Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology)

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Home administration of bortezomib in multiple myeloma is cost-effective and is preferred by patients compared with hospital administration: results of a prospective single-center study. Ann Oncol ; 27 : — Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN against multiple myeloma cells. Clin Cancer Res ; 17 : — Evaluation of the proteasome inhibitor MLN in preclinical models of human cancer. Cancer Res ; 70 : — Antitumor activity of the investigational proteasome inhibitor MLN in mouse models of B-cell and plasma cell malignancies.

Lancet Oncol ; 15 : — Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. A phase 2 study of single-agent carfilzomib PXA1 in patients with relapsed and refractory multiple myeloma. An open-label single-arm pilot phase II study PXA0 of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma.

Clin Lymphoma Myeloma Leuk ; 12 : — Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. Haematologica ; : 1— Elotuzumab therapy for relapsed or refractory multiple myeloma. Targeting CD38 with daratumumab monotherapy in multiple myeloma. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma SIRIUS : an open-label, randomised, phase 2 trial. Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinasedependent expression of MHC class I-related chain A and B.

Cancer Res ; 65 : — Nucleic Acids Res ; 34 : — The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Phase I trial of oral vorinostat suberoylanilide hydroxamic acid, SAHA in patients with advanced multiple myeloma. Leuk Lymphoma ; 49 : — Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma.

Clin Cancer Res ; 15 : — Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma VANTAGE : a multicentre, randomised, double-blind study. Lancet Oncol ; 14 : — Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma.

Blood Cancer J ; 4 : e Lenalidomide and vorinostat maintenance after autologous transplant in multiple myeloma. Br J Haematol ; : 74— The histone deacetylase inhibitor LBH is a potent antimyeloma agent that overcomes drug resistance. Cancer Res ; 66 : — Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase TDAC inhibitor LBH are synergistic in myeloma cells. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial.

Evidence of long-term disease control with panobinostat maintenance in patients with relapsed multiple myeloma. Haematologica ; : e—e Download references. The other authors declare no conflict of interest.

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Correspondence to M Mohty. This work is licensed under a Creative Commons Attribution 4. Bone Marrow Transplantation Annals of Hematology Article metrics. Advanced search.

Multiple Myeloma - Hematology and Oncology - MSD Manual Professional Edition

Skip to main content. Subjects Combination drug therapy Myeloma. Abstract Transplant-eligible patients with multiple myeloma MM now have extended survival after diagnosis owing to effective modern treatment strategies that include new agents in induction therapy, autologous stem cell transplant ASCT , consolidation therapy and posttransplant maintenance therapy. Introduction In the past two decades, multiple myeloma MM has emerged from being an almost uniformly fatal hematological malignancy to one for which there is now a major arsenal of transformative new therapies. Thalidomide maintenance Thalidomide was the first of the novel drugs belonging to the class of immunomodulatory agents IMIDs to garner interest as potential post-ASCT maintenance.

Lenalidomide maintenance Lenalidomide, a less toxic and more potent derivative of thalidomide with similar immunomodulatory effects, has been shown to be active in relapsed or refractory MM. Table 2: Major studies of lenalidomide maintenance Full size table. Bortezomib maintenance Bortezomib, the first novel agent in the class of proteasome inhibitors, has been shown in early trials to have significant activity in MM.

Table 3: Major studies of bortezomib maintenance Full size table.

Pursuing the Plasma Cell

Summary of available trials Most of the data to support maintenance therapy in the after autologous stem cell setting are related to the use of the oral IMIDS, thalidomide and lenalidomide. Monoclonal antibodies Monoclonal antibodies directed against targets expressed on myeloma cells have emerged as an effective treatment for MM. Summary Maintenance therapy in MM is an integral part of improving patient outcome after autologous hematopoietic stem cell transplantation due to its role in suppression of residual disease.

References 1. PubMed Article Google Scholar 3. Google Scholar 4. PubMed Article Google Scholar 5. Google Scholar 8.

Google Scholar 9. PubMed Article Google Scholar Google Scholar Article Google Scholar Rights and permissions This work is licensed under a Creative Commons Attribution 4. About this article Publication history Received 20 December Accepted 31 January Published 24 March Gonsalves , Francis K.

