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

Evaluation of the Revised International Staging System in an independent cohort of unselected patients with multiple myeloma

The Revised International Staging System (R-ISS) was recently introduced in order to improve risk stratification over that provided by the widely used standard International Staging System. In addition to the parameters of the standard system, the R-ISS incorporates the presence of chromosomal abnormalities detected by interphase fluorescence in situ hybridization [t(4;14), t(14;16) and del17p] and elevated serum lactate dehydrogenase. The R-ISS was formulated on the basis of a large dataset of selected patients who had participated in clinical trials and has not been validated in an independent cohort of unselected patients. Thus, we evaluated the R-ISS in 475 consecutive, unselected patients, treated in a single center. Our patients were older and more often had severe renal dysfunction than those in the original publication on the R-ISS. As regards distribution by group, 18% had R-ISS-1, 64.5% R-ISS-2 and 18% R-ISS-3. According to R-ISS group, the 5-year survival rate was 77%, 53% and 19% for R-ISS-1, -2 and -3, respectively (P75 years. However, in patients with severe renal dysfunction the distinction between groups was less clear. In conclusion, our data in consecutive, unselected patients, with differences in the characteristics and treatment approaches compared to the original International Myeloma Working Group cohort, verified that R-ISS is a robust tool for risk stratification of newly diagnosed patients with symptomatic myeloma

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

Belantamab mafodotin, lenalidomide and dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma: Part 1 results of a phase I/II study

Preclinical and clinical data demonstrate synergy between belantamab mafodotin (belamaf) and immunomodulatory drugs with limited overlapping toxicities. We investigated the safety and efficacy of belamaf with lenalidomide 25mg on days 1-21 every 28 days and dexamethasone 40mg weekly (belamaf-Rd) in transplant ineligible patients with newly diagnosed multiple myeloma. 36 patients (median age 72.5 years) were randomized to receive belamaf at three different doses (2.5/1.9/1.4 mg/kg) every 8 weeks (q8w). Dosing schedule was extended to every 12 weeks (q12w) to account for ocular toxicity. Most common ≥ Grade (Gr) 3 adverse events were fatigue (n=21, 58.3%), rash (n=6, 16.7%), diarrhea (n=8, 22.2%) and COVID-19 (n=5, 13.9%). Gr 3-4 ocular adverse events (OAEs), comprising of visual acuity decline from baseline and/or keratopathy, were reported in 39/216(18.1%)/ 33/244(13.5%)/ 26/207(12.6%) ophthalmological assessments in cohorts 2.5/1.9/1.4 mg/kg. Importantly, Gr 3-4 keratopathy was identified in 9/216 (4.2%)/ 1/244(0.4%)/ 1/207(0.5%) assessments. Most patients (32/36, 88.9%) were treated in the extended q12w schedule, where dose holds due to OAEs were 40, 33 and 16 in cohorts 2.5/1.9/1.4. Overall, ≥VGPR and ≥CR rates were 83.3% and 52.8%, without significant differences among cohorts. Over a median follow-up of 20.3 months no disease progression was reported; 6 patients discontinued treatment due to infection-related death (n=4 COVID-19, n=2 pneumonia) and 1 patient withdrew consent. Based on toxicity/efficacy balance, the recommended phase 2 dose was 1.9 mg/kg q8w, extended to q12w for toxicity. Belamaf-Rd, with the extended schedule for belamaf, has shown important clinical activity and a significant improvement of OAEs with minimal impact on vision-related functioning in an elderly, non-transplant eligible population

Oncology during the COVID-19 pandemic: challenges, dilemmas and the psychosocial impact on cancer patients.

COVID-19 has caused unprecedented societal turmoil, triggering a rapid, still ongoing, transformation of healthcare provision on a global level. In this new landscape, it is highly important to acknowledge the challenges this pandemic poses on the care of the particularly vulnerable cancer patients and the subsequent psychosocial impact on them. We have outlined our clinical experience in managing patients with gastrointestinal, hematological, gynaecological, dermatological, neurological, thyroid, lung and paediatric cancers in the COVID-19 era and have reviewed the emerging literature around barriers to care of oncology patients and how this crisis affects them. Moreover, evolving treatment strategies and novel ways of addressing the needs of oncology patients in the new context of the pandemic are discussed

The role of bone metabolism, angiogenesis and chemokines in patients with primary AL systemic amyloidosis

