M. Delforge MD, PhD

Diagnosis and treatment of AL amyloidosis: Belgian guidelines

SUMMARY

Immunoglobulin light chain (AL) amyloidosis is a rare and serious disease due to the deposition of amyloid fibrils. In the past years, improvements have been made in the diagnosis, treatment and response criteria. Based on an extensive review of the recent literature on AL amyloidosis, we propose practical recommenddations that can be used by Belgian haematologists as a reference for daily practice. Management of other types of amyloidosis will not be covered by this review. Levels of evidence and grades of recommendations are based on previously published methods.¹ We recommend participation in clinical trials to gain knowledge in this evolving field.

(BELG J HEMATOL 2020;11(8):343-56)

Practical management of multiple myeloma: Update 2020

SUMMARY

With the introduction of immunomodulatory drugs, proteasome inhibitors and anti-CD38 monoclonal antibodies, major improvements have been achieved in the treatment and outcome of multiple myeloma (MM). Different treatment combinations are now in use and other therapies are being developed. This rapidly changing therapeutic landscape urges for an update on practical guidelines. Based on an extensive review of the recent literature, we propose recommendations on myeloma management, to be used by haematologists as a reference for daily practice.

(BELG J HEMATOL 2020;11(7):286-304)

In search of novel working mechanisms of proteasome inhibitors in multiple myeloma

SUMMARY

Proteasome inhibitors (PIs) constitute one of the cornerstones of the treatment of multiple myeloma (MM), with bortezomib, carfilzomib and ixazomib being approved for clinical use. Due to the relatively recent introduction of PIs to clinical practice, many aspects of the pleiotropic effects of PIs still remain unexplored, particularly for the second-generation PIs carfilzomib and ixazomib. Since MM still remains incurable and many patients will eventually develop treatment-refractory disease, the search for validated biomarkers to predict treatment response is of great clinical importance. In the first aim of this project, we evaluated the effect of proteasome inhibitors on erythropoiesis. During the follow-up of MM patients treated with PIs in the first part of this project, we observed a consistent and highly significant increase in the reticulocyte count during treatment with carfilzomib-based regimens in patients with relapsed multiple myeloma. This observation was not made in a matched cohort of bortezomib-treated patients. In subsequent ex vivo experiments, we demonstrated that carfilzomib exposure significantly impaired terminal erythroid maturation, independent of erythroid commitment, expansion or differentiation. Our results therefore report the first pharmacologically induced delay in erythroid maturation as a mechanism for carfilzomib-induced reticulocytosis in patients with multiple myeloma. These findings might therefore lead to new therapeutic applications for carfilzomib in disorders of mature erythrocytes, such as sickle cell anaemia. In the second part of this project, we evaluated proteasome activity as a potential biomarker for PI drug sensitivity. For this purpose, we measured proteasome activity in primary myeloma cells, purified from the bone marrow of patients with MM. Baseline proteasome activity was not significantly different in myeloma cells derived from treatment-responsive or –refractory MM patients. The degree of proteasome inhibition by PIs was similar in both groups. As a result, the clinical applicability of proteasome activity as a biomarker for drug sensitivity in MM currently remains limited. Nevertheless, these data also suggest that drug sensitivity to PIs is in part proteasome-independent, indicating that our understanding of PI drug resistance should be further improved. In a follow-up project to the present thesis, we have designed several genome-wide screening experiments using CRISPR-Cas9 technology to gain novel insights in the mechanisms driving drug resistance to PIs in MM.

(BELG J HEMATOL 2020;11(3):133–5)

P.17 Feasibility of next generation flow for minimal residual disease in multiple myeloma on a BD FACS Lyric flowcytometer

Highlights in multiple myeloma

Summary

By tradition, multiple myeloma (MM) was again well represented in the different sessions during ASH 2019. This overview focusses on the most important clinical developments in MM that were presented at the last ASH meeting taking place early December in Orlando. We have selected the abstracts and presentations that we consider to be relevant for the Belgian healthcare system and for haematologists treating MM patients.

(BELG J HEMATOL 2020;11(1):9–12)

Anti-CD38 monoclonal antibodies in the treatment of multiple myeloma

SUMMARY

As the surface antigen CD38 is highly expressed on malignant plasma cells, it provides an interesting therapeutic target for the treatment of multiple myeloma (MM). At present, three anti-CD38 monoclonal antibodies (mAb) have been studied in MM: daratumumab, isatuximab and MOR202. All three anti-CD38 mAb show complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibodydependent cellular phagocytosis (ADCP) activities. Moreover, immunomodulatory effects of daratumumab and isatuximab have been demonstrated. At present, daratumumab has been the most extensively studied anti-CD38 mAb in clinical trials. Following the excellent results of phase III clinical trials in relapsed/refractory MM (RRMM), daratumumab has recently also been studied in phase III clinical trials in newly diagnosed patients. The effects of isatuximab and MOR202 have been studied in phase III and phase I clinical trials, respectively, in patients with RRMM.

(BELG J HEMATOL 2019;10(8):326–31)

Highlights in multiple myeloma

SUMMARY

Over the last few years, the treatment landscape for patients with multiple myeloma (MM) changed dramatically. Also the 2019 annual meeting of the European Hematology Association featured several interesting MM abstracts. In this article we will discuss 6 highlights from the meeting. For a more complete overview of MM news at EHA 2019 we would like to refer to the congress website (https://ehaweb.org/congress/previous-congresses/eha24/abstracts-online-2/).

(BELG J HEMATOL 2019;10(5):203–7)