Radiation Fractionation Regimen Selection for Palliation of Metastatic Multiple Myeloma in the Era of Biological Therapeutics

Background: Isatuximab (Isa) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement. Exposure-Response (E-R) analysis and disease modelling of tumor burden were performed to evaluate the relationship between Isa exposure and efficacy outcomes. This analysis also supports the Isatuximab dosing regimen selection/confirmation when administered in combination in relapsed/refractory multiple myeloma (RRMM) patients. Methods: To determine the optimal dose for the Phase 3 ICARIA-MM study, E-R analyses were conducted in 44 and 52 RRMM evaluable patients from two Phase 1 trials of Isa in combination with pomalidomide/dexamethasone (Pd) (NCT02283775) or with lenalidomide/dexamethasone (Rd) (NCT01749969), respectively. Isa was administered intravenously at doses from 3 to 20 mg/kg every 2 weeks or weekly for 4 weeks then every 2 weeks (QW/Q2W). In the E-R analyses, several Isa exposure parameters were tested to evaluate if they were predictors of response (partial response [PR] or better). Baseline covariates were also considered in the model to evaluate potential confounding effects. In addition, a second type of analysis was performed on 2 pooled datasets of 153 (single agent and combination with Pd) and 162 (single agent and combination with Rd) evaluable RRMM patients: disease response was also captured by modeling the dynamics of the serum M-protein using a joint model of tumor growth inhibition and drop-out. Trial simulations were then performed to evaluate different dosing regimens of interest. To confirm the dose, E-R analyses were conducted in 297 evaluable RRMM patients from the phase 3 trial (ICARIA-MM; NCT02990338) comparing Isa-Pd (N=148) and Pd (N=149). Isa was administered intravenously at 10 mg/kg QW/Q2W in the Isa-Pd arm. Cox and Weibull (Progression-Free Survival [PFS]) or logistic regression (overall response rate [ORR]) models were used. Results: In the two combination Phase 1 trials, Isa appeared to be well tolerated with no clear dose response relationship between 10 and 20 mg/kg. E-R analyses suggested that higher Isa exposure represented by log Ctrough at 4 weeks (CT4W) was associated with increased ORR. Both models predicted an increased ORR with decreased beta-2 microglobulin and lower number of prior lines of therapy (Rd only), together with higher log CT4W. Clinical trial simulations showed that the probability of success to reach the targeted ORR was high with 10 mg/kg QW/Q2W for both Pd (83% for ORR ≥60%) and Rd (96% for ORR ≥50%). Serum M-protein reduction was greater at doses ≥10 mg/kg compared to doses <10 mg/kg, with minimal differences between 10 and 20 mg/kg QW/Q2W. These analyses supported the rationale for 10 mg/kg QW/Q2W selection for the Phase 3 combination study. In the Phase 3 ICARIA-MM study, the E-R analysis showed that higher CT4W was associated with higher ORR (predicted ORR below and above the median CT4W being 52% and 72%, respectively). The final model also included time since diagnosis and Revised International Staging System (R-ISS) stage at baseline and an interaction between time since diagnosis and R-ISS; ORR increased as time since diagnosis increased and decreased with higher R-ISS stage. For PFS, in addition to CT4W, the model included plasmacytomas, serum albumin level and R-ISS at baseline. The predicted distribution of PFS indicated that patients with greater Isa CT4W had longer PFS, patients with R-ISS Stage III and plasmacytomas had shorter PFS. Matched analyses to Pd indicated that even patients with concentrations ≤median CT4W benefited from Isa treatment (PFS hazard ratio: 0.773). Conclusion: Model-based drug development was successfully applied to support Phase 3 Isa dosing regimen selection for use in combination with Pd in RRMM patients. E-R and clinical data from the Phase 3 ICARIA-MM study confirmed the efficacy and safety of 10 mg/kg QW/Q2W dose/regimen selected. Disclosures Rachedi: Sanofi: Employment. Koiwai:Sanofi: Employment. Gaudel-Dedieu:Sanofi: Employment. Sebastien:Sanofi: Employment. Thai:Sanofi: Employment. El-Cheikh:Sanofi: Employment. Brillac:Sanofi: Employment. Fau:Sanofi: Employment. Nguyen:Sanofi: Employment. Liu:Sanofi: Employment. Campana:Sanofi: Employment. van de Velde:Sanofi: Employment. Semiond:Sanofi: Employment.

