Biology and management of myeloma-related bone disease

Bone disease is one of the most common complications of multiple myeloma. It is the result of increased osteoclast activity which is not compensated by osteoblast activity and leads to osteolytic lesions characterized by bone pain and increased risk for pathological fracture, spinal cord compression and need for radiotherapy or surgery to the bone. Recent studies have revealed novel pathways and molecules that are involved in the biology of myeloma bone disease including the receptor activator of nuclear factor-kappa B ligand/osteoprotegerin pathway, the Wnt signaling inhibitors dickkopf-1 and sclerostin, macrophage inflammatory proteins, activin A, and others. A thorough study of these pathways have provided novel agents that may play a critical role in the management of myeloma related bone disease in the near future, such as denosumab (anti-RANKL), sotatercept (activin A antagonist), romosozumab (anti-sclerostin) or BHQ-880 (anti-dickkopf 1). Currently, bisphosphonates are the cornerstone in the treatment of myeloma related bone disease. Zoledronic acid and pamidronate are used in this setting with very good results in reducing skeletal-related events, but they cannot be used in patients with severe renal impairment. Furthermore, they have some rare but serious adverse events including osteonecrosis of the jaw and acute renal insufficiency. This review paper focuses on the latest advances in the pathophysiology of myeloma bone disease and in the current and future treatment options for its management

Antibody Therapies for Multiple Myeloma

Multiple Myeloma (MM) is characterized by the abberant proliferation and expansion of plasma cells in the Bone marrow. Despite the broad use of proteasome inhibitors and IMiDs, Multiple Myeloma remains an incurable disease. The introduction of Monoclonal antibodies, along with bi-specific antibodies and check point inhibitors, has significantly enhanced the armamentarium of available therapeutic options in the relapsed setting. The incorporation of the above-mentioned novel agents in triplet or quadruplet therapeutic regimens has led to significant prolongation of overall survival (OS) and progression free survival (PFS), without adding significant toxicity. Anti-CD38 monoclonal antibodies has become the cornerstone of antimyeloma therapy in both the newly diagnosed and relapsed setting

Impact of minimal residual disease detection by next-generation flow cytometry in multiple myeloma patients with sustained complete remission after frontline therapy

Minimal residual disease (MRD) was monitored in 52 patients with sustained CR (≥2 years) after frontline therapy using next-generation flow (NGF) cytometry. 25% of patients initially MRD- reversed to MRD+. 56% of patients in sustained CR were MRD+; 45% at the level of 10−5; 17% at 10−6. All patients who relapsed during follow-up were MRD+ at the latest MRD assessment, including those with ultra-low tumor burden. MRD persistence was associated with specific phenotypic profiles: higher erythroblasts’ and tumor-associated monocytes/macrophages’ predominance in the bone marrow niche. NGF emerges as a suitable method for periodic, reproducible, highly-sensitive MRD-detection at the level of 10−6

Personalised progression prediction in patients with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma (PANGEA): a retrospective, multicohort study

