Novel therapeutic strategies for multiple myeloma

Mimura, Naoya; Hideshima, Teru; Anderson, Kenneth C.

doi:10.1016/j.exphem.2015.04.010

Cited by 93 publications

(78 citation statements)

References 155 publications

(171 reference statements)

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“…The prognosis of patients with multiple myeloma (MM) has improved since the introduction of novel agents including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and, more recently, monoclonal antibodies and histone deacetylase inhibitors (Kumar, 2010; Moreau, 2012; Mimura et al , 2015). Improved treatment outcomes have increased the focus on extended treatment, including maintenance therapy.…”

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confidence: 99%

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

et al. 2016

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SummaryRenal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single‐dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end‐stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total ixazomib concentrations were similar in pre‐ and post‐dialyser samples collected from ESRD patients; therefore, ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI/ESRD.

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confidence: 99%

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

et al. 2016

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“…1,2 The response rate and overall survival of MM patients have significantly improved due to new therapeutics such as immunomodulators, proteasome inhibitors, and autologous stem cell transplantation. 2,3 However, de novo or acquired resistance to therapy arises and is the major cause of lethality. MM resistance is thought to be due, at least in part, to the emergence of cancer stem-like cells (CSLCs).…”

Section: Introductionmentioning

confidence: 99%

HIF-1α and rapamycin act as gerosuppressant in multiple myeloma cells upon genotoxic stress

et al. 2016

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Multiple myeloma (MM) is still an incurable hematological malignancy. Despite recent progress due to new anti-myeloma agents, the pathology is characterized by a high frequency of de novo or acquired resistance. Delineating the mechanisms of MM resistance is essential for therapeutic advances. We previously showed that long-term genotoxic stress induces the establishment of a senescence-associated secretory phenotype, a pro-inflammatory response that favors the emergence of cells with cancer stem-like properties. Here, we studied the short-term response of MM cells following treatment with various DNA damaging agents such as the energetic C-ion irradiation. MM cells are highly resistant to all treatments and do not enter apoptosis after they arrest cycling at the G2 phase. Although the DNA damage response pathway was activated, DNA breaks remained chronically in damaged MM cells. We found, using a transcriptomic approach that RAD50, a major DNA repair gene was downregulated early after genotoxic stress. In two gerosuppression situations: induction of hypoxia and inhibition of the mammalian target of rapamycin (mTOR) pathway, we observed, after the treatment with a DNA damaging agent, a normalization of RAD50 expression concomitant with the absence of cell cycle arrest. We propose that combining inhibitors of mTOR with genotoxic agents could avoid MM cells to senesce and secrete proinflammatory factors responsible for cancer stem-like cell emergence and, in turn, relapse of MM patients.

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“…1 It is characterized by the clonal expansion of malignant paraprotein-producing plasma cells that reside in the highly active immune environment of the bone marrow. 2 Myeloma is currently considered incurable for the majority of patients, with allogeneic hematopoietic stem cell transplantation (HSCT) being to date the only treatment modality that reports long-term remissions in a small subset of patients.…”

Section: Introductionmentioning

confidence: 99%

A transplant “immunome” screening platform defines a targetable epitope fingerprint of multiple myeloma

Schieferdecker

Oberle

Thiele

et al. 2016

Blood

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Key Points• The myeloma transplant B-cell immunome is predictive for response to treatment.• It may be exploited by immunosequencing and library technology as a source for unique target structures and antibodies for immunotherapy.Multiple myeloma (MM) is a hematological cancer for which immune-based treatments are currently in development. Many of these rely on the identification of highly diseasespecific, strongly and stably expressed antigens. Here, we profiled the myeloma B-cell immunome both to explore its predictive role in the context of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and to identify novel immunotherapeutic targets. We used random peptide phage display, reverse immunization, and nextgeneration sequencing-assisted antibody phage display to establish a highly myelomaspecific epitope fingerprint targeted by B-cell responses of 18 patients in clinical remission. We found that allogeneic HSCT more efficiently allowed production of myeloma-specific antibodies compared with autologous HSCT and that a highly reactive epitope recognition signature correlated with superior response to treatment. Next, we performed myeloma cell surface screenings of phage-displayed patient transplant immunomes. Although some of the screenings yielded clear-cut surface binders, the majority of screenings did not, suggesting that many of the targeted antigens may in fact not be accessible to the B-cell immune system in untreated myeloma cells. This fit well with the identification of heat-shock proteins as a class of antigens that showed overall the broadest reactivity with myeloma patient sera after allogeneic HSCT and that may be significantly translocated to the cell surface upon treatment as a result of immunogenic cell death. Our data reveal a disease-specific epitope signature of MM that is predictive for response to treatment. Mining of transplant immunomes for strong myeloma surface binders may open up avenues for myeloma immunotherapy. (Blood. 2016;127(25):3202-3214)

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Novel therapeutic strategies for multiple myeloma

Cited by 93 publications

References 155 publications

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

HIF-1α and rapamycin act as gerosuppressant in multiple myeloma cells upon genotoxic stress

A transplant “immunome” screening platform defines a targetable epitope fingerprint of multiple myeloma

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