scholarly journals Patient Characteristics and Outcomes of Relapsed/Refractory Multiple Myeloma in Patients Treated with Proteasome Inhibitors in Germany

2020 ◽  
Vol 43 (9) ◽  
pp. 449-459 ◽  
Author(s):  
H. Tilman Steinmetz ◽  
Moushmi Singh ◽  
Andrea Lebioda ◽  
Sebastian Gonzalez-McQuire ◽  
Achim Rieth ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Patient Characteristics ◽  
Refractory Multiple Myeloma

Real-world treatment patterns in relapsed/refractory multiple myeloma: Clinical and economic outcomes in patients treated with pomalidomide or daratumumab

2021 ◽  
pp. 107815522199553
Author(s):  
Joshua Richter ◽  
Vamshi Ruthwik Anupindi ◽  
Jason Yeaw ◽  
Suneel Kudaravalli ◽  
Stojan Zavisic ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Real World ◽  
Treatment Options ◽  
Proteasome Inhibitors ◽  
Economic Outcomes ◽  
Office Visits ◽  
Refractory Multiple Myeloma ◽  
Kaplan Meier ◽  
Real World Evidence ◽  
New Treatment

Introduction Real-world evidence on later line treatment of relapsed/refractory multiple myeloma (RRMM) is sparse. We evaluated clinical outcomes among RRMM patients in the 1-year following treatment with pomalidomide or daratumumab and compared economic outcomes between RRMM patients and non-MM patients. Patient and Methods Adult patients with ≥1 claim of pomalidomide or daratumumab were identified between January 2012 and February 2018 using IQVIA PharMetrics® Plus US claims database. Patients were required to have a diagnosis or treatment for MM and a claim of any immunomodulatory drugs and proteasome inhibitors before the index date. Mean time to new therapy, overall survival (OS) using Kaplan-Meier curve and adverse events (AEs) were reported over the 1-year post-index period. RRMM patients were also matched to a non-MM comparator cohort and economic outcomes were compared between the two cohorts. Results 289 RRMM patients were matched to 1,445 patients without MM. Most prevalent hematological AE was anemia (72.0%) and non-hematological AE was infections (75.4%). Mean (SD) time to a new treatment was 4.7 (5.3) months and median OS was 14.6 months. RRMM patients had significantly higher hospitalizations and physician office visits (Both P < .0001) compared to non-MM patients. Adjusting for baseline characteristics, patients with RRMM had 4.9 times (95% CI 3.8-6.4, P < .0001) the total healthcare costs compared with patients without MM. The major driver of total costs among RRMM patients was pharmacy costs (67.3%). Conclusion RRMM patients showed a high frequency of AEs, low OS, and a substantial economic burden suggesting need for effective treatment options.

scholarly journals The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110196
Author(s):  
Albert Oriol ◽  
Laura Abril ◽  
Anna Torrent ◽  
Gladys Ibarra ◽  
Josep-Maria Ribera
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Safety Profile ◽  
Proteasome Inhibitors ◽  
Clinical Development ◽  
Phase Iii ◽  
Acceptable Safety Profile ◽  
Refractory Multiple Myeloma ◽  
High Risk Patients ◽  
Risk Patients

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

scholarly journals Quantitative PK/PD Prediction of the Efficacious and Safe Dose Ranges of the LMP7 Inhibitor M3258 for Phase I Application in Relapsed/Refractory Multiple Myeloma Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5582-5582
Author(s):  
Florian Lignet ◽  
Christina Esdar ◽  
Manja Friese-Hamim ◽  
Andreas Becker ◽  
Elise Drouin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research And Development ◽  
Phase I ◽  
Dose Escalation ◽  
Single Agent ◽  
Proteasome Inhibitors ◽  
Refractory Multiple Myeloma ◽  
Oral Application ◽  
Development Institute ◽  
Safe Dose