BACKGROUND: Patients with precursors to multiple myeloma are dichotomised as having monoclonal gammopathy of undetermined significance or smouldering multiple myeloma on the basis of monoclonal protein concentrations or bone marrow plasma cell percentage. Current risk stratifications use laboratory measurements at diagnosis and do not incorporate time-varying biomarkers. Our goal was to develop a monoclonal gammopathy of undetermined significance and smouldering multiple myeloma stratification algorithm that utilised accessible, time-varying biomarkers to model risk of progression to multiple myeloma. METHODS: In this retrospective, multicohort study, we included patients who were 18 years or older with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma. We evaluated several modelling approaches for predicting disease progression to multiple myeloma using a training cohort (with patients at Dana-Farber Cancer Institute, Boston, MA, USA; annotated from Nov, 13, 2019, to April, 13, 2022). We created the PANGEA models, which used data on biomarkers (monoclonal protein concentration, free light chain ratio, age, creatinine concentration, and bone marrow plasma cell percentage) and haemoglobin trajectories from medical records to predict progression from precursor disease to multiple myeloma. The models were validated in two independent validation cohorts from National and Kapodistrian University of Athens (Athens, Greece; from Jan 26, 2020, to Feb 7, 2022; validation cohort 1), University College London (London, UK; from June 9, 2020, to April 10, 2022; validation cohort 1), and Registry of Monoclonal Gammopathies (Czech Republic, Czech Republic; Jan 5, 2004, to March 10, 2022; validation cohort 2). We compared the PANGEA models (with bone marrow [BM] data and without bone marrow [no BM] data) to current criteria (International Myeloma Working Group [IMWG] monoclonal gammopathy of undetermined significance and 20/2/20 smouldering multiple myeloma risk criteria). FINDINGS: We included 6441 patients, 4931 (77%) with monoclonal gammopathy of undetermined significance and 1510 (23%) with smouldering multiple myeloma. 3430 (53%) of 6441 participants were female. The PANGEA model (BM) improved prediction of progression from smouldering multiple myeloma to multiple myeloma compared with the 20/2/20 model, with a C-statistic increase from 0·533 (0·480-0·709) to 0·756 (0·629-0·785) at patient visit 1 to the clinic, 0·613 (0·504-0·704) to 0·720 (0·592-0·775) at visit 2, and 0·637 (0·386-0·841) to 0·756 (0·547-0·830) at visit three in validation cohort 1. The PANGEA model (no BM) improved prediction of smouldering multiple myeloma progression to multiple myeloma compared with the 20/2/20 model with a C-statistic increase from 0·534 (0·501-0·672) to 0·692 (0·614-0·736) at visit 1, 0·573 (0·518-0·647) to 0·693 (0·605-0·734) at visit 2, and 0·560 (0·497-0·645) to 0·692 (0·570-0·708) at visit 3 in validation cohort 1. The PANGEA models improved prediction of monoclonal gammopathy of undetermined significance progression to multiple myeloma compared with the IMWG rolling model at visit 1 in validation cohort 2, with C-statistics increases from 0·640 (0·518-0·718) to 0·729 (0·643-0·941) for the PANGEA model (BM) and 0·670 (0·523-0·729) to 0·879 (0·586-0·938) for the PANGEA model (no BM). INTERPRETATION: Use of the PANGEA models in clinical practice will allow patients with precursor disease to receive more accurate measures of their risk of progression to multiple myeloma, thus prompting for more appropriate treatment strategies. FUNDING: SU2C Dream Team and Cancer Research UK

Μελέτη έκφρασης γενετικών πολυμορφισμών που συνδέονται με μεταβολές της οστικής πυκνότητας σε ασθενείς με Πολλαπλό Μυέλωμα

