scholarly journals Evolution of Therapy for Relapsed/Refractory Multiple Myeloma

2019 ◽  
Vol 17 (11.5) ◽  
pp. 1433-1436 ◽  
Author(s):  
Jorge J. Castillo
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Export ◽  
Histone Deacetylase Inhibitors ◽  
Proteasome Inhibitors ◽  
Hematologic Malignancies ◽  
Current Treatment ◽  
Related Factors ◽  
Refractory Multiple Myeloma ◽  
Annual Congress ◽  
Individual Disease

With so many recent advances in relapsed/refractory multiple myeloma, keeping abreast with current treatment recommendations can be challenging. Novel immunomodulators, proteasome inhibitors, monoclonal antibodies, histone deacetylase inhibitors, and nuclear export inhibitors have all been added to the armamentarium, and the choice of which of these drugs or drug combinations to use depends on individual disease-related and patient-related factors, previous therapies, and treatment toxicities. At the NCCN 2019 Annual Congress: Hematologic Malignancies, Dr. Jorge J. Castillo provided an overview of the myriad treatments available for patients with relapsed/refractory multiple myeloma, as well as therapies on the horizon.

scholarly journals How I treat relapsed and/or refractory multiple myeloma

2020 ◽  
Vol 12 (s1) ◽  
Author(s):  
Hans C. Lee ◽  
Claudio Cerchione
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Export ◽  
Histone Deacetylase Inhibitors ◽  
Alkylating Agents ◽  
Treatment Options ◽  
Unmet Need ◽  
Proteasome Inhibitors ◽  
Antibody Drug Conjugate ◽  
Refractory Multiple Myeloma ◽  
Therapeutic Landscape

The expanding therapeutic landscape of relapsed and/or refractory multiple myeloma (RRMM) has contributed to significant improvements in patient outcomes. These have included combinations of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), histone deacetylase inhibitors, and/or alkylating agents. More recently, the approval of the first-in-class nuclear export inhibitor selinexor and the first-in-class B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC) belantamab mafodotin has helped address the current unmet need in patients refractory to PI, IMiD, and anti-CD38 mAb directed therapy, otherwise known as triple class refractory myeloma. With the growing number of treatment options in the RRMM therapeutic landscape, the choice and sequencing of drugs and combinations has become increasingly complex. In this review we discuss our approach and considerations in the treatment of both early and late RRRM based on best available data and our clinical experience.

scholarly journals Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma

Blood ◽  
2018 ◽  
Vol 132 (24) ◽  
pp. 2546-2554 ◽  
Author(s):  
Nizar J. Bahlis ◽  
Heather Sutherland ◽  
Darrell White ◽  
Michael Sebag ◽  
Suzanne Lentzsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Export ◽  
Low Dose ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Nuclear Retention ◽  
Refractory Multiple Myeloma ◽  
Nuclear Export Protein ◽  
Grade 3 ◽  
Export Protein

Abstract Selinexor is an oral inhibitor of the nuclear export protein exportin 1. Preclinical studies demonstrated synergistic antimyeloma activity between selinexor and proteasome inhibitors (PI) through suppression of NF-κB signaling and nuclear retention of tumor suppressor proteins. We tested selinexor in combination with low-dose bortezomib and dexamethasone (SVd) for the treatment of relapsed or refractory multiple myeloma (MM). The primary objectives of this study were to determine the safety profile, overall response rate (ORR), and a recommended phase 2 dose (RP2D) of SVd. We enrolled 42 patients to receive selinexor (60, 80, or 100 mg orally) plus bortezomib (1.3 mg/m2 subcutaneously) and dexamethasone (20 mg orally) once or twice weekly in 21- or 35-day cycles. Patients had a median of 3 (range 1-11) prior lines of therapy, and 50% were refractory to a PI. Treatment-related grade 3 or 4 adverse events reported in ≥10% of patients were thrombocytopenia (45%), neutropenia (24%), fatigue (14%), and anemia (12%). Incidence (4 patients, 10%) and grade (≤2) of peripheral neuropathy were low. The ORR for the entire population was 63%: 84% ORR for PI nonrefractory and 43% for PI-refractory patients. The median progression-free survival for all patients was 9.0 months; 17.8 months for PI nonrefractory, and 6.1 months for PI refractory. SVd treatment produced high response rates in patients with relapsed or refractory MM, including borezomib-refractory MM, with no unexpected side effects. The RP2D is selinexor (100 mg once weekly), bortezomib (1.3 mg/m2 once weekly for 4 weeks), and dexamethasone (40 mg once weekly) per 35-day cycle. This trial was registered at www.clinicaltrials.gov as #NCT02343042.

