scholarly journals Contemporary patient-tailored treatment strategies against high risk and relapsed or refractory multiple myeloma

EBioMedicine ◽  
2019 ◽  
Vol 39 ◽  
pp. 612-620 ◽  
Author(s):  
Fatih M. Uckun ◽  
Sanjive Qazi ◽  
Taner Demirer ◽  
Richard E. Champlin
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Treatment Strategies ◽  
Refractory Multiple Myeloma ◽  
Tailored Treatment

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.

How I Treat High-risk Multiple Myeloma

Blood ◽  
2021 ◽  
Author(s):  
Elena Zamagni ◽  
Simona Barbato ◽  
Michele Cavo
Keyword(s):  
Quality Of Life ◽  
Risk Factors ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
High Risk ◽  
Tumor Biology ◽  
Treatment Strategies ◽  
Specific Drug ◽  
Improve Quality

Survival of multiple myeloma (MM) has significantly improved over the last decade; however, a composed group of patients (15-20%), named high-risk (HR) MM, still experience reduced survival. Both tumor biology and suboptimal/absent responses to therapy may underlie HR definition and a clear uniform identification of risk factors is crucial for a proper management of these patients. In biologic-HRMM, MRD negativity attainment and sustain, inside and outside BM, should be the primary goal and therapy should be adapted in patients with frailty to reduce toxicity and improve quality of life. MM treatment has traditionally been tailored on age and more recently frailty or comorbidities, but very rarely on the biology of the disease, mainly because of the lack of a clear benefit derived from a specific drug/combination, inhomogeneity in HR definition and lack of data coming from prospective, properly designed clinical trials. Some attempts have been successfully made recently in this direction. In this review, we are discussing the current different definitions of HR and the need for a consensus, the results of available trials in HR patients and the way through risk-adapted treatment strategies. For this purpose, we are proposing several clinical cases of difficult-to-treat patients throughout different treatment phases.

scholarly journals Carfilzomib Based Treatment Strategies in the Management of Relapsed/Refractory Multiple Myeloma with Extramedullary Disease

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1035 ◽  
Author(s):  
Xiang Zhou ◽  
Patricia Flüchter ◽  
Katharina Nickel ◽  
Katharina Meckel ◽  
Janin Messerschmidt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Serological Response ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Extramedullary Disease ◽  
Heavily Pretreated ◽  
Pretreated Patients

Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40–80) years. Twenty (44%) and 25 (56%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59%. Extramedullary response was evaluable in 33 patients, nine (27%) of them achieved partial remission (PR) (ORR = 27%). In 15 (33%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95% CI, 3.5–6.5) and ten (95% CI, 7.5–12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS (p = 0.004) and OS (p = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients.

scholarly journals Smoldering multiple myeloma: evolving diagnostic criteria and treatment strategies

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 673-681
Author(s):  
Alissa Visram ◽  
Joselle Cook ◽  
Rahma Warsame
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Risk Stratification ◽  
Risk Model ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Free Survival ◽  
Smoldering Myeloma ◽  
Insight Into ◽  
Made In

Abstract The adage for smoldering myeloma (SMM) has been to observe without treatment, until criteria for active multiple myeloma were satisfied. Definitions and risk stratification models have become more sophisticated, with prognostication tailored to include high-risk cytogenetics as per the most recent International Myeloma Working Group 2020 risk model. Moreover, progress in defining genomic evolution and changes in the bone marrow microenvironment through the monoclonal continuum have given insight into the complexities underlying the different patterns of progression observed in SMM. Given recent data showing improved progression-free survival with early intervention in high-risk SMM, the current dilemma is focused on how these patients should be treated. This case-based article maps the significant advancements made in the diagnosis and risk stratification of SMM. Data from landmark clinical trials will also be discussed, and ongoing trials are summarized. Ultimately, we outline our approach to SMM and hope to impart to the reader a sound concept of the current clinical management of SMM.

scholarly journals Prognostic Value of FDG-PET/CT Parameters in Patients with Relapse/Refractory Multiple Myeloma before Anti-CD38 Based Therapy