Το Πολλαπλό Μυέλωμα (ΠΜ) αποτελεί μία από τις συχνότερες κακοήθειες. Αντιστοιχεί στο 10% των αιματολογικών και στο 1% του συνόλου των κακοηθειών [1]. Το 2018, οι νέες διαγνώσεις ήταν 48.300 ενώ 30.900 άτομα υπολογίστηκε ότι πέθαναν από τη νόσο [2]. Η διάμεση ηλικία κατά τη διάγνωση είναι τα 65 έτη. Λιγότερο από το 3% των ασθενών διαγιγνώσκονται πριν από την ηλικία των 40 ετών. Ένα από τα βασικά χαρακτηριστικά του ΠΜ είναι η οστική νόσος, η οποία προκύπτει ως αποτέλεσμα αυξημένης λειτουργίας των οστεοκλαστών η οποία δεν συνοδεύεται από αποτελεσματική λειτουργία των οστεοβλαστών[3]. Οστεολυτικές βλάβες ανιχνεύονται στο 70-80% των ασθενών κατά τη διάγνωση και αυξάνουν τον κίνδυνο για σκελετικά συμβάντα (SREs: παθολογικά κατάγματα, συμπίεση νωτιαίου μυελού (SCC), απαίτηση για χειρουργική επέμβαση ή ακτινοθεραπεία στα οστά). Τα SRE έχουν αντίκτυπο στην ποιότητα ζωής (QoL) και την επιβίωση των ασθενών με ΠΜ και επηρεάζουν τόσο την κλινική εικόνα όσο και τις οικονομικές πτυχές της ζωής τους Οι πληροφορίες αναφορικά με τη συχνότητα των σκελετικών συμβάντων (SREs) σε νεοδιαγνωσθέντες ασθενείς με πολλαπλό μυέλωμα (ΠΜ) στην εποχή των νεότερων παραγόντων είναι πολύ περιορισμένες. Για το λόγο αυτό, πραγματοποιήσαμε αυτήν την μονοκεντρική, προοπτική, μελέτη παρατήρησης για να προσδιορίσουμε την επίπτωση των SREs μεταξύ των νεοδιαγνωσθέντων ασθενών με ΠΜ και για τη διερεύνηση των πιθανών συσχετίσεων με τα χαρακτηριστικά της νόσου, απεικονιστικά ευρήματα και πρόγνωση των ασθενών. Έλαβαν μέρος συνολικά 370 ασθενείς. Μεταξύ αυτών, 208 (56%) παρουσίασαν τουλάχιστον ένα SRE στο διάγνωση. Τα κατάγματα ήταν τα πιο συχνά αναφερόμενα SRE (48%). Η συχνότητα εμφάνισης SRE κατά τη διάγνωση ήταν υψηλότερη σε ασθενείς με οστεολυτικές βλάβες, παθολογικό πρότυπο μαγνητικής τομογραφίας, υπερασβεστιαιμία και δίηθηση μυελού μεγαλύτερη από 60%. Σημαντικό εύρημα της παρούσας μελέτης αποτελεί το γεγονός ότι οι ασθενείς με φυσιολογικό πρότυπο μαγνητικής τομογραφίας και απουσία σκελετικών συμβαμάτων κατά τη διάγνωση, είχαν στατιστικά σημαντικά βελτιωμένη διάμεση συνολική επιβίωση (OS) σε σύγκριση με τους ασθενείς που είχαν παθολογικά πρότυπα μαγνητικής τομογραφίας ή/και παρουσία SRE κατά τη διάγνωση (9,3 vs. 6,6 έτη, p = 0,048). Τα δεδομένα μας, τα οποία αντιπροσωπεύουν μία από τις λίγες συστηματικές αναφορές για τη συχνότητα και χαρακτηριστικά των SREs στην εποχή των νεότερων παραγόντων, ανέδειξαν υψηλή συχνότητα εμφάνισης SRE κατά τη διάγνωση. Η έγκαιρη ανίχνευση της οστικής νόσου και η εξατομικευμένη διαχείριση του ασθενούς είναι απαραίτητα για τη βελτιστοποίηση των αποτελεσμάτων.Multiple myeloma (MM) represents one of the most common hematological malignancy, accounting for 10 %of all hematologic malignancies and 1% of all cancers [1]. In 2018, 48,300 adults were estimated to be newly diagnosed with MM (NDMM), and 30 900 have died from the disease [2]. The median age at diagnosis is 65 years. Less than 3% of patients are diagnosed before the age of 40. One of MM hallmarks is osteolytic bone disease due to an elevated function of osteoclasts which is not accompanied by effective osteoblast function[3]. Osteolytic lesions are detected in 70–80% of patients at diagnosis and increase the risk for skeletal-related events (SREs: pathologic fractures, spinal cord compression (SCC), requirement for surgery or palliative radiotherapy to bone). SREs have a profound impact on the quality of life (QoL) and survival of MM patients and affect both clinical and economic aspects of their life Contemporary information is sparse on the frequency of skeletal-related events (SREs) in multiple myeloma (MM) patients at a population-based level in the era of novel agents. In this context, we conducted this single-center, prospective, observational study to determine the incidence of SREs among newly diagnosed MMs (NDMM) and to explore the possible correlations with disease characteristics, imaging finding, and patient prognosis. A total of 370 patients with available baseline MRIs were included. Among them, 208 (56%) presented with at least one SRE at diagnosis. Fractures were the most common reported SREs (48%). The incidence of SREs at diagnosis was higher in patients with osteolytic lesions, abnormal MRI pattern, hypercalcemia, and at least 60% bone marrow infiltration by plasma cells. Importantly, the patients with normal MRI pattern, who did not present with SREs at diagnosis, had statistically significant improved median OS in comparison with the patients who had abnormal MRI patterns and/or the presence of SREs at diagnosis (9.3 vs. 6.6 years, p = 0.048). Our data, which represent one of a few systematic reports on the incidence and characteristics of SREs in the era of novel agents, was indicative of a high incidence of SREs at the time of MM diagnosis. Early detection of myeloma bone disease and tailored patient management are essential to optimize patient outcomes

