Percutaneous Hepatic Perfusion (PHP) with Melphalan in Liver-Dominant Metastatic Uveal Melanoma: The German Experience

Percutaneous hepatic perfusion (PHP) delivers high-dose melphalan to the liver while minimizing systemic toxicity via filtration of the venous hepatic blood. This two-center study aimed to examine the safety, response to therapy, and survival of patients with hepatic-dominant metastatic uveal melanoma (UM) treated with PHP. A total of 66 patients with liver-dominant metastasized uveal melanoma, treated with 145 PHP between April 2014 and May 2020, were retrospectively analyzed with regard to adverse events (AEs; CTCAE v5.0), response (overall response rate (ORR)), and disease control rate (DCR) according to RECIST1.1, as well as progression-free and overall survival (PFS and OS). With an ORR of 59% and a DCR of 93.4%, the response was encouraging. After initial PHP, median hepatic PFS was 12.4 (confidence interval (CI) 4–18.4) months and median OS was 18.4 (CI 7–24.6) months. Hematologic toxicity was the most frequent AE (grade 3 or 4 thrombocytopenia after 24.8% of the procedures); less frequent was grade 3 or 4 hepatic toxicity (increased aspartate transaminase (AST) and alanine transaminase (ALT) after 7.6% and 6.9% of the interventions, respectively). Cardiovascular events included four cases of ischemic stroke (2.8%) and one patient with central pulmonary embolism (0.7%). In conclusion, PHP is a safe and effective salvage treatment for liver-dominant metastatic uveal melanoma. Serious AEs—though rare—demand careful patient selection.

Differences and Similarities in Treatment Paradigms and Goals Between AL Amyloidosis and Multiple Myeloma

Although there are similarities in the treatment paradigms between AL amyloidosis and multiple myeloma, there are also fundamental differences. A similarity is of course the use of anti-plasma cell drugs in both diseases; however, the most serious mistake a hemato-oncologist can make is to use the same treatment schedule in dosing and frequency in AL amyloidosis patients as in multiple myeloma patients. AL amyloidosis patients with >10% bone marrow plasma cell infiltration in particular are at risk of receiving a more intensive treatment than they can tolerate. This difference in dosing and frequency is true for many anti-clonal drugs, but it is most apparent in the use of high-dose melphalan and autologous stem cell transplantation. While in multiple myeloma in the age group of ≤70 years, more than 80% of patients are fit enough to receive this intensive treatment, this is the case in less than 20% of AL amyloidosis patients. A similarity is the alignment in the goal of treatment. Although in AL amyloidosis has long been recognized that the goal should be complete hematological remission, this has become more apparent in multiple myeloma in recent years. A common goal in the coming years will be to evaluate the role of minimal residual disease to improve survival in both diseases.

Ice-cream used as cryotherapy during high-dose melphalan conditioning reduces oral mucositis after autologous hematopoietic stem cell transplantation

Oral mucositis (OM) is one of the most frequent adverse events of high-dose conditioning chemotherapy with melphalan prior to autologous hematopoietic stem cell transplantation (AHSCT). It significantly reduces the patients’ quality of life. One of the preventive strategies for OM is cryotherapy. We retrospectively analyzed whether commercially available ice-cream could prevent OM during the melphalan infusion. We retrospectively analyzed 74 patients after AHSCT to see whether there is any correlation between OM and cryotherapy (ice-cream), melphalan dose (140 mg/m2 or 200 mg/m2). The incidence of OM in our study inversely correlated with cryotherapy in the form of ice-cream. Out of 74 patients receiving conditioning chemotherapy with high-dose melphalan, 52 received cryotherapy. Fifteen patients in the cryotherapy group (28.84%) developed OM, whereas 13 patients (59.09%) developed it in the group without cryotherapy. In a multiple linear regression test cryotherapy remained a significant protective factor against OM (p = 0.02) We have also seen the relationship between melphalan dose with OM (p < 0.005). Cryotherapy in the form of ice-cream is associated with a lower rate of OM and, therefore, could potentially be used as a cost-effective, less burdensome, and easy to implement method in prevention of oral mucositis.