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4323
Author(s):  
Guillemette Fouquet ◽  
Myriam Wartski ◽  
Amina Dechmi ◽  
Lise Willems ◽  
Bénédicte Deau-Fischer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Fdg Pet ◽  
Multivariable Analysis ◽  
High Risk Group ◽  
Focal Lesions ◽  
Refractory Multiple Myeloma ◽  
Pet Ct ◽  
Poor Outcomes ◽  
Fdg Pet Ct

Although anti-CD38 monoclonal antibodies have improved the prognosis of relapsed/refractory multiple myeloma (RRMM), some patients still experience early relapses with poor outcomes. This present study evaluated the predictive value of FDG PET/CT parameters for RRMM prior to initiating anti-CD38 treatment. We included 38 consecutive RRMM patients who underwent a PET/CT scan treated at our institution at relapse. The median PFS was 12.5 months and the median OS was not reached. 42% of the patients had an initial ISS score of 1, 37% of 2, and 21% of 3. The presence of >3 focal lesions (FLs, n = 19) and the ISS score were associated with inferior PFS (p = 0.0036 and p = 0.0026) and OS (p = 0.025 and p = 0.0098). Patients with >3 FLs had a higher initial ISS score (p = 0.028). In multivariable analysis, the ISS score and >3 FLs were independent prognostic factors for PFS (p = 0.010 and p = 0.025 respectively), and combined they individualized a high-risk group with a median PFS and OS of 3.1 months and 8.5 months respectively vs. not reached for the other patients. The presence of >3 FLs on PET was predictive of survival outcomes in patients with RRMM treated using CD38 targeted therapy. Combined with the initial ISS, an ultra-high-risk RRMM population can thus be identified.

scholarly journals Pmd-107: Marizomib, Pomalidomide and Low Dose-Dexamethasone Combination Study in Relapsed/Refractory Multiple Myeloma (NCT02103335): Full Enrollment Results from a Phase-1 Multicenter, Open Label Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3326-3326 ◽  
Author(s):  
Andrew Spencer ◽  
Simon Harrison ◽  
Jacob P. Laubach ◽  
Jeffrey Zonder ◽  
Ashraf Z Badros ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Employment Equity ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Heavily Pretreated ◽  
Equity Ownership