scholarly journals The 39th David A. Karnofsky Lecture: Bench-to-Bedside Translation of Targeted Therapies in Multiple Myeloma

2012 ◽  
Vol 30 (4) ◽  
pp. 445-452 ◽  
Author(s):  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Histone Deacetylase Inhibitors ◽  
Enzyme Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Proteasome Inhibitors ◽  
Hematologic Malignancies ◽  
Direct Result ◽  
Bone Biology ◽  
Dendritic Cell Vaccines ◽  
Definition Of

Multiple myeloma (MM) is a remarkable example of rapid bench-to-bedside translation in new drug development. The proteasome inhibitor bortezomib and immunomodulatory drug lenalidomide targeted MM cells in the bone marrow (BM) microenvironment to overcome conventional drug resistance in laboratory and animal models and were rapidly translated into clinical trials demonstrating their efficacy in patients with relapsed and then newly diagnosed MM, with a doubling of the median survival as a direct result. The future is even brighter. First, immune-based therapies are being developed (eg, elotuzumab monoclonal antibody [MoAb]; CD138DM immunotoxin; MM cell–dendritic cell vaccines; CD138, CS-1, and XBP-1 peptide vaccines; anti-17 MoAb; and other treatments to overcome causes of immune dysfunction). Second, promising next-generation agents target the MM cell in its microenvironment (eg, deubiquitinating enzyme inhibitors; chymotryptic [carfilzomib, Onyx 0912, MLN 9708] and broader [NPI-0052] proteasome inhibitors; immunoproteasome inhibitors; and pomalidamide). Moreover, agents targeting bone biology (eg, zoledronic acid, anti–DKK-1 MoAb, anti–B-cell activating factor MoAb and bortezomib, Btk inhibitor) show promise not only in preserving bone integrity but also against MM. Third, rationally based combination therapies, including bortezomib with Akt, mammalian target of rapamycin, or histone deacetylase inhibitors, are active even in bortezomib-refractory MM. Finally, genomics is currently being used in the definition of MM heterogeneity, new target discovery, and development of personalized therapy. Myeloma therefore represents a paradigm for targeting the tumor in its microenvironment, which has already markedly improved patient outcome in MM and has great potential in other hematologic malignancies and solid tumors as well.

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 Role of Histone Deacetylase Inhibitors in Relapsed Refractory Multiple Myeloma: A Focus on Vorinostat and Panobinostat

2015 ◽  
Vol 35 (12) ◽  
pp. 1173-1188 ◽  
Author(s):  
Salma Afifi ◽  
Angela Michael ◽  
Mahshid Azimi ◽  
Mabel Rodriguez ◽  
Nikoletta Lendvai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
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.

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

scholarly journals Sequencing multiple myeloma therapies with and after antibody therapies

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 248-258
Author(s):  
Niels W. C. J. van de Donk
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Related Factors ◽  
Prior Therapy ◽  
Choice Of Treatment ◽  
Heavily Pretreated ◽  
First Relapse ◽  
Pretreated Patients ◽  
New Treatment ◽  
Selection Of

Abstract In multiple myeloma (MM), treatment selection and sequencing become increasingly complex with the increasing number of therapeutic options, including antibodies. Choice of treatment is dependent on various factors including patient- and tumor-related features. In addition, treatment-related factors, such as type and response to prior therapy, are also critical in terms of the selection of a new treatment regimen. Furthermore, approval status and reimbursement policies influence treatment choice. At the time of first relapse, patients who received a bortezomib-based regimen can switch to lenalidomide-based treatment, whereas patients who received lenalidomide until progression can switch to a proteasome inhibitor–based therapy. Alternatively, there is increasing evidence that pomalidomide-based triplets are also effective following the development of lenalidomide-refractory disease both in early and later relapse settings. Patients who become refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies have a poor prognosis. These triple-class refractory patients may benefit from novel, recently approved agents such as XPO1 inhibitors or from participation in a clinical trial. Furthermore, retreatment with agents that were received in previous lines of therapy can also be considered in heavily pretreated patients, for example, in combination with classic cytotoxic drugs. Importantly, with the increasing use of CD38 antibodies in newly diagnosed and early relapsed/refractory MM, more information is needed on the potential value of retreatment with CD38 antibodies. With the introduction of new immunotherapies with novel modes of action, we also need a better understanding of sequencing of immunotherapeutic agents by taking into account the effect of prior therapy on immune function.

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.

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