Preliminary Results from a Phase I Study of Isatuximab (ISA) in Combination with Bortezomib, Lenalidomide, Dexamethasone (VRd), and in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Non-Eligible for Transplant

Ocio, Enrique M.; Otero, Paula Rodríguez; Bringhen, Sara; Oliva, Stefania; Nogai, Axel; Attal, Michel; Moreau, Philippe; Kanagavel, Dheepak; Fitzmaurice, Thomas; Wu, Junlong; López, Joaquín Martínez

doi:10.1182/blood-2018-99-111244

Cited by 24 publications

(19 citation statements)

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“…Lastly, isatuximab is being assessed in combination with either bortezomib, cyclophosphamide, and dexamethasone or bortezomib, lenalidomide, and dexamethasone in patients with NDMM who are not eligible for, or elect not to receive transplantation (ClinicalTrials.gov, NCT02513186). Interim analysis from both arms of this trial have been reported [48,49].…”

Section: Isatuximab In Patients With Newly Diagnosed MMmentioning

confidence: 99%

“…Patients with NDMM ineligible for transplantation were treated in an induction phase with either isatuximab 10 mg/kg or 20 mg/kg weekly (cycle 1), followed by every 2 weeks (cycles 2-12); bortezomib (1.3 mg/m 2 ) for cycles 1-12; cyclophosphamide (300 mg/m 2 ) for cycles 1-12; and dexamethasone (20 mg/day) for cycles 1-12, followed by a maintenance phase of 4-week cycles that included isatuximab at the assigned dose and dexamethasone (20 mg) on day 1 for all cycles [48]. The maintenance phase was followed by an isatuximab 10 mg/kg dose expansion phase.…”

Section: Isatuximab In Patients With Newly Diagnosed MMmentioning

confidence: 99%

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Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab

Martin

Corzo

Chiron

et al. 2019

Cells

119

151

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CD38 is a transmembrane glycoprotein with ectoenzymatic activity involved in regulation of migration, signal transduction, and receptor-mediated adhesion. CD38 is highly expressed on various malignant cells, including multiple myeloma (MM), and at relatively low levels in other tissues, making it a suitable target for therapeutic antibodies. Several anti-CD38 therapies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab (SAR650984), respectively. Studies have shown that anti-CD38 therapies are effective in the treatment of relapsed/refractory MM and are well tolerated, with infusion reactions being the most common side effects. They can be used as monotherapy or in combination with immunomodulatory agents, such as pomalidomide, or proteasome inhibitors to potentiate their activity. Here we examine isatuximab and several anti-CD38 agents in development that were generated using new antibody engineering techniques and that may lead to more effective CD38 targeting. We also summarize trials assessing these antibodies in MM, other malignancies, and solid organ transplantation. Finally, we propose that further research on the mechanisms of resistance to anti-CD38 therapy and the development of biomarkers and new backbone regimens with CD38 antibodies will be important steps in building more personalized treatment for patients with MM.

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Section: Isatuximab In Patients With Newly Diagnosed MMmentioning

confidence: 99%

Section: Isatuximab In Patients With Newly Diagnosed MMmentioning

confidence: 99%

Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab

Martin

Corzo

Chiron

et al. 2019

Cells

119

151

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“…Another phase Ib trial is evaluating induction with 12 cycles of isatuximab (10/20 mg/kg) plus bortezomib-cyclophosphamide-dexamethasone (VCd), followed by maintenance with single-agent isatuximab in a similar patient population. The ORR was 87%, whereas data on MRD status and PFS are not yet available [48].…”

Section: Isatuximabmentioning

confidence: 97%

“…In transplant-ineligible NDMM patients, isatuximab (10 mg/kg) is being evaluated in a phase Ib trial in combination with VRd as induction (4 cycles) followed by maintenance with Isa-Rd. Preliminary results showed an ORR of 93%, with 38.5% of patients achieving MRD negativity [47]. Another phase Ib trial is evaluating induction with 12 cycles of isatuximab (10/20 mg/kg) plus bortezomib-cyclophosphamide-dexamethasone (VCd), followed by maintenance with single-agent isatuximab in a similar patient population.…”

Section: Isatuximabmentioning

confidence: 99%

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

Bonello

Mina

Boccadoro

2019

Cancers

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Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs ® ), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation.Cancers 2020, 12, 15 2 of 24 Cancers 2020, 12, 15 3 of 24 (Bregs, which promote tumor growth and immune escape), as well as a subset of regulatory T cells (Tregs) express CD38, and their levels are reduced after daratumumab exposure. Conversely, daratumumab results in significant expansion of CD8+ cytotoxic and CD4+ helper T cells, likely following the depletion of regulatory cells. Remarkably, expanded effector T cells also show increased killing capacity due to augmented levels of granzyme B, which activates caspases and triggers cell apoptosis [23][24][25]. In addition, among the activities promoted by CD38, there is a nicotinamide adenine dinucleotide (NAD)-ase activity, which results in reduced levels of NAD+ in T cells, responsible for the loss of their effector functions (exhausted T cells). In murine models, anti-CD38 mAbs administration induced higher levels of NAD+ in T effector cells, thus enhancing their antitumor activity [23]. The main mechanisms of action of anti-CD38 monoclonal antibodies are summarized in Figure 1.

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“…An ongoing phase I study is investigating isatuximab, in combination with VRd (Isa-VRd): the first report on 22 patients showed good tolerability, with 46% of grade ≥3 AEs, mostly hematologic. Besides, response rates are promising, with MRD negativity rates (10 −6 ) by NGS of 33% and by NGF 18% [111].…”

Section: Asct-ineligible Patientsmentioning

confidence: 98%

Pursuing a Curative Approach in Multiple Myeloma: A Review of New Therapeutic Strategies

D’Agostino

Bertamini

Oliva

et al. 2019

Cancers

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Multiple myeloma (MM) is still considered an incurable hematologic cancer and, in the last decades, the treatment goal has been to obtain a long-lasting disease control. However, the recent availability of new effective drugs has led to unprecedented high-quality responses and prolonged progression-free survival and overall survival. The improvement of response rates has prompted the development of new, very sensitive methods to measure residual disease, even when monoclonal components become undetectable in patients' serum and urine. Several scientific efforts have been made to develop reliable and validated techniques to measure minimal residual disease (MRD), both within and outside the bone marrow. With the newest multidrug combinations, a good proportion of MM patients can achieve MRD negativity. Long-lasting MRD negativity may prove to be a marker of "operational cure", although the follow-up of the currently ongoing studies is still too short to draw conclusions. In this article, we focus on results obtained with new-generation multidrug combinations in the treatment of high-risk smoldering MM and newly diagnosed MM, including the potential role of MRD and MRD-driven treatment strategies in clinical trials, in order to optimize and individualize treatment.

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Preliminary Results from a Phase I Study of Isatuximab (ISA) in Combination with Bortezomib, Lenalidomide, Dexamethasone (VRd), and in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Non-Eligible for Transplant

Cited by 24 publications

References 0 publications

Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab

Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

Pursuing a Curative Approach in Multiple Myeloma: A Review of New Therapeutic Strategies

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