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma

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