Abstract Marizomib (MRZ) is a novel, irreversible, pan subunit proteasome inhibitor (PI) with preclinical evidence demonstrating in vitro and in vivo activity in multiple myeloma (MM). This study was designed to evaluate the safety and antimyeloma activity of pomalidomide (POM), MRZ and low dose dexamethasone (Lo-DEX) (PMD) in patients with relapsed and refractory multiple myeloma (RRMM). Thirty-eight heavily pretreated patients with RRMM were enrolled [dose-escalation cohort (n=14); recommended Phase 2 dose (RP2D) cohort (n=24)]. IV MRZ (0.3 to 0.5 mg/m2) was administered on Days (D) 1, 4, 8, 11; POM (3 or 4 mg) on D1 through 21; and Lo-DEX (5 or 10 mg) on D1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, 23 of every 28-D cycle. Patients received a median of 4 (range 1-9) prior lines of therapy; 100% received prior lenalidomide (LEN) and bortezomib (BTZ), 34% carfilzomib (CFZ), and 50% thalidomide. 53% of patients were refractory to both LEN and BTZ and 21% were refractory to LEN, BTZ, and CFZ. There were no dose limiting toxicities during the study. The most common study treatment related ≥Grade 3 adverse events (AEs) were neutropenia (11/38 pts: 29%), pneumonia (4/38 pts 11%), anemia (4/38 pts; 11%), thrombocytopenia (4/38 pts; 11%), and febrile neutropenia (2/38 pts; 5%), with two grade 4 AEs (neutropenia related to POM and viral infection related to DEX), and one grade 5 AE (cardio-respiratory arrest from a suspected PE related to POM). Overall, MRZ was well tolerated, did not add to the incidence or severity of POM/Lo-DEX AEs and the regimen may have fewer hematological and infectious AEs compared to that observed with POM/Lo-DEX. MRZ pharmacokinetic analysis revealed that it was rapidly cleared with a short T1/2 (6.2-11mins) and a large volume of distribution (41-86L) suggesting extensive tissue distribution. Pharmacodynamic analysis demonstrated rapid and robust inhibition of chymotrypsin-like activity in both packed whole blood (PWB) and peripheral blood mononuclear cells (PMBCs), reflecting the irreversible binding nature of MRZ. Evolving inhibition of trypsin-like and caspase-like proteasome activity was also observed in PWB and PBMC with continued dosing. The overall response rate (ORR) and clinical benefit rate (CBR) for the 36 response evaluable patients was 53% (19/36) and 64% (23/36), respectively (Table 1). Subpopulation analysis demonstrated an ORR of 50% (5/10) in high risk cytogenetic patients, 56% (10/18) in LEN/BTZ refractory patients, 71% (5/7) in LEN/BTZ/CFZ refractory patients and 80% (8/10) in CFZ refractory patients. These data compare favorably against POM/Lo-Dex with a near doubling of ORR in both the total patient population and the double refractory patients. Substantial activity in high-risk patients that are triple refractory and in patients that are refractory to CFZ in prior last regimen was observed. MRZ activity in RRMM patients exposed and/or refractory to multiple PIs is likely a consequence of its unique pan proteasome subunit inhibitory actions. In conclusion, MRZ in combination with POM and Lo-DEX was well tolerated and demonstrated promising activity in heavily pretreated, high-risk RRMM patients. Table 1 Table 1. Disclosures Harrison: Janssen-Cilag: Research Funding, Speakers Bureau; Celgene: Honoraria. Zonder:Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Khot:Amgen: Honoraria; Janssen: Consultancy; Pfizer: Speakers Bureau. Anderson:C4 Therapeutics: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; C4 Therapeutics: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Oncoprep: Equity Ownership; Millennuim: 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; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. MacLaren:Triphase Accelerator: Employment, Equity Ownership. Reich:Triphase Accelerator: Consultancy. Trikha:Encycle Therapeutics: Consultancy, Equity Ownership; Triphase Accelerator: Employment, Equity Ownership. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Development and Validation of a Risk Assessment Model for Early Infection during the First 3 Months in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Yufeng Shang ◽  
Weida Wang ◽  
Minghui Liu ◽  
Xiaoqin Chen ◽  
Zhongjun Xia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Model Building ◽  
Risk Model ◽  
Conflicts Of Interest ◽  
Treatment Strategies ◽  
Risk Groups ◽  
Assessment Model ◽  
Early Infection ◽  
Lasso Regression

PurposeEarly infection was an important cause of mortality in patients with multiple myeloma (MM). The study aimed to assess factors affecting early infection and identify patients with high risk developing infection. MethodsDuring January 2010 to June 2019, patients with MM were analyzed, retrospectively. The data was divided into training and independent validation cohort. The least absolute shrinkage and selection operator (LASSO) regression model was used for data dimension reduction, feature selection, and model building. ResultsOf 745 confirmed MM patients, 540 eligible cases were included in final analyses. In total, 165 patients (30.6%) suffered infections, while 110 patients (20.4%) occurred early infections during the first 3 months after diagnosis. Bacteria and the respiratory tract were the most common pathogen and localization of infection, respectively. In training cohort, PS≥2, HGB<100g/L, β2MG≥6.0mg/L and GLB≥80g/L were identified associated with early infections by LASSO regression. Based on the four factors, an early infection risk model of MM (IRMM) was established to define high- and low-risk groups, which showed significantly different rates of infection (35.3% vs. 9.4%,P<0.001, HR=4.381 [95% CI, 2.802-7.221]). IRMM displayed good discrimination (AUC=0.756) and calibration (P=0.94). ConclusionWe determined risk factors for early infection and established a predictive model to help clinicians identify patients with high-risk infection. It can help clinicians to determine whether to adjust monitoring and treatment strategies, or apply prophylactic interventions to high-risk patients. Disclosures No relevant conflicts of interest to declare.