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome; a crucial component of the cellular protein degradation machinery, which is highly expressed in malignant hematopoietic cells including multiple myeloma. M3258 was previously shown to deliver strong in vivo preclinical efficacy in multiple myeloma xenograft models, as well as a more benign non-clinical safety profile compared to approved pan-proteasome inhibitors, exemplified by a lack of effects on the central and peripheral nervous systems and cardiac and respiratory organs. Here we describe preclinical PK/PD and PK/efficacy modelling which led to a prediction of the PK profile, and the efficacious and safe dose ranges of M3258 in human which were used to guide the design of the phase I dose-escalation trial of M3258 in >3 line relapsed/refractory multiple myeloma (RRMM) patients. Mouse, rat, dog and monkey PK, plasma protein binding and intrinsic clearance data were used to estimate a half-life of approximately 6 hours for M3258 in human. The human total clearance and volume of distribution for M3258 were predicted to be 0.033 L/h/kg and 0.28 L/kg, respectively, whilst oral bioavailability was estimated to be above 80%. LMP7 proteolytic activity was assessed as a PD readout in human multiple myeloma tumor cells xenografted to mice as well as in dog peripheral blood mononuclear cells (PBMCs). A strong PK/PD relationship was observed for M3258 across both species. LMP7 inhibition by M3258 also correlated strongly with anti-tumor efficacy in multiple myeloma xenografts, with maximal efficacy observed at M3258 exposure delivering sustained inhibition of tumor LMP7 activity. Quantitative PK/PD/efficacy modeling predicted the biologically efficacious dose (BED) of M3258 upon oral application to be between 10 - 90 mg daily in human. By incorporating data from nonclinical safety studies, these data suggest an attractive human PK profile of M3258, enabling oral application, as well as an improved human therapeutic index compared to approved pan-proteasome inhibitors. M3258 is being investigated in a phase I, first-in-man, 2-part, open label clinical study designed to determine the safety, tolerability, PK, PD and early signs of efficacy of M3258 as a single agent (dose-escalation) and co-administered with dexamethasone (dose-expansion) in participants with RRMM whose disease has progressed following > 3 prior lines of therapy and for whom no effective standard therapy exists. Integration of these data will guide the selection of the BED for potential further clinical development of M3258. Disclosures Lignet: Merck Healthcare KGaA: Employment. Esdar:Merck Healthcare KGaA: Employment. Friese-Hamim:Merck Healthcare KGaA: Employment. Becker:Merck Healthcare KGaA: Employment, Other: Holding shares with a value below 1000-USD. Drouin:EMD Serono Research and Development Institute: Employment. El Bawab:Merck Healthcare KGaA: Employment. Goodstal:EMD Serono Research and Development Institute: Employment. Gimmi:Merck Healthcare KGaA: Employment. Haselmayer:Merck Healthcare KGaA: Employment. Jährling:Merck Healthcare KGaA: Employment. Sanderson:Merck Healthcare KGaA: Employment. Sloot:Merck Healthcare KGaA: Employment. Stinchi:Merck Healthcare KGaA: Employment. Victor:Merck Healthcare KGaA: Employment. Walter:Merck Healthcare KGaA: Employment. Rohdich:Merck Healthcare KGaA: Employment.

Arterial Hypertension and Multiple Myeloma: Physiopathology and Cardiovascular Risk and ‘Practical’ Indications in Patients Receiving Carfilzomib

2019 ◽  
Vol 15 (1) ◽  
pp. 47-53 ◽  
Author(s):  
Alberto Milan ◽  
Giulia Bruno ◽  
Ilaria Maffei ◽  
Andrea Iannaccone ◽  
Agnese Ravera ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Cardiovascular Risk ◽  
Arterial Hypertension ◽  
Proteasome Inhibitors ◽  
Good Control ◽  
Cardiovascular Complications ◽  
Uncontrolled Hypertension ◽  
Refractory Multiple Myeloma ◽  
Current Guidelines

The introduction of carfilzomib in the treatment of relapsing and refractory multiple myeloma has allowed a significant increase in survival. The most frequent adverse effect of Carfilzomib treatment is arterial hypertension, even though the exact physiopathological mechanism are still unclear. MM patients, on the other hand, often present significant cardiovascular risk factors and comorbidities. Uncontrolled hypertension is frequently the cause of cardiovascular complications. It has been estimated that up to 50% of subjects in the general population are unaware of their hypertensive condition and only half of those who are aware of this risk factor present good control of blood pressure. Although the management of arterial hypertension is clearly important in reducing the risk of cardiovascular events, and is well described by the current guidelines, no clear indications are provided on how to approach and treat specifically MM patients undergoing treatment with proteasome inhibitors. The aim of our work is to summarize a practical approach to the stratification of cardiovascular risk of hypertensive in patients who are candidates for or actively treated with carfilzomib for refractory multiple myeloma (MMR). MM patients eligible for carfilzomib treatment should preliminary undergo a careful cardiovascular risk stratification. Perspective studies will help to better identify the specific risk factors that should be considered and treated in these patients.

scholarly journals Real-world comparative effectiveness of triplets containing bortezomib (B), carfilzomib (C), daratumumab (D), or ixazomib (I) in relapsed/refractory multiple myeloma (RRMM) in the US

2021 ◽  
Author(s):  
Faith Davies ◽  
Robert Rifkin ◽  
Caitlin Costello ◽  
Gareth Morgan ◽  
Saad Usmani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Real World ◽  
Comparative Effectiveness ◽  
Proteasome Inhibitors ◽  
Refractory Multiple Myeloma ◽  
Kaplan Meier ◽  
The Us ◽  
Cox Proportional Hazard Models ◽  
Comparative Effectiveness Analysis ◽  
Line Of Therapy

AbstractMultiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum’s deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.

scholarly journals Refractory IgD Multiple Myeloma Treated with Daratumumab: A Case Report and Literature Review

2016 ◽  
Vol 2016 ◽  
pp. 1-4 ◽  
Author(s):  
Muhammad Husnain ◽  
Sandra Kurtin ◽  
Nikki Barkett ◽  
Irbaz Bin Riaz ◽  
Amit Agarwal
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Median Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Human Monoclonal Antibody ◽  
Proteasome Inhibitors ◽  
Recent Analysis ◽  
Immunomodulatory Drugs ◽  
Refractory Multiple Myeloma

Patients with relapsed and refractory multiple myeloma have poor prognosis. A recent analysis of patients with relapsed and refractory multiple myeloma who were refractory to both proteasome inhibitors and immunomodulatory drugs showed the median overall survival of 9 months only. Daratumumab is the first-in-class human monoclonal antibody against CD38 cells which was studied in phase I/II trials for treatment of these patients with relapsed refractory multiple myeloma. It showed an overall response rate of 36% and a median overall survival (OS) of 17 months in these patients. We report a case of 40-year-old man with immunoglobulin D (IgD) multiple myeloma whose disease was refractory to at least 5 different chemotherapy regimens including proteasome inhibitors and immunomodulatory drugs. The clinical studies assessing daratumumab did not include any patients with IgD myeloma which is a rare form of multiple myeloma and to our knowledge is the first study reporting use of daratumumab in IgD myeloma.

scholarly journals Efficacy of Once-Weekly Bortezomib with Daratumumab for Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1958-1958
Author(s):  
Natalia Gut ◽  
Filiz Yucebay ◽  
Jessica Dempsey ◽  
Junan Li ◽  
Don M. Benson
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Hematologic Malignancy ◽  
Small Sample Size ◽  
Single Agent ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Small Sample ◽  
Weekly Schedule ◽  
Refractory Multiple Myeloma

Abstract Background Multiple Myeloma (MM) is an essentially incurable hematologic malignancy with the goals of therapy being disease control, improved quality of life, and prolonged survival.1,2 Despite improved survival with proteasome inhibitors and immunomodulatory agents, outcomes for patients with refractory disease, resistant to these classes of therapy, are poor. Daratumumab, an anti-CD38 antibody, is a commonly utilized therapy for relapsed/refractory multiple myeloma (RRMM) as a single agent based on the SIRIUS study which resulted in adequate response and acceptable safety profiles.3,4 Currently, it is approved in various combinations including with bortezomib. The approval of daratumumab in combination with bortezomib days 1, 4, 8, and 11 of a 21-day cycle was based on the CASTOR study which resulted in high response rates and acceptable safety profiles.5With the addition of bortezomib, additional toxicities in this RRMM setting may be a concern.6 Previous studies of bortezomib in RRMM patients have demonstrated that once-weekly bortezomib is equally as efficacious and better tolerated than the standard twice-weekly schedule, with a lower incidence of peripheral neuropathy and myelosuppression.8,9 However, there are currently no published reports of combining once-weekly bortezomib with daratumumab for patients with RRMM. Methods The present study sought to evaluate the progression-free survival (PFS) of daratumumab administered with once-weekly bortezomib for patients with RRMM. Secondary objectives included evaluation of overall survival (OS), overall response rate (ORR), time to response (TTR), and toxicity of once-weekly bortezomib with daratumumab. Eighteen patients were identified in an Institutional Review Board (IRB)-approved retrospective review of our institutional experience with daratumumab and once-weekly bortezomib. The median age of patients was 65 years (range 47 - 76, Table 1). Ten patients (55.6%) had three or more prior lines of therapy. Twelve patients (66.7%) had previous autologous stem cell transplantation. Sixteen patients (88.9%) had prior proteasome inhibitor (PI) therapy. Thirteen patients (72.2%) had disease refractory to their last line of therapy. Results The median PFS was 3.5 months. Median OS was not reached and TTR were undetermined due to the small sample size. The ORR was 33.3%, with 6 out of 18 patients experiencing an objective partial response or better (Table 2). Of those that responded, 4 patients (66.7%) remained on therapy at the time of data collection.The side effect profile was more tolerable, with less thrombocytopenia (27.8% all grade) and peripheral neuropathy (33.3% all grade) than previously reported (Table 3). Conclusions Daratumumab monotherapy was approved in heavily pretreated RRMM based on the SIRIUS trial showing promising efficacy and a favorable safety profile.4 The median PFS was 3.7 months compared to our PFS of 3.5 months. The combination of daratumumab with bortezomib administered twice weekly was approved based results from the CASTOR trial showing superiority of daratumumab in combination with bortezomib and dexamethasone over bortezomib and dexamethasone.5 As depicted in Table 2, our ORR of 33.3% is similar to the ORR of 29.2% in the SIRIUS trial, however differs greatly from 82.9% in the CASTOR trial. While the present work is retrospective and hypothesis-generating, our results suggest that further prospective inquiry is necessary to determine the additional efficacy of adding once-weekly bortezomib to daratumumab. Disclosures Dempsey: Heron Therapeutics: Honoraria; TESARO: Honoraria.