How I Treat Frontline Transplant-eligible Multiple Myeloma

High dose Melphalan supported by autologous transplantation is the standard of care for eligible patients with newly diagnosed multiple myeloma for more than 25 years. Several randomized clinical trials have recently reaffirmed the strong position of transplant in the era of proteasome inhibitors and immunomodulatory drugs combinations, demonstrating a significant reduction of progression or death in comparison with strategies without transplant. Immunotherapy is currently changing the paradigm of multiple myeloma management and daratumumab is the first-in-class human monoclonal antibody targeting CD38 approved in the setting of newly diagnosed multiple myeloma. Quadruplets become the new standard in the transplantation programs, but outcomes remain heterogeneous with various response depth and duration. Otherwise, the development of sensitive and specific tools for disease prognostication allows to consider adaptive strategy to a dynamic risk. I discuss in this review the different available options for the treatment of transplant-eligible multiple myeloma patients in frontline setting.

A Phase 2 Multi-Center, Open Label Study of Isatuximab Added to Standard Cybord Induction and Lenalidomide Maintenance Treatments in Newly Diagnosed, Transplant Eligible Multiple Myeloma

Background: Despite recent improvements, myeloma is still incurable. There is need to add new therapeutic tools. For young and fit patients, the current standard first-line therapy is a proteasome inhibitor (PI) containing induction, followed by stem cell collection, high dose Melphalan and autologous stem cell transplantation, followed by maintenance lenalidomide therapy in Canada. The anti-CD38 antibodies showed interesting activity in myeloma, and significant synergism with PI and IMiD based regimens. This CMRG-008 trial is designed to explore the benefit of adding Isatuximab to the current Canadian standard of care (CyBorD induction/Autologous SCT/Maintenance Len) in a single arm phase II trial. Design and Methods: Phase II study. Transplant eligible newly diagnosed myeloma patients (TE-NDMM) will receive Isatuximab added to four cycles of standard induction CyBorD chemotherapy (Cyclophosphamide 300 mg/m 2 PO, Bortezomib 1.5 mg/m 2 SC, and Dex 40 mg PO, all given on days 1, 8, 15 and 22 of 28-day cycles; Isatuximab 10 mg/kg IV days 1, 8, 15 and 22 of cycle 1; days 1 and 15 of cycles 2-4). After the completion of the induction treatment, subjects achieving at least stable disease will receive stem cell mobilization, collection of hematopoietic stem cells, high dose melphalan chemotherapy, and autologous stem cell transplantation. Maintenance treatment will start at 100 days (+/- 7 days) after the transplantation date (and to be continued until disease progression). The maintenance treatment will consist of Isatuximab administered in combination with Lenalidomide in 28-day cycles (Lenalidomide: 10 mg daily on days 1-21 of every cycle; Isatuximab: 10 mg/kg IV on days days 1, 8, 15 and 22 of cycle 1; days 1 & 15 of cycles 2-3; then day 1 of each subsequent cycle). The objectives: To evaluate the benefit of adding Isatuximab to CyBorD (induction = Isa + CyBorD) and Lenalidomide (maintenance = Isa + Lenalidomide) in transplant-eligible myeloma patients. Primary Endpoint: To determine the response rate (VGPR or better) defined by IMWG criteria at 100 days (+/- 7 days) after the autologous stem cell transplant (ASCT). Secondary Endpoints: A) To determine the response rate (VGPR or better) after induction treatment (before ASCT), and at 12 months, 24 months and 36 months. B) To evaluate additional efficacy outcomes including progression free survival (PFS), and overall survival (OS), time to response and duration of response. C) To confirm the feasibility, safety and tolerability of adding Isatuximab to CyBorD and to maintenance lenalidomide in transplant-eligible newly diagnosed myeloma patients. D) To determine the feasibility of autologous stem cell collection after Isa + CyBorD induction treatment. The key inclusion criteria are having a TE-NDMM with a measurable disease; adequate performance status; and adequate organ functions. The key exclusion criteria include previous exposure to anti-CD38 therapy, intolerance to CyBorD, adverse cardiac history, pulmonary disease, central nervous system disease, congenital or acquired immune suppression, and other concurrent severe or uncontrolled medical conditions. Statistics and Sample Size: Considering that the response rate (VGPR or better) after CyBorD induction therapy, high dose chemotherapy and autologous SCT is about 70-78%; and assuming a response rate (VGPR or better) to Isa-CyBorD induction and autologous stem cell transplant at 100 +/- 7 days of 88%; a sample size of 65 evaluable subjects will allow estimating the 95% confidence interval with a precision of +/- 7.9%. For the assumed rate and sample size, the lower bound of the confidence interval will be estimated to be larger than 80%. Assuming a 10% drop out rate, a total study size of 72 patients will be considered. This study is expected to open to recruitment in the third quarter of 2021. Clinicaltrials.gov #: NCT04786028. Disclosures Kotb: Janssen: Honoraria; Merck: Honoraria, Research Funding; Amgen: Honoraria; Akcea: Honoraria; Celgene: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company. Reece: BMS: Honoraria, Research Funding; GSK: Honoraria; Karyopharm: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Millennium: Research Funding; Sanofi: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