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Proteasome inhibitors as therapeutics

Essays in Biochemistry ◽

10.1042/bse0410205 ◽

2005 ◽

Vol 41 ◽

pp. 205-218

Author(s):

Constantine S. Mitsiades ◽

Nicholas Mitsiades ◽

Teru Hideshima ◽

Paul G. Richardson ◽

Kenneth C. Anderson

Keyword(s):

Multiple Myeloma ◽

Drug Class ◽

Proteasome Inhibitors ◽

Cell Cycle Regulators ◽

Current State ◽

Intracellular Mechanism ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Hodgkin's Lymphomas ◽

Clinical Research Data

The ubiquitin–proteasome pathway is a principle intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies, because of the pleiotropic cell-cycle regulators and modulators of apoptosis that are controlled by proteasome function. In this chapter, we review the current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma. Particular emphasis is placed on the pre-clinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and a appraisal of possible uses in other haematological malignancies, such non-Hodgkin's lymphomas.

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Framework for Selecting Vocabulary for Preliterate Children Who Use Augmentative and Alternative Communication

American Journal of Speech-Language Pathology ◽

10.1044/2019_ajslp-18-0041 ◽

2019 ◽

Vol 28 (3) ◽

pp. 1000-1009

Author(s):

Allison Bean ◽

Lindsey Paden Cargill ◽

Samantha Lyle

Keyword(s):

Language Impairment ◽

Augmentative And Alternative Communication ◽

Developmentally Appropriate ◽

School Age Children ◽

Alternative Communication ◽

School Based ◽

Selection For ◽

Nonverbal Children ◽

Grammatical Structures ◽

Insufficient Knowledge

Purpose Nearly 50% of school-based speech-language pathologists (SLPs) provide services to school-age children who use augmentative and alternative communication (AAC). However, many SLPs report having insufficient knowledge in the area of AAC implementation. The objective of this tutorial is to provide clinicians with a framework for supporting 1 area of AAC implementation: vocabulary selection for preliterate children who use AAC. Method This tutorial focuses on 4 variables that clinicians should consider when selecting vocabulary: (a) contexts/environments where the vocabulary can be used, (b) time span during which the vocabulary will be relevant, (c) whether the vocabulary can elicit and maintain interactions with other people, and (d) whether the vocabulary will facilitate developmentally appropriate grammatical structures. This tutorial focuses on the role that these variables play in language development in verbal children with typical development, verbal children with language impairment, and nonverbal children who use AAC. Results Use of the 4 variables highlighted above may help practicing SLPs select vocabulary that will best facilitate language acquisition in preliterate children who use AAC.

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Teaching Partners to Support Communication for Adults with Acquired Communication Impairment

Perspectives on Augmentative and Alternative Communication ◽

10.1044/aac22.1.4 ◽

2013 ◽

Vol 22 (1) ◽

pp. 4-15 ◽

Cited By ~ 3

Author(s):

Laura J. Ball ◽

Joanne Lasker

Keyword(s):

Practice Patterns ◽

Communicative Competence ◽

Communication Disorders ◽

Communication Impairment ◽

Communication Partner ◽

Communication Partners ◽

Selection For ◽

Communication Needs ◽

End Of Life Communication ◽

Lateral Sclerosis

Abstract For adults with acquired communication impairment, particularly those who have communication disorders associated with stroke or neurodegenerative disease, communication partners play an important role in establishing and maintaining communicative competence. In this paper, we assemble some evidence on this topic and integrate it with current preferred practice patterns (American Speech-Language-Hearing Association, 2004). Our goals are to help speech-language pathologists (SLPs) identify and describe partner-based communication strategies for adults with acquired impairment, implement evidence-based approaches for teaching strategies to communication partners, and employ a Personnel Framework (Binger et al., 2012) to clarify partners? roles in acquiring and supporting communication tools for individuals with acquired impairments. We offer specific guidance about AAC techniques and message selection for communication partners involved with chronic, degenerative, and end of life communication. We discuss research and provide examples of communication partner supports for person(s) with aphasia and person(s) with amyotrophic lateral sclerosis who have complex communication needs.

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