Bortezomib Retreatment in Relapsed Multiple Myeloma – Results from a Retrospective Multicentre Survey in Germany and Switzerland

Hrusovsky, Irena; Emmerich, B.; Rohr, A. von; Voegeli, Jerome; Taverna, Christian; Olie, Robert A.; Pliskat, Harold; Frohn, Claas; Heß, Georg

doi:10.1159/000322866

Cited by 40 publications

(51 citation statements)

References 27 publications

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“…Specifically, BTZ treatment of patients experienced progressive disease during BTZ treatment and BTZ based re-treatment as second-line therapy is known to be less efficient compared with BTZ treatment of patients who were BTZ-naïve. 44,45 These observations may support the hypothesis of the emergence of BTZ-resistant clones upon proteasome inhibitor-based drug therapy, and hence, supported clonal selection following cycles of retreatment. Such post-drug treatment specimens were not available for analysis in this study, because progressive disease is generally defined by an increase in M protein levels in combination with CRAB criteria (elevated Calcium, Renal failure, Anemia and Bone lesions), without the need for bone marrow analysis.…”

Section: Discussionsupporting

confidence: 66%

Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells

et al. 2011

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Proteasome inhibition is a novel treatment for several hematological malignancies. However, resistance to the proteasome inhibitor bortezomib (BTZ, Velcade) is an emerging clinical impediment. Mutations in the b5 subunit of the proteasome, the primary target of BTZ, have been associated with drug resistance. However, the exact mechanism by which these mutations contribute to BTZ resistance, is still largely unknown. Toward this end, we here developed BTZ-resistant multiple myeloma (8226) and acute lymphoblastic leukemia (CCRF-CEM) cell line models by exposure to stepwise increasing concentrations of BTZ. Characterization of the various BTZresistant cells revealed upregulation of mutant b5 subunit of the proteasome. These newly identified b5-subunit mutations, along with previously described mutations, formed a mutation cluster region in the BTZ-binding pocket of the b5 subunit, that of the S1 specificity pocket in particular. Moreover, we provide the first evidence that the mechanism underlying BTZ resistance in these tumor cells is impaired binding of BTZ to the mutant b5 subunit of the proteasome. We propose that proteasome subunit overexpression is an essential compensatory mechanism for the impaired catalytic activity of these mutant proteasomes. Our findings further suggest that second-generation proteasome inhibitors that target the a7 subunit of the proteasome can overcome this drug resistance modality.

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Section: Discussionsupporting

confidence: 66%

Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells

et al. 2011

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“…Also, in that POMP overexpression or suppression was by itself sufficient to confer resistance or sensitization to bortezomib, respectively, our findings indicate that POMP alone, aside from any impact on NRF2, is a mediator of bortezomib sensitivity. Thus, our cell lines may serve to some extent as models of what is seen clinically, because retreatment with bortezomib, even in patients who had all previously responded well to this agent, produces response rates of only 50 -60% (54,55), indicating a rapid acquisition of resistance. Moreover, the involvement of POMP may provide some indication of why these patients have a poor overall prognosis, because both NRF2 (56) and POMP (30) have been linked to cellular defense mechanisms against electrophilic and oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

The Nuclear Factor (Erythroid-derived 2)-like 2 and Proteasome Maturation Protein Axis Mediate Bortezomib Resistance in Multiple Myeloma

Chen

et al. 2015

Journal of Biological Chemistry

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Background: Acquired proteasome inhibitor resistance emerges in myeloma patients through incompletely understood mechanisms. Results: Activation of nuclear factor (erythroid-derived 2)-like 2 (NRF2) and proteassemblin (POMP) was linked to bortezomib resistance, while their inhibition reversed resistance. Conclusion:The NRF2/POMP axis contributes to bortezomib resistance. Significance: NRF2/POMP axis inhibition can be translated to the clinic to reverse bortezomib resistance and induce chemosensitization.

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“…In a retrospective multicenter survey of 94 relapsed MM patients who had responded to initial bortezomib treatment, no uncommon toxicity with bortezomib retreatment was identified, and efficacy data showed that 63% of patients responded to retreatment, with a median TTP of 9.3 months, consistent with sustained sensitivity to bortezomib. 46 A similar prospective phase 2 trial demonstrated an ORR of 32% and 42% in patients who received single-agent bortezomib and bortezomib-dexamethasone, respectively, as retreatment after initial response to bortezomib. 47 …”

Section: Re-treatment With Bortezomib For Relapsed MMmentioning

confidence: 97%

Proteasome inhibitors in multiple myeloma: 10 years later

Moreau

Richardson

Cavo

et al. 2012

Blood

449

369

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Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy.

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Bortezomib Retreatment in Relapsed Multiple Myeloma – Results from a Retrospective Multicentre Survey in Germany and Switzerland

Abstract: clusions: These results demonstrate that relapsed multiple myeloma patients who respond to initial bortezomib treatment have a sustained susceptibility to bortezomib and do not experience uncommon toxicity to retreatment.

Cited by 40 publications

References 27 publications

Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells

Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells

The Nuclear Factor (Erythroid-derived 2)-like 2 and Proteasome Maturation Protein Axis Mediate Bortezomib Resistance in Multiple Myeloma

Proteasome inhibitors in multiple myeloma: 10 years later

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