High-Dose Melphalan in 1 Day Versus over 2 Days Followed By Autologous Stem Cell Transplantation As Consolidation Treatment in Patients with Multiple Myeloma

Background High-dose melphalan (HDM) at 200 mg/m2 is a myeloablative consolidation treatment prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) and is administered in 1-day or divided over 2-days. Although the 1-day regimen (lower AUC) has been shown to result in significantly less gastro-intestinal toxicity, it is not completely clear whether this administration strategy has any deleterious effects on efficacy, compared to the 2-day regimen. In this retrospective cohort study, we aimed to evaluate the effects of 1- or 2-day dosing of HDM on disease remission, progression-free survival (PFS) and overall survival (OS) in patients with MM. Methods Data from two academic centers in Amsterdam that have recently merged were used for the analysis, with one of the centers using the 1-day regimen and the other the 2-days regimen. A total of 265 patients with MM divided over the 1-day group (n=174) and 2-day group (n=91) treated between July 2017 and February 2020, were included in the study. The primary endpoint was the proportion of patients with at least very good partial remission (≥VGPR) at day ±90 post-ASCT. Secondary endpoints were overall survival (OS), progression-free survival (PFS), duration of hospitalization post-ASCT, engraftment period of neutrophils and platelets, and complications (other than mucositis) during hospitalization. Results Patient characteristics are summarized in Table 1. Remission status of ≥VGPR was comparable between the 1-day and 2-day groups (84% vs. 80% respectively). After a median follow-up of 21 months, OS (92% vs. 91%) and PFS (80% vs. 81%) were comparable in the 1-day and 2-day group respectively. There were no differences in the incidence of hematologic adverse events between the 1-day and 2-day groups (neutropenia; 98% vs. 100%, thrombocytopenia; 90% vs. 96% respectively). Median time to neutrophil engraftment (ANC &gt;0.5 x10 9 L -1) was significantly shorter in the 2-day group than in the 1-day group (14 days vs. 18 days, p = 0.002). Median time to platelet engraftment (platelets &gt;20 x10 9 L -1) was comparable between the groups. Lower CD34+ cell counts were administered in the 1-day group compared to the 2-day group (2.6 vs. 3.4 x10 6/kg, p &lt;0.0001). A significant negative correlation between the reinfused CD34+ cell counts and time to neutrophil engraftment was found (R= - 0.244). Table 2 shows the number of hospitalization days after ASCT. The median number was 18 days in the 1-day group and 15 days in the 2-day group (OR 1.22, 95% C.I. (1.10-1.35), p &lt;0.0001). Incidences of infectious complications, febrile neutropenia and intensive care unit (ICU) admissions were not different between the groups. Conclusion The use of 1-day HDM as consolidation treatment in MM patients resulted in equal disease response, progression-free survival and overall survival as compared to 2-day HDM. Based on the results of this study showing comparable efficacy and earlier findings of reduced toxicity with the 1-day HDM administration, we recommend the 1-day protocol for HDM. Interestingly, our results also confirmed that patients might benefit from higher counts of reinfused CD34+/enucleated cells. Figure 1 Figure 1. Disclosures Wondergem: Novartis: Honoraria. de Leeuw: Takeda: Membership on an entity's Board of Directors or advisory committees. Biemond: Sanquin: Research Funding; Celgene: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Global Blood Therapeutics: Honoraria, Research Funding, Speakers Bureau. van de Donk: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding. Zweegman: Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nur: Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Research Funding, Speakers Bureau.