Experts’ consensus on the definition and management of high risk multiple myeloma

High risk multiple myeloma (HRMM) at diagnosis is currently recognized according to the Revised International Staging System (R-ISS) which was set up in 2015. Since then, new clinical and biological prognostic factors have been developed, which could implement the definition of High Risk (HR) category. We conducted a survey in order to identify which additional parameters, both clinical and biological, are considered more useful for the clinical practice and to evaluate if the management of Multiple Myeloma (MM) should change on the basis of the risk category. A questionnaire, consisting of 8 statements, was submitted to 6 Italian experts, from the European Myeloma Network (EMN) Research Italy, using the Delphi method. The colleagues were asked to answer each question using a scale between 0 and 100. If a statement did not reach at least 75 out of 100 points from all the participants, it was rephrased on the basis of the proposal of the experts and resubmitted in a second or further round, until a consensus was reached among all. From the first round of the survey a strong consensus was reached regarding the opportunity to revise the R-ISS including chromosome 1 abnormality, TP53 mutation or deletion, circulating plasma cells by next generation flow and extramedullary plasmacytomas. No consensus was reached for the definition of “double hit” MM and for the application in clinical practice of treatment strategies based on the risk category. In the second round of the Delphi questionnaire, “double-hit” MM was recognized by the association of at least two high-risk cytogenetic or molecular abnormalities. Moreover, the experts agreed to reserve an intensified treatment only to specific conditions, such as plasma cell leukaemia or patients with multiple extramedullary plasmacytomas, while they admitted that there are not sufficient real word data in order to modify treatment on the basis of MRD assessment in clinical practice. This survey suggests that the definition of HRMM should be implemented by additional clinical and biological risk factors, that will be useful to guide treatment in the future

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective real-world experience with 200 cases outside of controlled clinical trials

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved a superior clinical benefit over Pd with a manageable toxicity profile, leading to its approval in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI). We report here a real-world experience of 200 RRMMs treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was 2, with 51% of cases undergoing autologous stem cell transplant (ASCT) and 73% exposed to daratumumab. After a median follow-up of 9 months, 126 patients stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate (ORR) was 55.4%, in line with the pivotal trial results. Regarding adverse events, our cohort experienced a toxicity profile similar to the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival (PFS) was 7 months, shorter than that observed in the ELOQUENT-3, probably due to the different clinical characteristics of the two cohorts. Interestingly, the ISS stage III (HR:2.55) was associated with worse PFS. Finally, our series's median overall survival (OS) was shorter than that observed in the ELOQUENT-3 trial (17.5 versus 29.8 months). In conclusion, our real-world study confirms EloPd as a safe and possible therapeutic choice for RRMM who received at least two prior therapies, including lenalidomide and a PI

Management of Renal Failure in Multiple Myeloma

Multiple myeloma (MM) is a monoclonal plasma cell neoplasia that commonly involves the kidney. Renal impairment is a serious complication during the course of the disease, and it is associated with increased morbidity and mortality. The most frequent mechanism of injury is represented by the precipitation of monoclonal free light chains (FLCs) in the distal tubule of nephron, defining a dramatic condition known as light chain cast nephropathy (LCCN). A prompt and early identification of the cause of renal disease, particularly in case of acute kidney injury (AKI), is mandatory for its effective management, avoiding the development of chronic kidney disease (CKD). In case of LCCN, in order to achieve renal recovery, it is needed, besides preventive measures, urgent intervention based on vigorous rehydration, correction of precipitating factors and effective anti-plasma cell chemotherapy. Currently, the association of the Proteasome Inhibitor Bortezomib with high-dose of Dexamethasone represents the standard association in newly diagnosed patients. The addition of another drug such as Cyclophosphamide or an Immunomodulatory Drugs may improve FLCs reduction but could be toxic. Interesting is the role of the newest therapeutic agents, particularly anti-CD38 Monoclonal Antibodies, whose efficacy and tolerance have been documented in patients without renal impairment. Despite controversial results from randomized studies, recent data suggest that in patients with LCCN and AKI requiring dialysis the association of systemic therapy with an extra-corporeal approach of FLCs removal, may increase renal response recovery rates. In this chapter, it is summarized physio-pathological basis of MM renal impairment, clinical manifestations, diagnostic procedures, and therapeutic management, included autologous stem cell transplantation

How I Manage Frontline Transplant-Ineligible Multiple Myeloma

The Multiple Myeloma (MM) is a plasma cells hematological malignancy with a median age of 69 years at diagnosis. The autologous stem cell transplantation is the standard of care for this disease but less than half of newly diagnosed patients are assessed for this treatment due to comorbidities or complications of disease. The management of transplant ineligible MM patients is based on the balance safety and efficacy of the new available regimen and a careful assessment of the frailty status is mandatory to define the goals. In this review we discuss of the clinical dilemmas in the management and define how to manage them based on the evidence from clinical trials and “real life” experience

Percutaneous CT-Guided Microwave Ablation Combined with Pedicle Screw Fixation Followed by Vertebroplasty (MASFVA): Initial Experience of a Minimally Invasive Treatment of Vertebral Metastases with Extension to the Vertebral Pedicle

