Johannes Waldschmidt

Potent in vitro and in vivo activity of sorafenib in multiple myeloma: induction of cell death, CD138-downregulation and inhibition of migration through actin depolymerization.

Despite considerable advances, multiple myeloma (MM) remains incurable and the development of novel therapies targeting the interplay between plasma cells (PCs) and their bone marrow (BM) microenvironment remains essential. We investigated the effect of various agents in vitro on the proliferation, phenotype, morphology, actin polymerization and migration of MM cells and, in vivo, the tumour growth of L363‐bearing non‐obese diabetic severe combined immunodeficient mice with a deficient interleukin‐2 receptor gamma chain (NSG). In vitro, we observed a dose‐dependent cytotoxicity with bortezomib and sorafenib. Using RPMI8226 cells co‐expressing histone 2B‐mCherry and cytochrome c‐GFP, bortezomib‐ and sorafenib‐induced apoptosis was confirmed, and both agents combined showed synergism. Sorafenib induced CD138‐downregulation and abolished CXCL12‐induced actin polymerization. L363 cells expressed CCR4 and CCR5 and migrated to their common ligand CCL5. Chemotaxis to BM stroma cells was notable and significantly reduced by sorafenib. Downregulation of phospho‐ERK appeared relevant for the inhibition of actin polymerization and chemotaxis. Sorafenib alone, and combined with bortezomib, showed substantial antitumour activity in L363‐bearing NSG. Correspondingly, sorafenib induced clinical responses in MM‐/AL‐amyloidosis patients. We conclude that, in addition to the cytotoxic and anti‐angiogenic effects of sorafenib, blocking of MM cell migration and homing represent promising mechanisms to interrupt the interplay between PCs and their supportive microenvironment.

Large registry analysis to accurately define second malignancy rates and risks in a well-characterized cohort of 744 consecutive multiple myeloma patients followed-up for 25 years

Additional malignancies in multiple myeloma patients after first-line and maintenance treatment have been observed, questioning whether specific risks exist. Second primary malignancies have also gained attention since randomized data showed associations to newer drugs. We have conducted this large registry analysis in 744 consecutive patients and analyzed: 1) frequency and onset of additional malignancies; and 2) second primary malignancy- and myeloma-specific risks. We assessed the frequency of additional malignancies in terms of host-, myeloma- and treatment-specific characteristics. To compare these risks, we estimated cumulative incidence rates for second malignancies and myeloma with Fine and Gray regression models taking into account competing risks. Additional malignancies were found in 118 patients: prior or synchronous malignancies in 63% and subsequent in 37%. Cumulative incidence rates for second malignancies were increased in IgG-myeloma and decreased in bortezomib-treated patients (P<0.05). Cumulative incidence rates for myeloma death were increased with higher stage and age, but decreased in IgG-subtypes and due to anti-myeloma treatment (P<0.05). Cytogenetics in patients acquiring second primary malignancies were predominantly favorable, suggesting that indolent myeloma and long disease latency may allow the manifestation of additional malignancies. An assessment of the Surveillance, Epidemiology, and End Result Program of the National Cancer Institute and our data with long-term follow up of 25 years confirmed a prevalence of second malignancy of 10% at 25 years, whereas death from myeloma decreased from 90% to 83%, respectively. Our important findings widen our knowledge of second malignancies and show that they are of increasing relevance as the prognosis in myeloma improves and mortality rates decrease.

Preclinical models of multiple myeloma: a critical appraisal

Introduction: Preclinical models, by definition, are an approximation of reality, and their use in developing anticancer drugs is eagerly explored. Positive clinical correlations have been identified with different test systems, in addition to limitations and a need to improve preclinical model systems. Predicting whether a potential new anticancer agent will have a positive therapeutic index in patients remains a challenge. Areas covered: We here review the fundamental requirements and remarkable progress of preclinical in vitro and in vivo assays used to assess the therapeutic potential of experimental anticancer drugs in multiple myeloma (MM). In MM, the interaction with the bone marrow microenvironment (BMM) plays a crucial role in disease progression, including resistance to antimyeloma agents. In vitro and in vivo approaches are, therefore, discussed with respect to their ability to mimic the important characteristics of MM and its BMM. In general, MM models should parallel the biological, genetic, etiological, immunological and therapeutic properties of the human disease. Expert opinion: All models discussed here have their defined strengths, but also limitations with respect to their predictive features. Understanding the preclinical models in a more profound way should lead to optimized clinical trials, thereby expanding the therapeutic arsenal and improving patient outcome further.