Expression of genetic polymorphism associated with changes in bone mineral density in patients with Multiple Myeloma: a single-center study

Multiple myeloma (MM) represents one of the most common hematological malignancy, accounting for 10 %of all hematologic malignancies and 1% of all cancers [1]. In 2018, 48,300 adults were estimated to be newly diagnosed with MM (NDMM), and 30 900 have died from the disease [2]. The median age at diagnosis is 65 years. Less than 3% of patients are diagnosed before the age of 40. One of MM hallmarks is osteolytic bone disease due to an elevated function of osteoclasts which is not accompanied by effective osteoblast function[3]. Osteolytic lesions are detected in 70–80% of patients at diagnosis and increase the risk for skeletal-related events (SREs: pathologic fractures, spinal cord compression (SCC), requirement for surgery or palliative radiotherapy to bone). SREs have a profound impact on the quality of life (QoL) and survival of MM patients and affect both clinical and economic aspects of their lifeContemporary information is sparse on the frequency of skeletal-related events (SREs) in multiple myeloma (MM) patients at a population-based level in the era of novel agents. In this context, we conducted this single-center, prospective, observational study to determine the incidence of SREs among newly diagnosed MMs (NDMM) and to explore the possible correlations with disease characteristics, imaging finding, and patient prognosis. A total of 370 patients with available baseline MRIs were included. Among them, 208 (56%) presented with at least one SRE at diagnosis. Fractures were the most common reported SREs (48%). The incidence of SREs at diagnosis was higher in patients with osteolytic lesions, abnormal MRI pattern, hypercalcemia, and at least 60% bone marrow infiltration by plasma cells. Importantly, the patients with normal MRI pattern, who did not present with SREs at diagnosis, had statistically significant improved median OS in comparison with the patients who had abnormal MRI patterns and/or the presence of SREs at diagnosis (9.3 vs. 6.6 years, p = 0.048). Our data, which represent one of a few systematic reports on the incidence and characteristics of SREs in the era of novel agents, was indicative of a high incidence of SREs at the time of MM diagnosis. Early detection of myeloma bone disease and tailored patient management are essential to optimize patient outcomes.Το Πολλαπλό Μυέλωμα (ΠΜ) αποτελεί μία από τις συχνότερες κακοήθειες. Αντιστοιχεί στο 10% των αιματολογικών και στο 1% του συνόλου των κακοηθειών [1]. Το 2018, οι νέες διαγνώσεις ήταν 48.300 ενώ 30.900 άτομα υπολογίστηκε ότι πέθαναν από τη νόσο [2]. Η διάμεση ηλικία κατά τη διάγνωση είναι τα 65 έτη. Λιγότερο από το 3% των ασθενών διαγιγνώσκονται πριν από την ηλικία των 40 ετών. Ένα από τα βασικά χαρακτηριστικά του ΠΜ είναι η οστική νόσος, η οποία προκύπτει ως αποτέλεσμα αυξημένης λειτουργίας των οστεοκλαστών η οποία δεν συνοδεύεται από αποτελεσματική λειτουργία των οστεοβλαστών[3]. Οστεολυτικές βλάβες ανιχνεύονται στο 70-80% των ασθενών κατά τη διάγνωση και αυξάνουν τον κίνδυνο για σκελετικά συμβάντα (SREs: παθολογικά κατάγματα, συμπίεση νωτιαίου μυελού (SCC), απαίτηση για χειρουργική επέμβαση ή ακτινοθεραπεία στα οστά). Τα SRE έχουν αντίκτυπο στην ποιότητα ζωής (QoL) και την επιβίωση των ασθενών με ΠΜ και επηρεάζουν τόσο την κλινική εικόνα όσο και τις οικονομικές πτυχές της ζωής τουςΟι πληροφορίες αναφορικά με τη συχνότητα των σκελετικών συμβάντων (SREs) σε νεοδιαγνωσθέντες ασθενείς με πολλαπλό μυέλωμα (ΠΜ) στην εποχή των νεότερων παραγόντων είναι πολύ περιορισμένες. Για το λόγο αυτό, πραγματοποιήσαμε αυτήν την μονοκεντρική, προοπτική, μελέτη παρατήρησης για να προσδιορίσουμε την επίπτωση των SREs μεταξύ των νεοδιαγνωσθέντων ασθενών με ΠΜ και για τη διερεύνηση των πιθανών συσχετίσεων με τα χαρακτηριστικά της νόσου, απεικονιστικά ευρήματα και πρόγνωση των ασθενών. Έλαβαν μέρος συνολικά 370 ασθενείς. Μεταξύ αυτών, 208 (56%) παρουσίασαν τουλάχιστον ένα SRE στο διάγνωση. Τα κατάγματα ήταν τα πιο συχνά αναφερόμενα SRE (48%). Η συχνότητα εμφάνισης SRE κατά τη διάγνωση ήταν υψηλότερη σε ασθενείς με οστεολυτικές βλάβες, παθολογικό πρότυπο μαγνητικής τομογραφίας, υπερασβεστιαιμία και δίηθηση μυελού μεγαλύτερη από 60%. Σημαντικό εύρημα της παρούσας μελέτης αποτελεί το γεγονός ότι οι ασθενείς με φυσιολογικό πρότυπο μαγνητικής τομογραφίας και απουσία σκελετικών συμβαμάτων κατά τη διάγνωση, είχαν στατιστικά σημαντικά βελτιωμένη διάμεση συνολική επιβίωση (OS) σε σύγκριση με τους ασθενείς που είχαν παθολογικά πρότυπα μαγνητικής τομογραφίας ή/και παρουσία SRE κατά τη διάγνωση (9,3 vs. 6,6 έτη, p = 0,048). Τα δεδομένα μας, τα οποία αντιπροσωπεύουν μία από τις λίγες συστηματικές αναφορές για τη συχνότητα και χαρακτηριστικά των SREs στην εποχή των νεότερων παραγόντων, ανέδειξαν υψηλή συχνότητα εμφάνισης SRE κατά τη διάγνωση. Η έγκαιρη ανίχνευση της οστικής νόσου και η εξατομικευμένη διαχείριση του ασθενούς είναι απαραίτητα για τη βελτιστοποίηση των αποτελεσμάτων