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Buadi , Sikander Ailawadhi , P. Leif Bergsagel , Asher A. Hayman , Prashant Kapoor , Taxiarchis V. Kourelis , Martha Q. Please be sure to include your name and mailing address exactly as they appear on the printed marketing materials you received. Emails : To opt out of receiving marketing communications via email, please send an unsubscribe request to the email address below or click on the unsubscribe link at the bottom of the email that was sent to you and follow the directions on the resulting web page.

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Pursuing the Plasma Cell

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If you withdraw your consent to the use or sharing of your Personal Data for the purposes set out in these Disclosures, you may not have access to all or any of the Website, and we might not be able to provide you all or any of the Website. Though we were not able to functionally assay myeloma-propagating capability in fresh samples from our clinical trial subjects, our analysis of bone marrow aspirates from a separate cohort of patients showed that ex vivo treatment with either CTL or anti-BCMA CAR T cells alone failed to reliably eliminate in vitro clonogenicity Figure 5.

We therefore suspect that surface immunophenotype is an imperfect predictor of myeloma-propagating potential; rather, the cell-surface immunophenotype of clinically important myeloma-propagating populations likely varies from patient to patient and may even change over time within individual patients during the long natural history of multiple myeloma. From a therapeutic perspective, together with evidence that less mature phenotypes become more frequent with successive lines of therapy 8 , 52 , our results provide rationale to broadly target both B cells and plasma cells to maximize the likelihood of eliminating all aspects of the myeloma clone, both the dominant plasma cell population and minor populations with less mature phenotypes.

Despite persistence of rare multiple myeloma plasma cells in bone marrow in both subjects, overt bone marrow relapse was not apparent. Isolated extramedullary progression i. A similar phenomenon has been observed in acute leukemia patients treated with allogeneic stem cell transplantation Thus, isolated extramedullary relapse may indicate effective anti-myeloma immune surveillance of the bone marrow.

Moreover, extramedullary progression in these subjects occurred long after CTL cells were no longer detectable in circulation or marrow.

Multiple Myeloma

These findings suggest that CTL induced clinically active, secondary immune responses that persisted even after loss of CTL engraftment. Epitope spreading has previously been observed in patients with solid tumors treated with anti-mesothelin CAR T cells Epitope spreading could potentially be enhanced by combining CAR T cell therapies with other immunomodulatory approaches such as immune checkpoint blockade. Though we did not in this study undertake a broad search for targets of epitope spreading, we were specifically interested in anti-Sox2 immune responses due to the potential mechanistic role of Sox2 in a myeloma-propagating phenotype 44 , Sox2 is a transcription factor that maintains capacity for self-renewal and pluripotency in embryonic stem cells In some human cancers, Sox2 defines a subset of cells with unique capacity to propagate malignancy i.

For example, Sox2 confers capacity for long-lived latency in breast cancer cells, and immune surveillance against these latent Sox2-expressing cells prevents metastatic outbreak Prior studies have implicated Sox2 in myeloma-propagating phenotypes in vitro 44 , Spontaneous anti-Sox2 immune responses are associated with decreased risk of progression from MGUS to symptomatic multiple myeloma but are generally not observed in patients with active myeloma except after allogeneic but not autologous stem cell transplantation 46 , 47 , Though anti-Sox2 immune responses themselves may or may not be directly clinically active, anti-Sox2 immune responses may be a marker of immune recognition and active surveillance against myeloma-propagating cells; this surveillance may contribute to clinical disease quiescence typical of MGUS, and loss of this surveillance may allow the aggressive growth that characterizes active multiple myeloma.

Others have observed induction of anti-Sox2 immune responses after immunotherapy targeting the B cell antigen CD20 63 that, like CD19, is typically absent on multiple myeloma plasma cells. Our finding that anti-Sox2 immune responses emerged in subjects 1 and 5 as their multiple myeloma transitioned to a more indolent clinical course suggests that induction of immunity against myeloma-propagating cells is a promising therapeutic strategy.

Moreover, our results suggest that Sox2 expression may be a more biologically relevant marker of myeloma-propagating cells than any particular cell-surface immunophenotype. Identification and monitoring of Sox2-expressing cells in patients may enable more specific targeting of myeloma-propagating cells with immunotherapies or other modalities.

