scholarly journals Daratumumab in untreated newly diagnosed multiple myeloma

2019 ◽  
Vol 10 ◽  
pp. 204062071989487 ◽  
Author(s):  
Nadine Abdallah ◽  
Shaji K. Kumar
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Clinical Trials ◽  
High Risk ◽  
Human Monoclonal Antibody ◽  
Proteasome Inhibitors ◽  
Immunomodulatory Drugs ◽  
Newly Diagnosed ◽  
Infusion Reactions

The treatment of multiple myeloma has evolved markedly in the last decade, but mortality remains high, emphasizing the need for more effective therapies. Daratumumab, a fully human monoclonal antibody targeting CD38, has shown clinical efficacy in relapsed/refractory multiple myeloma both as monotherapy and in combination with other drugs, including novel agents. More recently, promising results have been reported in patients with untreated newly diagnosed multiple myeloma (NDMM). Clinical trials thus far have shown enhanced efficacy and tolerability of several daratumumab-based combinations in both transplant ineligible and eligible patients, without compromising transplant ability. However, benefit in high-risk subpopulations is still unclear. A subcutaneous formulation of daratumumab has been introduced to decrease the risk of infusion reactions, with preliminary results showing non-inferior efficacy. The antimyeloma activity of daratumumab is achieved through multiple mechanisms including direct, Fc-dependent, and immunomodulatory mechanisms. Enhanced efficacy of daratumumab in combination with immunomodulatory drugs and proteasome inhibitors is supported by preclinical data showing synergism. This review will focus on the role of daratumumab in untreated NDMM patients, highlighting the results of major clinical trials, and listing ongoing trials that are evaluating various daratumumab-based combinations in this setting.

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 Molecularly Targeted Therapies in Multiple Myeloma

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Pilar de la Puente ◽  
Barbara Muz ◽  
Feda Azab ◽  
Micah Luderer ◽  
Abdel Kareem Azab
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Tumor Microenvironment ◽  
Cell Signaling ◽  
Targeted Therapies ◽  
Proteasome Inhibitors ◽  
Novel Agents ◽  
Immunomodulatory Drugs ◽  
Therapeutic Outcomes

Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted.

scholarly journals DARATUMUMAB FOR THE TREATMENT OF MULTIPLE MYELOMA

2017 ◽  
pp. 94-102
Author(s):  
V. V. Ryzhko ◽  
M. L. Kanaeva
Keyword(s):  
Multiple Myeloma ◽  
Clinical Practice ◽  
Human Monoclonal Antibody ◽  
Proteasome Inhibitors ◽  
Published Data ◽  
Immunomodulatory Drugs ◽  
Combination Therapies ◽  
The Past ◽  
Excellent Safety Profile ◽  
Improvement In Survival

The use of proteasome inhibitors and immunomodulatory drugs in the clinical practice has contributed to the significant improvement in survival for patients with multiple myeloma over the past decades. Alongside this, due to the recurrent course of the disease, there is a need to introduce new classes of drugs to clinical practice. In 2015,  the FDA (USA) approved two monoclonal  antibodies  for use  in  patients  with  relapsed  multiple  myeloma,  and  immunotherapy has  rapidly become indispensable  in the management of such patients. The article presents an analysis of the published data regarding the mechanism of action, safety and clinical efficacy of daratumumab, a human monoclonal antibody that targets CD38 tumor protein, for the  treatment  of patients  with multiple  myeloma. In Russia, daratumumab is registered  (RU LP-004367  of 07.07.2017) and is indicated as monotherapy for patients with relapsed or refractory multiple myeloma, who have received prior therapies, incuding proteasome  inhibitors and immunomodulatory drugs. Daratumumab demonstrated  an excellent safety profile. In the context of daratumumab therapy, the moderate-grade infusion-related reactions occurring mostly during the  first infusion  are the  main adverse  events.  Daratumumab-based combination  therapies  are currently under active evaluation in patients with relapsed and newly diagnosed myeloma.

scholarly journals Significance of Modified Risk Stratification Msmart 3.0 and Autologous Stem Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5593-5593
Author(s):  
Andrey Garifullin ◽  
Sergei Voloshin ◽  
Vasily Shuvaev ◽  
Irina Martynkevich ◽  
Elizaveta Kleina ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Risk Stratification ◽  
Risk Group ◽  
High Risk Group ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Genetic Abnormalities ◽  
Standard Risk

