Phase I study of LY2127399, a human anti-BAFF antibody, and bortezomib in patients with previously treated multiple myeloma.

Raje, N.; Hohl, Raymond J.; Faber, Edward A.; Richardson, PG; Forero-Torres, A.; Schiller, Gary J.; Cohen, Alexa; Carpenter, Shana K.; Cronier, Damien M.; Pashkevich, Maksim; Wooldridge, James E.; Anderson, K. C.

doi:10.1200/jco.2011.29.15_suppl.8012

Cited by 14 publications

(8 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, preliminary results from phase 1 and 2 trials with several other antibodies and antibody-drug conjugates are very encouraging. [89][90][91][92][93][94][95][96][97][98][99][100] Given their unique mechanism of action as well as favorable tolerability, this new class of agents offers tremendous promise in further improving patient outcome in MM. The treatment of MM patients with antibody-based therapies will thus be a valuable approach in the relapsed/refractory setting especially in combination and should prove important for patients with newly diagnosed disease.…”

Section: Discussionmentioning

confidence: 99%

Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma

Donk

Moreau²,

Plesner

et al. 2016

Blood

183

146

View full text Add to dashboard Cite

Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma

Donk

Moreau²,

Plesner

et al. 2016

Blood

183

146

View full text Add to dashboard Cite

show abstract

“…In MCL cells autocrine secretion of BAFF appears to mediate a pro-survival effect that can be blocked with a BAFF-neutralizing antibody in vitro 4,5 . The BAFF-neutralizing antibody LY2127399 in combination with bortezomib induced PRs in 11 of 20 patients with relapsed myeloma 14 and may be worth studying in MCL.…”

Section: Targeting B-cell Activationmentioning

confidence: 99%

New molecular targets in mantle cell lymphoma

Parekh

Weniger

Wiestner

2011

Seminars in Cancer Biology

View full text Add to dashboard Cite

Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by aberrant expression of cyclin D1 due to the translocation t(11;14). Epigenomic and genomic lesions in pathways regulating B-cell activation, cell cycle progression, protein homeostasis, DNA damage response, cell proliferation and apoptosis contribute to its pathogenesis. While patients typically respond to first-line chemotherapy, relapse is the rule resulting in a median survival of 5–7 years. The PI3K/AKT/mTOR appears as a key pathway in the pathogenesis and can be targeted with small molecules. Most experience is with mTOR inhibitors of the rapamycin class. Second-generation mTOR inhibitors and the PI3K inhibitor CAL-101 are novel options to more effectively target this pathway. Bruton’s tyrosine kinase inhibition by PCI-32765 has promising activity and indicates immunoreceptor signaling as a novel therapeutic target. Up to 50% of relapsed patients respond to the proteasome inhibitor bortezomib suggesting that MCL may be particularly sensitive to disruption of protein homeostasis and/or induction of oxidative stress. Recent work has focused on elucidating the mechanism of bortezomib-induced cytotoxicity and the development of second-generation proteasome inhibitors. DNA hypomethylating agents and histone deacetylase inhibitors effect epigenetic de-repression of aberrantly silenced genes. These epigenetic pharmaceuticals and HSP90 inhibitors can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients a chance to benefit from these advances and is essential to maintain the momentum of progress. Innovative trial designs may be needed to expedite the clinical development of these targeted agents.

show abstract

“…An anti-BAFF MoAb, tabalumab, has been combined with bortezomib with or without dexamethasone with 46% achieving PR or better (table 3). 99 Siltuximab has a different mechanism as it is not directed against surface antigens but it targets soluble IL-6. Its purpose is to sequester this cytokine and prevent its binding to IL6-R .…”

Section: Agents With Novel Mechanisms Of Actionmentioning

confidence: 99%

New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG)

et al. 2013

View full text Add to dashboard Cite

Treatment in medical oncology is gradually shifting from the use of non-specific chemotherapeutic agents towards an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation- proteasome inhibitors, immunomodulatory agents (IMIDs) and alkylators). Then we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAb), cell cycle specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors, and kinase inhibitors. Among this plethora of new agents or mechanisms some are specially promising: Anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Also the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, that has produced exciting results in the relapsed/refractory setting.

show abstract

Phase I study of LY2127399, a human anti-BAFF antibody, and bortezomib in patients with previously treated multiple myeloma.

Cited by 14 publications

References 0 publications

Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma

Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma

New molecular targets in mantle cell lymphoma

New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG)

Contact Info

Product

Resources

About