scholarly journals Novel Non-Immunologic Agents for Relapsed and Refractory Multiple Myeloma: A Review Article

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5210
Author(s):  
Arthur Bobin ◽  
Cécile Gruchet ◽  
Stéphanie Guidez ◽  
Hélène Gardeney ◽  
Laly Nsiala Makunza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Alkylating Agents ◽  
Treatment Options ◽  
Hdac Inhibitors ◽  
Proteasome Inhibitors ◽  
Curative Therapy ◽  
Refractory Multiple Myeloma ◽  
Novel Treatments ◽  
Treatment Regimens ◽  
Drug Classes

Novel treatments are needed to address the lack of options for patients with relapsed or refractory multiple myeloma. Even though immunotherapy-based treatments have revolutionized the field in recent years, offering new opportunities for patients, there is still no curative therapy. Thus, non-immunologic agents, which have proven effective for decades, are still central to the treatment of multiple myeloma, especially for advanced disease. Building on their efficacy in myeloma, the development of proteasome inhibitors and immunomodulatory drugs has been pursued, and has led to the emergence of a novel generation of agents (e.g., carfilzomib, ixazomib, pomalidomide). The use of alkylating agents is decreasing in most treatment regimens, but melflufen, a peptide-conjugated alkylator with a completely new mechanism of action, offers interesting opportunities. Moreover, with the identification of novel targets, new drug classes have entered the myeloma armamentarium, such as XPO1 inhibitors (selinexor), HDAC inhibitors (panobinostat), and anti-BCL-2 agents (venetoclax). New pathways are still being explored, especially the possibility of a mutation-driven strategy, as biomarkers and targeted treatments are increasing. Though multiple myeloma is still considered incurable, the treatment options are expanding and are progressively becoming more diverse, largely because of the continuous development of non-immunologic agents.

New and emerging therapies for relapse/refractory multiple myeloma: Impact of education on practice behaviors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18096-e18096
Author(s):  
Anne Roc ◽  
Wendy Turell ◽  
David Dingli
Keyword(s):  
Multiple Myeloma ◽  
Panel Discussion ◽  
Hdac Inhibitors ◽  
Proteasome Inhibitors ◽  
Lessons Learned ◽  
Case Scenario ◽  
Refractory Multiple Myeloma ◽  
Relative Safety ◽  
Emerging Therapies ◽  
The Impact

e18096 Background: Newly approved and emerging agents with novel mechanisms of action present unique challenges to treating patients with relapsed/refractory multiple myeloma (RRMM), including keeping abreast of rapid and ever-aggregating data on their safety, tolerability and efficacy. To address these challenges, an education activity focused on new and emerging therapies for RRMM was developed and learner responses were evaluated to determine the impact of education. Methods: A live-online 1-hour video panel discussion with slides, polling, and live questions was produced in 2016 and made available on-demand at OMedLive.com for 6 months. Survey responses (pre-, post-, 8 weeks post-activity), polling responses, and live questions asked were tracked to measure engagement, lessons learned, and additional education gaps. Results: 51 of 288 learners completed all pre/post/follow-up surveys, 67% of which reported the activity positively impacted patient experience or outcome and 61% reported it positively impacted their clinical practice. These learners reported improvements in their ability to: assess the relative safety and efficacy of emerging agents (50%), differentiate available agents and their relative efficacy (50% with proteasome inhibitors, 39% with monoclonal antibodies), see the potential benefit of HDAC inhibitors (35%), use combination regimens (29%), and adjust treatments for patients who’ve experienced disease progression (29%). As the result of education, 95 of 288 learners reported commitments to change in regards to: medical/practice knowledge (95%), care attitudes (89%), practice behavior (76%), and patient clinical outcomes (81%). Learners also demonstrated improved competence via a case scenario which required identifying the optimal next step for a patient with biochemical progression, and improved knowledge on the characteristics of daratumumab, elotuzumab, and selinexor. Conclusions: New and emerging therapies promise to improve the lives of patients with RRMM, but complicates the already difficult task of managing the disease. Ongoing education on RRMM is recommended and can yield immediate and sustained gains in knowledge, competence, and performance.

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