(1) Background: The aim of this study was to retrospectively evaluate the safety and efficacy of a combined CT-guided percutaneous microwave ablation (MWA) and pedicle screw fixation followed by vertebroplasty (MASFVA) for the treatment and stabilization of painful vertebral metastases with vertebral pedicle involvement. (2) Methods: from January 2013 to January 2017 11 patients with 16 vertebral metastatic lesions (7 men and 5 women; mean age, 65 ± 11 years) with vertebral metastases underwent CT-guided microwave ablation and screw fixation followed by vertebroplasty (MASFVA). Technical success, complication rate, pain evaluation using a visual analogue scale (VAS), Oswestry Disability Index (ODI) and local tumor control were examined. (3) Results: Technical success rate was 100%. No procedure-related major complications occurred. VAS score decreased from 6.8 ± 0.7 to 0.6 ± 0.6. ODI score decreased from 3.1 ± 0.7 to 1.2 ± 0.4. All patients could walk independently without neurological complication after one week from the procedure. No new bone fractures or local disease recurrence occurred during a median follow-up of 12 months. (4) Conclusions: Our results suggest that MWA and percutaneous pedicle screw fixation followed by vertebroplasty for the treatment of painful vertebral metastases is a safe and effective procedure for painful vertebral metastases with vertebral pedicle involvement, allowing pain relief and local tumor control

Experts' consensus on the definition and management of high risk multiple myeloma

High risk multiple myeloma (HRMM) at diagnosis is currently recognized according to the Revised International Staging System (R-ISS) which was set up in 2015. Since then, new clinical and biological prognostic factors have been developed, which could implement the definition of High Risk (HR) category. We conducted a survey in order to identify which additional parameters, both clinical and biological, are considered more useful for the clinical practice and to evaluate if the management of Multiple Myeloma (MM) should change on the basis of the risk category. A questionnaire, consisting of 8 statements, was submitted to 6 Italian experts, from the European Myeloma Network (EMN) Research Italy, using the Delphi method. The colleagues were asked to answer each question using a scale between 0 and 100. If a statement did not reach at least 75 out of 100 points from all the participants, it was rephrased on the basis of the proposal of the experts and resubmitted in a second or further round, until a consensus was reached among all. From the first round of the survey a strong consensus was reached regarding the opportunity to revise the R-ISS including chromosome 1 abnormality, TP53 mutation or deletion, circulating plasma cells by next generation flow and extramedullary plasmacytomas. No consensus was reached for the definition of "double hit" MM and for the application in clinical practice of treatment strategies based on the risk category. In the second round of the Delphi questionnaire, "double-hit" MM was recognized by the association of at least two high-risk cytogenetic or molecular abnormalities. Moreover, the experts agreed to reserve an intensified treatment only to specific conditions, such as plasma cell leukaemia or patients with multiple extramedullary plasmacytomas, while they admitted that there are not sufficient real word data in order to modify treatment on the basis of MRD assessment in clinical practice. This survey suggests that the definition of HRMM should be implemented by additional clinical and biological risk factors, that will be useful to guide treatment in the future

Chimeric Antigen Receptor T-Cell Therapy: What We Expect Soon

The treatment landscape for hematologic malignancies has changed since the recent approval of highly effective chimeric antigen receptor T-cell therapies (CAR-T). Moreover, more than 600 active trials are currently ongoing. However, early enthusiasm should be tempered since several issues are still unsolved and represent the challenges for the coming years. The lack of initial responses and early relapse are some hurdles to be tackled. Moreover, new strategies are needed to increase the safety profile or shorten the manufacturing process during CAR-T cells therapy production. Nowadays, most clinically evaluated CAR-T cells products are derived from autologous immune cells. The use of allogeneic CAR-T cells products generated using cells from healthy donors has the potential to change the scenario and overcome many of these limitations. In addition, CAR-T cells carry a high price tag, and there is an urgent need to understand how to pay for these therapies as many of today’s current payment systems do not feature the functionality to address the reimbursement gap. Finally, the clinical experience with CAR-T cells for solid tumors has been less encouraging, and development in this setting is desirable

Which is the best treatment strategy before autologous peripheral blood stem cell transplantation in POEMS syndrome?

: Autologous peripheral blood stem cell transplantation (aPBSCT) provides optimal outcomes in POEMS syndrome but the definition of the best treatment before aPBSCT remains to be defined, because of the disease rarity and the heterogeneity of published case series. We collected clinical and laboratory data of patients with POEMS syndrome undergoing aPBSCT from 1998 to 2020 in 10 Italian centres. The primary endpoint of the study was to evaluate the impact of prior therapies and mobilizing regimen on outcome. We divided patients in three groups: patients who did not receive any treatment before transplant (15 patients, group A: front-line), pre-treated patients with other agents (14 patients, group B) and patients treated with cyclophosphamide as mobilizing regimen (16 patients, group C). The three groups did not show differences in terms of demographic and clinical characteristics. All 45 patients underwent aPBSCT after high dose melphalan conditioning regimen, with a median follow-up of 77 months (37-169 months). The responses were not statistically different between the 3 groups (p 0.38). PFS and OS rates at 6 years were 65% (49-85) and 92% (84-100), respectively and did not differ in the 3 groups. The cumulative incidence of transplant related mortality and relapse was respectively 4% and 36%. In conclusion, in a relatively large number of patients with POEMS syndrome, undergoing an autologous transplant, pre-treatment and disease status at transplant did not appear to have an impact on major transplant outcomes

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HIF-1a of bone marrow endothelial cells implies relapse and drug resistance in patients with multiple myeloma and may act as a therapeutic target

Purpose: To investigate the role of hypoxia-inducible factor-1a (HIF-1a) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma. Experimental Design: HIF-1a mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1a inhibition by siRNA or panobinostat (an indirect HIF-1a inhibitor) on the expression of HIF-1a proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed. Results: Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1a protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1a protein correlated with the expression of its proangiogenic targets. The HIF-1a inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis-related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1a protein had shorter overall survival. Conclusions: The HIF-1a protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/ refractorymultiplemyeloma. Itmay also have prognostic significance. © 2014 American Association for Cancer Research