Use of depth of response to predict progression‐free survival in relapsed or refractory multiple myeloma: Evaluation of results from 102 clinical trials

Mangal, Naveen; Salem, Ahmed Hamed; Menon, Rajeev; Freise, Kevin J.

doi:10.1002/hon.2514

Cited by 13 publications

(11 citation statements)

References 29 publications

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“…stabilization, as evidenced by the prolonged maintenance of existing response compared with placebo. The association of depth of response with improved outcomes is well-established [19][20][21][22] and is supported by the data from TOURMALINE-MM3. In addition, our results showing superior PFS in patients achieving deepening of responses during maintenance are supported by data from other studies, including two separate retrospective analyses that demonstrated both PFS and OS improvements in patients who had a deepening response post-ASCT [3,4].…”

Section: Discussionmentioning

confidence: 58%

Deepening responses associated with improved progression-free survival with ixazomib versus placebo as posttransplant maintenance in multiple myeloma

et al. 2020

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In the TOURMALINE-MM3 study, post-autologous stem cell transplantation maintenance therapy with the oral proteasome inhibitor ixazomib versus placebo significantly improved progression-free survival (PFS), with a favorable safety profile. With ixazomib versus placebo maintenance, deepening responses occurred in 139/302 (46%) versus 60/187 (32%) patients with very good partial response or partial response (VGPR/PR) at study entry (relative risk 1.41, P = 0.004), and median time to best confirmed deepened response was 19.9 versus 30.8 months (24-month rate: 54.2 versus 41.4%; hazard ratio (HR): 1.384; P = 0.0342). Median PFS in patients with VGPR/PR at study entry was 26.2 versus 18.5 months (HR: 0.636, P < 0.001) with ixazomib versus placebo; in a pooled analysis across arms, in patients with versus without deepening responses, the median PFS was not reached versus 15.9 months (HR: 0.245, P < 0.001). In patients with deepening responses, 24-month PFS rate was 77.4 versus 68.3% with ixazomib versus placebo (HR: 0.831; P = 0.466); in patients without deepening responses, median PFS was 17.9 versus 14.1 months (HR: 0.741; P = 0.028). These analyses demonstrate the significantly higher rate of deepening responses with ixazomib versus placebo maintenance and the association between deepening response and prolonged PFS.

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Section: Discussionmentioning

confidence: 58%

Deepening responses associated with improved progression-free survival with ixazomib versus placebo as posttransplant maintenance in multiple myeloma

et al. 2020

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“…However, the degree of association may be different depending on patient and disease factors, and specific treatments received [ 34 – 37 ]. A large meta-analysis of data from 102 studies involving 13 322 patients with RRMM indicated a correlation between the rate of VGPR or better and median PFS ( R 2 = 0.63) [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety profile of deep responders to carfilzomib-based therapy: a subgroup analysis from ASPIRE and ENDEAVOR

et al. 2020

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To understand the profile of best responders (complete response or better [≥CR]) to carfilzomib, we described the characteristics, progression-free survival (PFS), overall survival (OS) data, and the safety of patients who achieved ≥CR to carfilzomib-based treatment in ASPIRE and ENDEAVOR. In post hoc analyses from ASPIRE and ENDEAVOR, median PFS and OS were longer for ≥CR patients versus those who achieved a very good partial response or partial response (VGPR/PR). In the carfilzomib arm of ASPIRE, median PFS was 50.4 months for ≥CR versus 22.1 months for VGPR/PR; median OS was 67.0 versus 44.2 months, respectively. In the carfilzomib arm of ENDEAVOR, median PFS was 34.0 for ≥CR versus 20.4 months for VGPR/PR; median OS was non-estimable. Despite the longer treatment duration, fewer patients with ≥CR versus VGPR/PR experienced treatment-emergent adverse events that led to discontinuation of carfilzomib-based treatment in ASPIRE or ENDEAVOR. Low serum lactate dehydrogenase was the only factor associated with achieving ≥CR vs patients not achieving CR in ASPIRE in multivariate regression analyses. No association was found between cytogenetic risk status and reaching ≥CR. Carfilzomib treatment may lead to rapid and deep responses, irrespective of most patient characteristics.

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“…For example, tumor size end points from tumor growth inhibition (TGI) model was used to link exposure and OS in exposure‐TGI‐OS models in an attempt to resolve the confounding effect by baseline prognostic disease marker 56–58 . The association between survival and a short‐term end point such as response rate 59–61 or TGI 58 has been shown in some indications, but more work needs to be done in this direction.…”

Section: Strategies To Mitigate the Confounding Effectmentioning

confidence: 99%

Characterizing Exposure–Response Relationship for Therapeutic Monoclonal Antibodies in Immuno‐Oncology and Beyond: Challenges, Perspectives, and Prospects

Dai

Vugmeyster

Mangal

2020

Clin Pharma and Therapeutics

Self Cite

111

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Recent data from immuno-oncology clinical studies have shown the exposure-response (E-R) relationship for therapeutic monoclonal antibodies (mAbs) was often confounded by various factors due to the complex interplay of patient characteristics, disease, drug exposure, clearance, and treatment response and presented challenges in characterization and interpretation of E-R analysis. To tackle the challenges, exposure relationships for therapeutic mAbs in immuno-oncology and oncology are reviewed, and a general framework for an integrative understanding of E-R relationship is proposed. In this framework, baseline factors, drug exposure, and treatment response are envisioned to form an interconnected triangle, driving the E-R relationship and underlying three components that compose the apparent relationship: exposure-driven E-R, baseline-driven E-R, and response-driven E-R. Various strategies in data analysis and study design to decouple those components and mitigate the confounding effect are reviewed for their merits and limitations, and a potential roadmap for selection of these strategies is proposed. Specifically, exposure metrics based on a single-dose pharmacokinetic model can be used to mitigate responsedriven E-R, while multivariable analysis and/or case control analysis of data obtained from multiple dose levels in a randomized study may be used to account for the baseline-driven E-R. In this context, the importance of collecting data from multiple dose levels, the role of prognostic factors and predictive factors, the potential utility of clearance at baseline and its change over time, and future directions are discussed.

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Use of depth of response to predict progression‐free survival in relapsed or refractory multiple myeloma: Evaluation of results from 102 clinical trials

Cited by 13 publications

References 29 publications

Deepening responses associated with improved progression-free survival with ixazomib versus placebo as posttransplant maintenance in multiple myeloma

Deepening responses associated with improved progression-free survival with ixazomib versus placebo as posttransplant maintenance in multiple myeloma

Efficacy and safety profile of deep responders to carfilzomib-based therapy: a subgroup analysis from ASPIRE and ENDEAVOR

Characterizing Exposure–Response Relationship for Therapeutic Monoclonal Antibodies in Immuno‐Oncology and Beyond: Challenges, Perspectives, and Prospects

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