Background The risk-stratification systems are repeatedly updated in accordance with the emergence of new information about the prognostic impact of anomalies and other factors. The most extensive and modern system in this time is mSMART risk stratification involving many parameters such as genetic anomalies, albumin, beta-2-microglobulin, LDH, Plasma Cell S-phase and GEP levels. It is possible to use risk-adapted treatment programs with or without ASCT. Nevertheless, the role of complex karyotype, combination of genetic abnormalities and ASCT remains unclear. Aims To estimate the genetic abnormalities in patients with newly diagnosed multiple myeloma and define the role of risk-stratification and ASCT in prognosis of disease. Methods The study included 159 patients (median age 63 years, range 28 - 83; male: female ratio - 1:1.37) with NDMM. Metaphase cytogenetics on bone marrow samples was done by standard GTG-method. FISH analyses were performed according to the manufacturer's protocol for detection primary IgH translocations, 13q (13q14/13q34) deletion, 1p32/1q21 amplification/deletion, P53/cen 17 deletion (MetaSystems DNA probes). We additional searched the t(4;14), t(6;14), t(11;14), t(14;16) and t(14;20) in patients with IgH translocation. All patient was treated by bortezomib-based programs (VD, CVD, VMP, PAD). ASCT was performed at 42% patients. Results The frequency of genetic abnormalities in NDMM patients was 49% (78/159). IgH translocation was detected in 26.4% (42/159) patients: t(11;14) - 16.3% (26/159), t(4;14) - 5.0% (8/159); TP53/del17p - 5.6% (9/159); 1p32/1q21 amp/del - 12% (19/159); hypodiploidy - 3.1% (5/159); hyperdiploidy - 1.25% (2/159); del5q - 0,6% (1/159); other - not found. Combination two aberrations was discovered in 11.9% (19/159) patients, complex abnormalities (>3 aberrations) - in 4.4% (7/159) patients. The median OS in "two aberration" and "complex abnormalities" groups were lower than in standard-risk mSMART 3.0 (normal, t(11;14), hypodiploidy, hyperdiploidy and other): 49 months, 26 months and was not reached, respectively (p=.00015). The median PFS for these groups was 12 months, 11 months and 30 months, respectively (p=.011). Differences between "two aberration" and "complex abnormalities" groups were not find (p> .05). We modified high-risk (gain 1q, p53 mutation, del 17p deletion, t(4;14), t(14;16), t(14;20), R-ISS stage III, double and triple hit myeloma) mSMART 3.0 by adding "two aberration" and "complex abnormalities" groups on based the OS and PFS results. The final analysis was based on the results of the complex examination of 87 patients: 53 patients in standard-risk group and 34 patients in high-risk group. The median OS in standard-risk mSMART 3.0 was not reached, in high-risk mSMART 3.0mod - 48 months; 5-years OS was 62% and 38%, respectively (p=0.0073). The median PFS was 43 and 29 months, respectively (p=.09). The best results of OS and PFS were reach in both groups of patient who performed ASCT. The median OS in standard-risk mSMART 3.0 with ASCT (n=37) was not reached, in high-risk mSMART 3.0mod with ASCT - 48 months (n=20); standard-risk mSMART 3.0 without ASCT - 40 months (n=16); in high-risk mSMART 3.0mod without ASCT - 22 months (n=14); 5-years OS was 81%, 60%, 33% and 28%, respectively (p=0.0015). The median PFS was not reached, 46, 22 and 19 months, respectively (p=.017). Conclusions The combination of two aberrations and complex abnormalities is unfavorable prognostic markers. The median OS and PFS was higher in standard-risk than high-risk group according mSMART 3.0mod. The ASCT can improve treatment's outcomes and life expectancy especially in patients with high-risk. It can be useful for update risk stratification in a future. Disclosures Shuvaev: Novartis: Consultancy; Pfize: Honoraria; Fusion Pharma: Consultancy; BMS: Consultancy.