The term "amyloidosis" describes a large class of disease entities attributable to protein deficiency to obtain a functional quaternary structure and relates to the conversion of peptides or proteins from soluble functional forms to fibrous degradation derivatives with secondary β-sheet structure. The most common form is primary systemic AL amyloidosis with an incidence estimated at around 8.9 cases per million population per year. Angiogenesis and bone metabolism have been studied in many malignancies for their role in the progression and prognosis of these diseases. The primary objective of this study is to study the biochemical model of bone metabolism and angiogenesis in patients with first-line AL primary systemic amyloidosis. Angiogenesis plays an important role in the progression of multiple myeloma, and is a component of complex interactions between the plasmatic cell and the microenvironment, and its expression is regulated by a plurality of molecules. Serum angiogenic serum cytokines have already been studied in multiple myeloma patients, have been found to be elevated and have been associated with the disease stage (132). In addition, they seem to be involved in the homeostasis of several organs such as renal glomerule, endothelium and peripheral nervous system, and potentially could have prognostic significance in patients with AL amyloidosis. Such data are not available. For this reason, the angiogenic cytokines were measured in this work and the possible correlations with the characteristics of the disease, the involvement of the target organs and the progression of the disease were analyzed. Correspondingly, bone metabolism is extremely disturbed in patients with multiple myeloma with predominant bone decomposition component and suppression of bone production. Bone metabolism has not been systematically studied in patients with primary systemic AL amyloidosis. The purpose of this prospective study is to evaluate bone metabolism in newly diagnosed patients and to compare the results with those with other plasma cell dyscrases such as multiple myeloma and monoclonal gammopathy of unspecified significance as well as to investigate possible correlations with the characteristics of the disease and Survival. Data from measurements of bone formation, bone degradation and angiogenic cytokines in serum of 102 patients with primary systemic amyloidosis were analyzed. Measurements were made by the ELISA method. The statistical analysis was done with the SPSS20 program.The results of this study support the presence of increased bone resorption and osteoclastic activity that is fully contrasted in patients with primary systemic AL amyloidosis. This also explains the absence of osteology in these patients. Elevated levels of osteoprotegerin in patients with AL amyloidosis are correlated independently with the prognosis of the disease and this association is independent of the Mayo Staging. This suggests that elevated levels of osteoprotegerin not only reflect the achievement of balance with increased osteoclastic activity but also the early onset of heart failure as well as generalized vascular and endothelial damage coexisting in patients with AL amyloidosis. The results of this study underline the role of osteoprotegerin in the biology of the disease and suggest the possible wider use of this useful biomarker as a prognostic factor. Serum angiogenic cytokine levels measured in this study were elevated in patients with AL amyloidosis compared to both healthy controls and patients with multiple myeloma. This is probably the result of the indirect or immediate action of amyloid fibrils or light chains or a counter-response to organ dysfunction. The large differences between the two diseases are indicative of the different pathophysiology of the two diseases.Ο όρος «αμυλοείδωση» περιγράφει μια μεγάλη κατηγορία νοσολογικών οντοτήτων που οφείλονται σε ανεπάρκεια των πρωτεινών να λάβουν λειτουργική τεταρτοταγή δομή και σχετίζεται με τη μετατροπή των πεπτιδίων ή των πρωτεϊνών από διαλυτές λειτουργικές μορφές σε ινώδη παράγωγα αποδόμησης με δευτεροταγή δομή β-φύλλου. Η συχνότερη μορφή είναι η πρωτοπαθής συστηματική αμυλοείδωση AL με επίπτωση που υπολογίζεται σε περίπου 8.9 περιπτώσεις ανά εκατομμύριο πληθυσμού ανά έτος. Η αγγειογένεση και ο οστικός μεταβολισμός έχουν μελετηθεί σε πολλές κακοήθειες για το ρόλο που διαδραματίζουν στην εξέλιξη και πρόγνωση των νοσημάτων αυτών. Ο πρωταρχικός στόχος αυτής της μελέτης είναι να μελετηθεί το βιοχημικό πρότυπο του οστικού μεταβολισμού και της αγγειογένεσης σε ασθενείς με πρωτοδιαγνωσθείσα AL πρωτοπαθή συστηματική αμυλοείδωση. Η αγγειογένεση διαδραματίζει σημαντικό