An alternative explanation is that anti-Sox2 responses were due to expansion of preexisting anti-Sox2 T cells during the CAR T cell manufacturing process. Our results do not exclude this possibility, but we think this is unlikely based on the emergence in subject 1 of anti-Sox2 T cells long after peak in vivo expansion of CTL and reactivity against multiple Sox2 peptides, including those to which reactivity was not detected in pre-ASCT samples i.

Our study has several limitations. Our patient-specific comparisons to PFS after prior ASCT and our comparisons to a historical cohort therefore provide only preliminary evidence of clinical benefit from CTL, and our conclusions are based on clinical and correlative findings in only 2 subjects with favorable outcome.

Nonetheless, our results provide clear basis for future investigations. Specifically, our results provide rationale for clinical studies testing whether CTL can increase the durability of response to anti-BCMA CAR T cells, for which phase 1 studies have shown promising safety and initial responses but durable response in only a subset of patients 50 , 51 , Our results also provide a framework for understanding heterogeneity between patients in the immunophenotype of myeloma-propagating cells.

Beyond multiple myeloma, our results provide clinical evidence in support of the cancer stem cell hypothesis 65 and the ability of potent immunotherapies targeted to minor disease-propagating populations to favorably alter the clinical trajectory of advanced cancers. Clinical trial design. The clinical trial was conducted at the University of Pennsylvania. Standard supportive care was provided after high-dose melphalan including hematopoietic support with transfusions and filgrastim. Maintenance lenalidomide beginning at approximately day after ASCT was permitted if subjects had received maintenance lenalidomide after prior ASCT.

The primary endpoint of the study was safety and feasibility of CTL administration in this clinical setting. CTL production. CTL cells were manufactured from an autologous leukapheresis product as previously described Autologous T cells were stimulated by paramagnetic polystyrene beads coated with anti-CD3 and anti-CD28 monoclonal antibodies and transduced with a lentiviral vector encoding an anti-CD19 single-chain variable fragment linked to BB and CD3-zeta signaling domains as previously described during an ex vivo expansion period of 9—10 days.

Multiple myeloma immunophenotyping. Permeabilization and fixation reagents were obtained from Becton Dickinson. Monitoring of in vivo CTL frequency and activity. Peripheral blood and bone marrow samples were processed and evaluated for CTL by flow cytometry using an antibody specific for the anti-CD19 idiotype and qPCR for lentiviral vector sequences as previously described Anti-Sox2 antibody detection. Plates were washed with PBS containing 0. After washing, detection reagent TMB substrate Thermo Fisher Scientific was added, and the detection reaction was terminated after 30 minutes at room temperature with 2N HCl.

Anti-Sox2 T cell detection. An overlapping SOX2 peptide library encompassing the entire SOX2 protein was generated as previously described 47 and peptides pooled into 4 mixes mix 1 containing SOX2 amino acids 1—89, mix 2 containing amino acids 79—, mix 3 containing amino acids —, and mix 4 containing amino acids — CEF peptide mix Sigma-Aldrich; 2. Ex vivo CAR T cell incubations and multiple myeloma colony formation assays. Myeloma tumor colonies were quantified using an inverted microscope 14—21 days after plating.

Statistical analyses were performed with Stata StataCorp. Study approvals. All patients gave informed consent in accordance with the Declaration of Helsinki. This study was registered at clinicaltrials. All authors participated in drafting and revision of the manuscript.

We gratefully acknowledge study subjects and their families for their participation in this clinical trial. We thank Jonathan Agudelo and Lee Dengel for clinical research support. Garfall, K08CA to M.

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Garfall and M. PAM has received consulting fees from Kite Pharma. Competing interests of authors from the University of Pennsylvania are managed in accordance with University policies. Reference information: JCI Insight. Go to The Journal of Clinical Investigation. Amendment history: Corrigendum February Figure 1 Subject flow diagram. Table 1 Patient characteristics and clinical responses. Table 2 Grade 3 or higher adverse events emerging after CTL

Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology) Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology)
Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology) Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology)
Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology) Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology)
Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology) Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology)
Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology) Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology)
Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology) Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology)
Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology) Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology)
Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology) Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology)
Myeloma Therapy: Pursuing the Plasma Cell (Contemporary Hematology)

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