How I Treat Frontline Transplant-eligible Multiple Myeloma

Blood ◽  
2021 ◽  
Author(s):  
Aurore Perrot
Keyword(s):  
Multiple Myeloma ◽  
Randomized Clinical Trials ◽  
Human Monoclonal Antibody ◽  
Autologous Transplantation ◽  
Proteasome Inhibitors ◽  
Standard Of Care ◽  
Adaptive Strategy ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Melphalan

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.

scholarly journals Current and emerging immunotherapeutic approaches to the treatment of multiple myeloma

2019 ◽  
Vol 10 ◽  
pp. 204062071985417
Author(s):  
Dawn Swan ◽  
Kevin Lynch ◽  
Mark Gurney ◽  
Michael O’Dwyer
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
Immune Evasion ◽  
Proteasome Inhibitors ◽  
Standard Of Care ◽  
Bispecific Antibodies ◽  
Clinical Use ◽  
Immunomodulatory Drugs ◽  
Care Regimes

Multiple myeloma (MM) has a worldwide incidence of 1–5/100,000/year. Outcomes have improved significantly in recent years following incorporation of immunomodulatory drugs and proteasome inhibitors into standard-of-care regimes. MM is profoundly immunosuppressive, enabling immune evasion, proliferation and disease progression. The role of the immune system in MM is becoming increasingly characterized and understood, and numerous therapies are under development or in routine clinical use targeting these elements of MM pathogenesis. In this review we discuss the immunosuppressive effects of MM, then the therapies targeting these defects. Specifically, we review the monoclonal and bispecific antibodies, alongside adoptive cellular therapies currently under investigation.

Immunomodulatory drugs in the treatment of multiple myeloma

2019 ◽  
Vol 49 (8) ◽  
pp. 695-702 ◽  
Author(s):  
Yu Abe ◽  
Tadao Ishida
Keyword(s):  
Multiple Myeloma ◽  
Ubiquitin Ligase ◽  
Proteasome Inhibitors ◽  
Novel Agents ◽  
Immunomodulatory Drugs ◽  
Newly Diagnosed ◽  
Ubiquitin Ligase Complex ◽  
Long Time ◽  
Molecular Mechanism Of Action ◽  
Direct Target

Abstract The prognosis of multiple myeloma was quite poor in the last century, but it has significantly improved with the incorporation of novel agents, immunomodulatory drugs (IMiDs) and proteasome inhibitors. Thalidomide was first developed as a sedative in 1950s, but it was withdrawn from the market because of teratogenicity. In 1990s, however, thalidomide received attention due to the discovery of its anticancer potential derived from antiangiogenic and immunomodulatory activities, and its therapeutic effect on myeloma. In 2006, the U.S. Food and Drug Administration approved the use of thalidomide under strict control for the treatment of multiple myeloma. After that, two new IMiDs, lenalidomide and pomalidomide, were developed for the sake of more antitumor activity and less adverse events than thalidomide. The molecular mechanism of action of IMiDs remained unclear for a long time until 2010 when the protein cereblon (CRBN) was identified as a primary direct target. IMiDs binds to CRBN and alters the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in breakdown of intrinsic downstream proteins such as IKZF1 (Ikaros) and IKZF3 (Aiolos). There are many clinical trials of multiple myeloma using IMiDs under various conditions, and most of them show the efficacy of IMiDs. Nowadays lenalidomide plays a central role in both newly diagnosed and relapsed/refractory settings, mainly in combination with other novel agents such as proteasome inhibitors and monoclonal antibodies. This review presents an overview of recent advances in immunomodulatory drugs in the treatment of multiple myeloma.

scholarly journals High-risk multiple myeloma: how to treat at diagnosis and relapse?

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 30-36
Author(s):  
María-Victoria Mateos ◽  
Borja Puertas Martínez ◽  
Verónica González-Calle
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
High Risk ◽  
Poor Prognosis ◽  
Proteasome Inhibitors ◽  
Past Century ◽  
The Past ◽  
Baseline Factors ◽  
Novel Therapeutic Strategies ◽  
Improvement In Survival