ρόλο στην πρόοδο του πολλαπλού μυελώματος, και αποτελεί συστατικό σύνθετων αλληλεπιδράσεων ανάμεσα στον πλασματοκυτταρικό κλώνο και στο μικροπεριβάλλον, η δε έκφραση της ρυθμίζεται από πληθώρα μορίων. Τα επίπεδα των αγγειογενετικών κυτοκινών στον ορό έχουν ήδη μελετηθεί σε ασθενείς με πολλαπλό μυέλωμα, έχουν βρεθεί αυξημένα και έχουν συσχετιστεί με το στάδιο της νόσου(132). Επιπλέον φαίνεται πως συμμετέχουν στην ομοιόσταση της λειτουργίας αρκετών οργάνων όπως το νεφρικό σπείραμα, το ενδοθήλιο και το περιφερικό νευρικό σύστημα και ενδεχομένως θα μπορούσαν να έχουν προγνωστική σημασία σε ασθενείς με AL αμυλοείδωση. Τέτοια δεδομένα δεν υπάρχουν διαθέσιμα. Για το λόγο αυτό στα πλαίσια της συγκεκριμένης εργασίας μετρήθηκαν τα επίπεδα των αγγειογενετικών κυτοκινών και αναλύθηκαν οι πιθανές συσχετίσεις με τα χαρακτηριστικά της νόσου, τη συμμετοχή των οργάνων στόχων και την εξέλιξη του νοσήματος. Κατά αντιστοιχία ο οστικός μεταβολισμός είναι εξαιρετικά διαταραγμένος σε ασθενείς με πολλαπλό μυέλωμα με προεξάρχουσα τη συνιστώσα της οστικής αποδόμησης και καταστολή της οστικής παραγωγής. Ο οστικός μεταβολισμός δεν έχει μελετηθεί συστηματικά σε ασθενείς με πρωτοπαθή συστηματική AL αμυλοείδωση. Σκοπός αυτής της προοπτικής μελέτης είναι να εκτιμήσει τον οστικό μεταβολισμό σε νεοδιαγνωσθέντες ασθενείς και να συγκρίνει τα αποτελέσματα με αυτά ασθενών με άλλες πλασματοκυτταρικές δυσκρασίες όπως το πολλαπλό μυέλωμα και η μονοκλωνική γαμμαπάθεια αδιευκρίνιστης σημασίας, αλλά και να διερευνήσει τις πιθανές συσχετίσεις με τα χαρακτηριστικά της νόσου και την επιβίωση. Αναλύθηκαν τα δεδομένα από μετρήσεις δεικτών οστικού σχηματισμού, οστικής αποδόμησης και αγγειογενετικών κυτοκινών στον ορό 102 ασθενών με πρωτοπαθή συστηματική αμυλοείδωση. Οι μετρήσεις έγιναν με τη μέθοδο ELISA. Η στατιστική ανάλυση έγινε με το πρόγραμμα SPSS20.Τα αποτελέσματα της συγκεκριμένης μελέτης υποστηρίζουν την παρουσία αυξημένης οστικής αποδόμησης και οστεοκλαστικής δραστηριότητος που αντιρροπείται πλήρως στους ασθενείς με πρωτοπαθή συστηματική AL αμυλοείδωση. Αυτό ερμηνεύει και τη απουσία οστεολύσεων στους ασθενείς αυτούς. Τα αυξημένα επίπεδα της οστεοπροτεγερίνης σε ασθενείς με AL αμυλοείδωση συσχετίζονται ανεξάρτητα με την πρόγνωση του νοσήματος και η συσχέτιση αυτή είναι ανεξάρτητη από τη σταδιοποίηση κατά Mayo. Αυτό υποδηλώνει πως τα αυξημένα επίπεδα της οστεοπροτεγερίνης δεν αντανακλούν μόνο την επίτευξη της ισορροπίας με την αυξημένη οστεοκλαστική δραστηριότητα αλλά και την πρώιμη έναρξη της καρδιακής ανεπάρκειας όπως και επίσης τη γενικευμένη αγγειακή και ενδοθηλιακή βλάβη που συνυπάρχουν στους ασθενείς με AL αμυλοείδωση. Τα αποτελέσματα της εν λόγω μελέτης υπογραμμίζουν το ρόλο της οστεοπροτεγερίνης στη βιολογία του νοσήματος και υποδεικνύουν την ενδεχόμενη ευρύτερη αξιοποίηση αυτού του χρήσιμου βιοδείκτη ως προγνωστικού παράγοντα. Τα επίπεδα των αγγειογενετικών κυτοκινών του ορού που μετρήθηκαν στα πλαίσια της συγκεκριμένης μελέτης ήταν αυξημένα στους ασθενείς με AL αμυλοείδωση συγκριτικά τόσο με τους υγιείς μάρτυρες όσο και με τους ασθενείς με πολλαπλό μυέλωμα. Αυτό πιθανότατα είναι αποτέλεσμα της έμμεσης ή άμεσης δράσης των ινιδίων του αμυλοειδούς ή των ελαφρών αλύσεων ή αντιρροπιστική απάντηση στη δυσλειτουργία των οργάνων. Οι μεγάλες διαφορές που διαπιστώνονται ανάμεσα στα δύο νοσήματα είναι ενδεικτικές της διαφορετικής παθοφυσιολογίας των δύο νοσημάτων

Biology and treatment of myeloma related bone disease

Myeloma bone disease (MBD) is the most common complication of multiple myeloma (MM), resulting in skeleton-related events (SREs) such as severe bone pain, pathologic fractures, vertebral collapse, hypercalcemia, and spinal cord compression that cause significant morbidity and mortality. It is due to an increased activity of osteoclasts coupled to the suppressed bone formation by osteoblasts. Novel molecules and pathways that are implicated in osteoclast activation and osteoblast inhibition have recently been described, including the receptor activator of nuclear factor-kB ligand/osteoprotegerin pathway, activin-A and the wingless-type signaling inhibitors, dickkopf-1 (DKK-1) and sclerostin. These molecules interfere with tumor growth and survival, providing possible targets for the development of novel drugs for the management of lytic disease in myeloma but also for the treatment of MM itself. Currently, bisphosphonates are the mainstay of the treatment of myeloma bone disease although several novel agents such as denosumab and sotatercept appear promising. This review focuses on recent advances in MBD pathophysiology and treatment, in addition to the established therapeutic guidelines. (C) 2017 Elsevier Inc. All rights reserved