CXCL12 and CXCR7 are relevant targets to reverse cell adhesion-mediated drug resistance in multiple myeloma

Cell adhesion‐mediated drug resistance (CAM‐DR) by the bone marrow (BM) is fundamental to multiple myeloma (MM) propagation and survival. Targeting BM protection to increase the efficacy of current anti‐myeloma treatment has not been extensively pursued. To extend the understanding of CAM‐DR, we hypothesized that the cytotoxic effects of novel anti‐myeloma agents may be abrogated by the presence of BM stroma cells (BMSCs) and restored by addition of the CXCL12 antagonist NOX‐A12 or the CXCR4 inhibitor plerixafor. Following this hypothesis, we evaluated different anti‐myeloma agents alone, with BMSCs and when combined with plerixafor or NOX‐A12. We verified CXCR4, CD49d (also termed ITGA4) and CD44 as essential mediators of BM adhesion on MM cells. Additionally, we show that CXCR7, the second receptor of stromal‐derived‐factor‐1 (CXCL12), is highly expressed in active MM. Co‐culture proved that co‐treatment with plerixafor or NOX‐A12, the latter inhibiting CXCR4 and CXCR7, functionally interfered with MM chemotaxis to the BM. This led to the resensitization of MM cells to the anti‐myeloma agents vorinostat and pomalidomide and both proteasome inhibitors bortezomib and carfilzomib. Within a multicentre phase I/II study, NOX‐A12 was tested in combination with bortezomib‐dexamethasone, underlining the feasibility of NOX‐A12 as an active add‐on agent to antagonize myeloma CAM‐DR.

From CLL to Multiple Myeloma - Spleen Tyrosine Kinase (SYK) influences multiple myeloma cell survival and migration

Arnaud Petit Andr e Baruchel Jacqueline Clavel Benôıt Brethon Yves Bertrand Patrick Lutz Fabienne Nacka St ephane Ducassou Unit of Paediatric Haematology and Oncology, Bordeaux University Hospital, Bordeaux-Cedex, Unit of Paediatric Haematology and Oncology, Armand Trousseau Hospital, Unit of Paediatric Haematology and Immunology, Robert Debr e Hospital, Paris, Institut National de la Sant e et de la recherche M edicale (INSERM), Unit754, Registry of Malignant Hemopathies in childhood, Villejuif, Institute of Paediatric Haematology and Oncology, 1, place du Professeur Joseph Renault, Lyon, Unit of Paediatric Haematology and Oncology, Hautepierre Hospital, Strasbourg, and Clinical Investigation Centre in Paediatrics CIC 1401, Bordeaux University Hospital, Bordeaux-Cedex, France E-mail: stephane.ducassou@chu-bordeaux.fr

Safety and efficacy of vorinostat, bortezomib, doxorubicin and dexamethasone in a phase I/II study for relapsed or refractory multiple myeloma (VERUMM study: vorinostat in elderly, relapsed and unfit multiple myeloma).

This phase I/II trial was conducted to investigate the safety, efficacy, and pharmacodynamics of the pan-HDAC-inhibitor (HDACi) vorinostat combined with bortezomib, doxorubicin, and dexamethasone (VBDD) in patients suffering from relapsed/refractory multiple myeloma (RRMM). In the phase I part of this study, 9/33 patients received dose-escalated vorinostat (100, 200, 300mg), using a 4-day-on and 4-day-off schedule, and a standard 3+3 design. In the phase II part of the study, 24/33 patients were included to further assess VBDDs safety and efficacy. Complementary analyses were performed throughout the trial to correlate clinical outcome with patient fitness, pharmacodynamics and potential biomarkers. The number of prior therapy lines was substantial with a median of 3 (1-9; prior bortezomib treatment: 88%). VBDD was well tolerated with no dose-limiting toxicity: 15 adverse events occurred in 9/33 (27%) patients. The best overall response rate was 67% and clinical benefit rate 94%. With a median follow-up of 30.8 months, median progression-free- and overall-survival were 9.6 and 33.8 months, respectively. VBDD-responders showed early pan-HDAC activity decreases in peripheral blood mononuclear cell samples (median 45% of pre-treatment levels), of bone marrow (BM) infiltration rates and of BM-HDAC6 expression. VBDD proved to be an effective, well-tolerated outpatient quadruplet regimen with promising responses in RRMM. Our intermittent HDACi schedule provides a novel treatment option as compared to previous maximum-tolerated-dose-driven HDACi approaches and may serve as a useful example for other HDACi combinations, demonstrating that a continuous epigenetic treatment, with proven synergy to antimyeloma agents, is relevant before HDACi are dismissed as antimyeloma agents.