Abstract Patients with multiple myeloma have experienced a great improvement in survival over the past century because of the introduction of novel therapeutic strategies. However, a subgroup of patients with poorer outcomes than expected is considered high risk and identified by the presence of patient- and disease-based factors such as frailty, extramedullary disease, cytogenetic abnormalities, or even relapses occurring earlier than expected according to the baseline factors. Although the management of patients with high-risk features is not well established because of the lack of specific trials in this subgroup of patients and because of their underrepresentation in the clinical trials, treatment should be planned on 2 pillars: (1) poor prognosis with the presence of high-risk features can be at least improved or even abrogated by achieving a deep and sustained response over time, and (2) this can most likely be obtained through using the best therapeutic options and in a response-adapted way. Some clinical trials that have been planned or are ongoing include only patients with high-risk features, using the most effective therapies (proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies) as well as chimeric antigen receptor T cells and T-cell engagers that will unravel what the best therapeutic approach will be to overcome the poor prognosis of the presence of high-risk features.

scholarly journals Treatment Patterns and Clinical Outcomes in High-Risk Multiple Myeloma Patients Carrying the 17p Deletion: A Multi-Center Retrospective Observational Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4510-4510
Author(s):  
Yael Cohen ◽  
Moshe E. Gatt ◽  
Noa Lavi ◽  
Chezi Ganzel ◽  
Hila Magen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Clinical Trials ◽  
High Risk ◽  
Plasma Cells ◽  
Response Rate ◽  
Treatment Patterns ◽  
Extramedullary Disease ◽  
Access Programs

Abstract Introduction Improvement in overall survival (OS) is seen primarily within standard risk Multiple Myeloma (MM), however, high risk MM OS was still around 2-3 years until recently. Del17p is a genomic imbalance which includes deletion of the TP53 locus. It occurs in ~7-10% of MM at diagnosis and is associated with extramedullary disease and is a strong poor prognostic factor. Recently approved novel agents and combinations have demonstrated improved outcomes also in patients with negative cytogenetic features; however, their long term impact remains to be seen. Access to newer agents depends on time of diagnosis as well as availability of clinical trials, access programs and insurance coverage. The goal of this study is to analyze real world data including treatment patterns and outcomes among MM patients carrying 17p deletion, in a retrospective multi-site study. Methods An observational, retrospective, multi-center study. Consecutive patients diagnosed with multiple myeloma in the 8 participating centers in Israel, diagnosed between 1.1.2008 - 3.1.2016 that were proven to carry 17p deletion by means of FISH studies (any % of plasma cells), were identified by searching hospital records including cytogenetic lab records. Data concerning patient demographics, disease characteristics, treatment regimens and clinical endpoints were collected. Results A total of 57 patients carrying 17p deletion of FISH were identified. Patient's characteristics are described in table. Notably, most patients had bone disease; extramedullary disease (EMD) rate was relatively high, as was the presence of additional high risk FISH abnormalities. Most patients received a bortezomib-based induction, over half underwent ASCT. Fifteen (26%) of the patients participated in clinical trials or access programs (or both) (table). Overall response rate (ORR) after induction was 84%, response rate declined in subsequent treatment lines (figure 1). The median follow-up was 21 (range, 4-94) months. Median overall survival (OS) was 43 months; Median Progression free survival (PFS) was 20 months (figure 2A,B). In univariate analysis, presence of extra-medullary disease at diagnosis was associated with worse PFS (7.4 vs. 21.4 months, p=0.05, figure 2C); presence of additional high risk FISH findings also trended towards shorter PFS (13.5 vs 21.4 months, p=0.0569), while age, gender, ISS, %plasma cells, % cells with del17p, time of del17p detection, M-Spike and iFLC levels were not significantly associated with PFS. Among patients with a PFS greater than 6 months, ASCT was associated with a significant improvement in PFS (25.7 vs 9.0 months, p=0.0022 log-rank test) (figure 2D), 4 patients underwent allotransplant, with a median OS of 69 months. Conclusions Our data confirm the poor prognosis of myeloma patients with del17p, in a multi-site observational setting, and an even worse prognosis in the presence of extramedullary disease and additional high-risk FISH features. While ORR after induction is similar to that generally expected in a newly diagnosed myeloma patients, responses are shorter and thus PFS is inferior compared to recently reported upfront bortezomib-based regimens ranging from 30-40+ months. Responses decline further in subsequent lines yet remain non-negligible even in advanced therapeutic lines. Our data support the role of ASCT in these high risk patients, and the potential role of allotransplant in selected patients. High rate of participation in clinical trials and access programs throughout the course of therapy reflects the valued role of newer agents in the management of myeloma patients. Disclosures Avivi: Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche.

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