scholarly journals Use of KRD-PACE as Salvage Therapy in Aggressive, Relapsed/Bortezomib-Refractory Extramedullary Multiple Myeloma: A Report of Two Cases and Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Ricardo D. Parrondo ◽  
Vivek Roy ◽  
Taimur Sher ◽  
Victoria Alegria ◽  
Asher A. Chanan-Khan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Poor Prognosis ◽  
Proteasome Inhibitors ◽  
Salvage Chemotherapy ◽  
First Line ◽  
Immunomodulatory Agents ◽  
Resistance To Therapy ◽  
Line Setting ◽  
Novel Agent

Extramedullary multiple myeloma is defined by the presence of plasma cell infiltration outside of the bone marrow. It is associated with a poor prognosis and resistance to therapy and is often associated with high-risk cytogenetics. Aggressive relapsed and refractory extramedullary multiple myeloma is often treated with salvage infusional chemotherapy to achieve rapid disease control. Commonly used regimens include DCEP, CVAD, and VTD-PACE. While VTD-PACE contains bortezomib and thalidomide which have potent antimyeloma activity, the advent of novel agent therapy with proteasome inhibitors and immunomodulatory agents being used in the first-line setting has resulted in many patients being refractory to bortezomib by the time they are treated with VTD-PACE. Herein, we discuss two cases of aggressive relapsed, high-risk, bortezomib-refractory extramedullary multiple myeloma treated with KRD-PACE and review the available clinical data on salvage chemotherapy regimens used in relapsed refractory myeloma.

Selinexor: a first-in-class SINE compound for treatment of relapsed refractory multiple myeloma

2020 ◽  
Vol 16 (19) ◽  
pp. 1331-1350 ◽  
Author(s):  
Shambavi Richard ◽  
Joshua Richter ◽  
Sundar Jagannath
Keyword(s):  
Multiple Myeloma ◽  
Poor Prognosis ◽  
Proteasome Inhibitors ◽  
Resistance Mechanisms ◽  
Mechanisms Of Action ◽  
Epigenetic Alterations ◽  
Oral Agent ◽  
Immunomodulatory Agents ◽  
Tumor Suppressor Proteins ◽  
Functional Inactivation

The progression of multiple myeloma is accompanied by complex cytogenetic and epigenetic alterations that include mutation or functional inactivation of tumor suppressor proteins and overexpression of oncoproteins. Patients whose myeloma is refractory to the three major classes of drugs including immunomodulatory agents, proteasome inhibitors and anti-CD38 monoclonal antibodies have a very poor prognosis. Drugs with novel mechanisms of action that can bypass resistance mechanisms are sorely needed for this group of patients. Selinexor represents a novel, oral agent with an innovative mechanism of action that offers a significant therapeutic advance in this group of heavily treated patients. Moreover, this novel mechanism may provide additional options for patients with less refractory disease.

The presence of bone marrow fibrosis is associated with poorer prognosis in newly diagnosed multiple myeloma treated with immunomodulatory agents and/or proteasome inhibitors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19514-e19514
Author(s):  
Barry Paul ◽  
Gavin Loitsch ◽  
Daniel Feinberg ◽  
Ian Barak ◽  
Zhiguo Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Poor Prognosis ◽  
Proteasome Inhibitors ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Bone Marrow Fibrosis ◽  
Bone Marrow Biopsies ◽  
Immunomodulatory Agents ◽  
Marrow Fibrosis

e19514 Background: The treatment of newly diagnosed multiple myeloma (NDMM) has evolved significantly with the advent of the immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs). While the presence of bone marrow fibrosis (BMF) has previously been associated with poor prognosis in multiple myeloma (MM), these studies were small and conducted prior to the widespread use of IMiDs and PIs. Here, we determined the incidence of BMF in NDMM patients and correlated the degree of BMF with prognosis in a population enriched for IMiD and/or PI exposure. Methods: Bone marrow biopsies from 306 MM patients seen at Duke between 2003 and 2013 were screened for BMF using a reticulin stain. Samples were scored as absent, mild, moderate, or severe fibrosis based on the degree and intensity of staining. The association between presence and degree of BMF to progression free survival (PFS) and overall survival (OS) was calculated using Kaplan-Meier analysis. Results: Of the 306 patients evaluated, 248 (81.0%) were treated with an IMiD, 241 (78.8%) were treated with a PI, and 217 (70.9%) received both. Additionally, 160 (52.3%) patients went on to receive an autologous stem cell transplant (HSCT). A total of 193 patients (63.1%) were evaluable for BMF. Of these, 96 (49.7%) had detectable BMF, while 97 (50.3%) had no BMF. The degree of BMF was mild in 60 patients (62.5%), and moderate or severe in 34 patients (35.4%). Median PFS in patients without BMF was 30.4 months, and 21.8 months in patients with BMF present (log-rank p = 0.02). Median OS was 61.1 months in patients without BMF, and 46.3 months in patients with BMF (log-rank p = 0.048). Patients with moderate or severe BMF had a particularly poor prognosis with a PFS of only 18.8 months and an OS of 32.7 months. Conclusions: Our study represents the largest dataset to date examining the incidence of BMF in MM patients, and is the only one to examine the association of BMF with prognosis in the era of novel therapies and widespread use of HSCT. Our data suggests that BMF is common in NDMM, and MM patients with BMF (particularly those with more extensive BMF) have a poorer prognosis even when treated with IMiDs and PIs. These data emphasize the importance of determining the presence and degree of BMF at time of MM diagnosis, and suggest a role for adjunctive therapies that target BMF in MM patients with co-existing BMF.

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.

New Targets and New Agents in High-Risk Multiple Myeloma

2016 ◽  
pp. e431-e441 ◽  
Author(s):  
Ajay K. Nooka ◽  
Sagar Lonial
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Personalized Medicine ◽  
Residual Disease ◽  
Proteasome Inhibitors ◽  
New Agents ◽  
Immunomodulatory Agents ◽  
Single Drug ◽  
Sequencing Studies ◽  
Minimal Residual

Advances in the treatment of multiple myeloma have resulted in dramatic improvements in outcomes for patients. The newly emerging profiling of mutations emerging as a consequence of large prospective sequencing studies such as the CoMMpass Study or other efforts from European investigators are not further helping to define the place and role for personalized medicine in myeloma. While mutations such as NRAS, KRAS, and BRAF do occur in myeloma, it is not clear that targeting them as a single drug strategy will result in meaningful responses or durations of response. Personalized medicine in multiple myeloma at this time likely entails the use of risk-based approaches for maintenance therapy, the use of current biology-based treatments such as proteasome inhibitors, and immunomodulatory agents, with an eye towards the use of mutation-specific treatments in the setting of minimal residual disease or in concert with biology-based treatments overall.

scholarly journals Distinct predictive impact of FISH abnormality in proteasome inhibitors and immunomodulatory agents response: redefining high-risk multiple myeloma in Asian patients

2018 ◽  
Vol 7 (3) ◽  
pp. 831-841 ◽  
Author(s):  
Ja Min Byun ◽  
Dong-Yeop Shin ◽  
Junshik Hong ◽  
Inho Kim ◽  
Hyun Kyung Kim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Proteasome Inhibitors ◽  
Immunomodulatory Agents ◽  
Asian Patients

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.

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