Carfilzomib vs bortezomib in patients with multiple myeloma and renal failure: a subgroup analysis of ENDEAVOR

Dimopoulos, Meletios A.; Siegel, David S.; White, Darrell; Boccia, Ralph V.; Iskander, Karim; Zhao, Yongming; Kimball, Amy; Mezzi, Khalid; Ludwig, Heinz; Niesvizky, Rubén

doi:10.1182/blood-2018-06-860015

Cited by 38 publications

(49 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3,4,18,45,46 However, recent studies have questioned the validity of this relation in the era of novel antimyeloma agents. 31,47,48 These studies were smaller, the definition of renal outcomes varied, initial eGFRs were higher, and the proportion with LCCN was unknown. de Vries et al 31 studied 131 patients newly diagnosed with MM and renal impairment and found that renal recovery was not associated with a better OS, even in patients with severe renal impairment.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study

Royal

Leung

Troyanov

et al. 2020

Blood

View full text Add to dashboard Cite

Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, β2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study

Royal

Leung

Troyanov

et al. 2020

Blood

View full text Add to dashboard Cite

show abstract

“…477 In patients with relapsed/refractory MM, carfilzomib and dexamethasone (Kd56) demonstrate a longer PFS than that of bortezomib and dexamethasone (Vd). 478 Panobinostat, an HDAC inhibitor, is also used with carfilzomib in MM patients and achieves a good response rate (ClinicalTrial.gov: NCT01549431). 359 In addition to combination treatment targeting UPS and other signaling pathways, combined inhibitors within the UPS also work in cancer treatment.…”

Section: Targeting E3 Enzymesmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

470

308

View full text Add to dashboard Cite

Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

show abstract

“…The median (range) number of cycles for patients with and without RI was 10 (1-18) and 10 (1-19) cycles with Isa-Pd (54 and 86 treated patients), and 5 (1-16) and 7 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) cycles with Pd (47 and 94 treated patients), respectively. The median duration of exposure for patients with and without RI was 41.6 (4.0-74.1) and 43.6 (3.1-76.7) weeks with Isa-Pd, and 19.3 (1.0-65.0) and 28.6 (1.7-73.7) weeks with Pd, respectively.…”

Section: Treatment Exposurementioning

confidence: 99%

Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis

et al. 2020

View full text Add to dashboard Cite

The randomized, phase 3 ICARIA-MM study investigated isatuximab (Isa) with pomalidomide and dexamethasone (Pd) versus Pd in patients with relapsed/refractory multiple myeloma and ≥2 prior lines. This prespecified subgroup analysis examined efficacy in patients with renal impairment (RI; estimated glomerular filtration rate <60 mL/min/1.73 m²). Isa 10 mg/kg was given intravenously once weekly in cycle 1, and every 2 weeks in subsequent 28-day cycles. Patients received standard doses of Pd. Median progression-free survival (PFS) for patients with RI was 9.5 months with Isa-Pd (n = 55) and 3.7 months with Pd (n = 49; hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.30-0.85). Without RI, median PFS was 12.7 months with Isa-Pd (n = 87) and 7.9 months with Pd (n = 96; HR 0.58; 95% CI, 0.38-0.88). The overall response rate (ORR) with and without RI was higher with Isa-Pd (56 and 68%) than Pd (25 and 43%). Complete renal response rates were 71.9% (23/32) with Isa-Pd and 38.1% (8/21) with Pd; these lasted ≥60 days in 31.3% (10/32) and 19.0% (4/21) of patients, respectively. Isa pharmacokinetics were comparable between the subgroups, suggesting no need for dose adjustment in patients with RI. In summary, the addition of Isa to Pd improved PFS, ORR and renal response rates.

show abstract

Carfilzomib vs bortezomib in patients with multiple myeloma and renal failure: a subgroup analysis of ENDEAVOR

Cited by 38 publications

References 42 publications

Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study

Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study

The role of ubiquitination in tumorigenesis and targeted drug discovery

Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis

Contact Info

Product

Resources

About