Management of multiple myeloma bone disease: impact of treatment on renal function

Introduction: Bone disease (BD) is one of the most common features of multiple myeloma. Seventy to eighty percent of patients at diagnosis present with lytic lesions which may lead to skeletal-related events. Areas covered: The aim of this review is to present the possible adverse profile of bisphosphonates (BPs) on renal function, the underlying mechanisms by which BPs may affect renal function and the novel therapeutic approaches on myeloma bone disease management. Expert commentary: BPs remain the cornerstone in the management of myeloma-related BD. Zoledronic acid and Pamidronate are currently the gold standard, however cannot be used in patients with severe renal dysfunction. Renal impairment is another hallmark of myeloma with approximately 60% of the patients presenting with or developing renal dysfunction during the disease course. Although BPs rarely cause renal impairment, they should be administered with caution in patients with impaired renal function. The exact mechanism by which BPs cause renal impairment is yet to be elucidated. Another promising agent is denosumab, a RANKL inhibitor, which can be administrated regardless of renal function and does not need the relevant dose-adjustments. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group

Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma

Multiple myeloma remains an incurable disease despite the introduction of the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib that have improved the outcome of patients with both newly diagnosed and relapsed/refractory disease. However, patients who relapse after treatment with these agents or are refractory to them represent an unmet need and highlight the necessity for the development of novel anti-myeloma agents. Pomalidomide is an IMiD, structurally related to thalidomide, with enhanced antiangiogenic, antineoplastic, and anti-inflammatory properties and exhibiting potent anti-myeloma activity in vitro and in vivo. Pomalidomide has shown remarkable activity in patients who were refractory to both bortezomib and lenalidomide in Phase II and III studies. This paper reviews the chemistry and mechanisms of action of pomalidomide as well as all the available data from clinical trials on pomalidomide use in patients with refractory/relapsed multiple myeloma