Lenalidomide in Relapsed and Refractory Multiple Myeloma Disease: Feasibility and Benefits of Long-Term Treatment

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4069-4069 ◽  
Author(s):  
Katharina Oehrlein ◽  
Corinna Rendl ◽  
Corinna Hahn-Ast ◽  
Lothar Kanz ◽  
Katja C Weisel
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Median Time ◽  
Allogeneic Transplantation ◽  
Term Treatment ◽  
Study Patient ◽  
Refractory Multiple Myeloma ◽  
Long Term Treatment ◽  
Unacceptable Toxicity

Abstract Abstract 4069 Despite the progress obtained by the introduction of novel agents, treatment of relapsed/refractory multiple myeloma (rrMM) remains a clinical challenge. Long-term treatment aims to delay progression of MM, but there is concern regarding tolerance, especially in the non-study patient (pt) population. The mode of action of Lenalidomide (len) as an immunomodulatory agent and the tolerability profile led to approval of the drug for continuous treatment until disease progression (PD) or unacceptable toxicity. Due to the lack/scarcity of reports assessing benefit and risk of long-term len treatment in non-selected rrMM patients, we retrospectively analysed the long-term outcome in pts with rrMM treated with len/dex. 67 pts who were treated with len/dex for rrMM in the approved indication until PD or unacceptable toxicity from 2007 to 2011 were included in this retrospective, single-centre analysis. Median age was 68 years (y) (range 40–84y), median number of pretreatments were 2 (range 1–6). 31 pts (46%) had relapsed after autologous stem cell transplant, 10 pts (15%) after allogeneic transplantation. 40 pts (60%) received prior treatment with bortezomib, 13 (19%) with thalidomide-containing regimen. Cytogenetic analysis was available in 28 pts (41.8%), 8 pts had cytogenetic high-risk disease defined as presence of t(4;14), del17 or +1q21 in FISH analysis. Overall response rate (ORR) under len/dex was 82.1% comprising 41 pts (61.2%) with PR, 9 pts (13.4%) with VGPR and 5 pts (7.5%) with CR. Median time to best response was 5.5 months (mo)., median time to documented CR 36.6 mo. Median treatment duration with len was 16.1 mo (range 0.7–47.4 mo). 45 pts (67.2%) were treated with len/dex >12 mo, 25 (37.3%) >24 mo, 9 (13.4%) >36 mo and 14 pts were still on treatment at the time of analysis. Of the 45 pts with len treatment >12 mo 21 pts underwent prior autologous transplant, and 7 pts allogeneic transplantation. 4/8 pts with high-risk cytogenetics were treated with len >12 mo. Among the 22 pts with len <12 mo, 12 pt discontinued treatment due to PD, in 8 pts treatment was stopped due to toxicity or patient's wish; 2 pts proceeded to allogenic transplantation. Reasons for treatment discontinuation other than PD were fatigue, subjective intolerance and, in one pt, a thrombembolic event. In pts >12 mo on len, documented main toxicities were hematologic with grade III/IV toxicity in 17 pts (37.8%). Median overall survival (OS) of the total pt population was 33.2 mo, whereas OS of pts discontinuing len before 12 mo was 14.4 mo (20.5 mo for pts stopping for other reasons than PD; p=0.0003), pts treated beyond 12 mo had a median OS of 42.9 mo (p<0.0001). OS of pt >12 mo on len treatment did not significantly differ between pts that had received autologous transplantation, allogeneic transplantation or conventional therapy (43.1 mo, 48.0 mo, 36.8 mo, respectively). To the best of our knowledge, this is the first report on feasibility and efficacy of long-term len treatment in a non-selected pt cohort with rrMM. We thereby provide evidence that len is an efficient and safe long-term treatment option providing clinical benefit for the majority of patients. Outcome of pt >12 mo on len is superior when compared to pt discontinued earlier for reasons other than PD. Furthermore, the favourable outcome of pts treated for more than 12 mo was independent of previous autologous and allogeneic transplantation. Our data confirm the current use of len as a continuous long-term treatment strategy. Disclosures: Weisel: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document