scholarly journals Early Dynamics and Depth of Response in Multiple Myeloma Patients Treated With BCMA CAR-T Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Sandy W. Wong ◽  
Nina Shah ◽  
Guy Ledergor ◽  
Thomas Martin ◽  
Jeffrey Wolf ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Free Survival ◽  
Depth Of Response ◽  
B Cell Maturation ◽  
Rapid Responses ◽  
Car T ◽  
New Treatment

Chimeric antigen receptor T-cell (CAR-T) therapy targeted against B-cell maturation antigen (BCMA) in multiple myeloma (MM) has produced rapid responses but many eventually relapse. In light of this new treatment, novel predictors of progression-free survival (PFS) are needed. We performed a single institution analysis of 54 BCMA-CAR-T patients. We analyzed patient’s overall response rate (ORR) by the IMWG criteria, involved serum-free light chains (iFLC), and minimal residual disease testing by next-generation sequencing (MRD-NGS). Between patients who achieved a ≤SD and those who achieved a ≥PR, PFS differed significantly (p < 0.0001); though there was no difference between patients who achieved a ≥CR vs. VGPR/PR (p = 0.2). In contrast, patients who achieved a nonelevated iFLC at 15 days (p < 0.0001, HR = 6.8; 95% CI, 2.7–17.3) or 30 days (p < 0.001, HR = 16.7; 95% CI, 3.9–71.7) had a prolonged PFS compared with those with an elevated iFLC. Patients achieving MRD-NGS less than the detectable limit at a sensitivity of 10−6 had a better PFS than those with detectable disease at 1 month (p = 0.02) and 3 months (p = 0.02). In conclusion, achieving a nonelevated iFLC and an undetectable MRD-NGS quickly were factors that were strongly associated with improved PFS. Further studies are needed to confirm the role of these markers in MM patients receiving CAR-T therapies.

The role of complete response in multiple myeloma

Blood ◽  
2009 ◽  
Vol 114 (15) ◽  
pp. 3139-3146 ◽  
Author(s):  
Jean-Luc Harousseau ◽  
Michel Attal ◽  
Herve Avet-Loiseau
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Complete Response ◽  
High Dose ◽  
Prognostic Impact ◽  
Free Survival ◽  
Depth Of Response ◽  
The Impact ◽  
Good Partial Response

AbstractIn multiple myeloma (MM), the impact of complete response (CR) could be shown only after introduction of high-dose therapy plus autologous stem cell transplantation (ASCT). In the context of ASCT, achieving CR (negative immunofixation and normal bone marrow) or at least very good partial response is associated with longer progression-free survival and in most studies longer survival. With novel agents, high CR rates are achieved and this prognostic impact of CR is being shown as well, both in relapsed and in newly diagnosed MM. However the benefit of CR achievement depends on the type of treatment and is not identical for all patients. In elderly patients, treatments inducing more CR may be more toxic. Although CR achievement is necessary in patients with poor-risk disease, it might not be as critical for long survival in more indolent MM. CR achievement is not the only objective of treatment because it is possible to further improve the depth of response and the outcome by continuing treatment after CR achievement. Finally, there are several levels of CR and in the future it will be necessary to confirm the prognostic impact of immunophenotypic or molecular CR or of CR defined by imaging procedures.

Isatuximab plus carfilzomib and dexamethasone in patients with relapsed multiple myeloma according to prior lines of treatment and refractory status: IKEMA subgroup analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8034-8034
Author(s):  
Roman Hajek ◽  
Philippe Moreau ◽  
Bradley Augustson ◽  
Nelson Castro ◽  
Tomas Pika ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Complete Response ◽  
Depth Of Response ◽  
Refractory Status ◽  
New Treatment ◽  
Grade 3 ◽  
D 20

8034 Background: Patients (pts) with multiple myeloma (MM) often relapse and become refractory to successive lines of therapy, warranting better treatment options. The Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) plus carfilzomib and dexamethasone (Kd) significantly improved progression-free survival (PFS) compared with Kd in pts with relapsed MM (RMM) (HR 0.53; 99% CI 0.32–0.89; P= 0.0007). We evaluated the efficacy and/or safety of Isa-Kd by number of prior lines of therapy (1 vs > 1) and refractoriness to lenalidomide (Len) or bortezomib (Bor). Methods: Pts were randomized (3:2) to Isa-Kd (n = 179) or Kd (n = 123). Isa (10 mg/kg IV) was given weekly for 4 weeks, then every 2 weeks. K (20 mg/m² days 1-2, then 56 mg/m²) was given twice-weekly 3 of 4 weeks, and d (20 mg) twice-weekly. The primary endpoint was PFS; key secondary endpoints were very good partial response or better (≥VGPR), minimal residual disease negativity (MRD-), and complete response (CR) rates. Results: Of the 302 randomized pts, 44.7% had 1 prior line, 55.3% had > 1 prior line, 32.8% were Len-refractory, and 30.1% were Bor-refractory. PFS was improved with Isa-Kd vs Kd in pts who received 1 prior line and > 1 prior line, as well as in pts refractory to Len, Len at last regimen, Bor, or Bor at last regimen (Table). The addition of Isa to Kd improved depth of response (≥VGPR, MRD-, and CR rates) in all subpopulations analyzed by prior treatment. Grade ≥3 treatment-emergent adverse events (TEAEs) were generally similar between the prior line subgroups (77.2% [Isa-Kd] vs 64.8% [Kd], 1 prior line; 76.5% [Isa-Kd] vs 69.1% [Kd], > 1 prior line) and the overall safety population (76.8% [Isa-Kd] vs 67.2% [Kd]). Serious AEs were 62.0% vs 48.1% in the 1 prior line subgroup, and 57.1% vs 64.7% in the > 1 prior line subgroup; TEAEs leading to discontinuations were 8.9% vs 11.1%, 1 prior line and 8.2% vs 16.2%, > 1 prior line. Conclusions: The addition of Isa to Kd improved PFS and depth of response, irrespective of prior lines of therapy or refractory status, consistent with the benefit observed in the overall IKEMA study population. Isa-Kd had a manageable safety profile regardless of number of prior lines. Isa-Kd is a potential new treatment option for pretreated pts with RMM. Clinical trial information: NCT03275285. [Table: see text]

scholarly journals Early Tumor Shrinkage and Depth of Response Evaluation in Metastatic Pancreatic Cancer Treated with First Line Chemotherapy: An Observational Retrospective Cohort Study

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 939 ◽  
Author(s):  
Caterina Vivaldi ◽  
Lorenzo Fornaro ◽  
Carla Cappelli ◽  
Irene Pecora ◽  
Silvia Catanese ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Progression Free Survival ◽  
Metastatic Pancreatic Cancer ◽  
Tumor Shrinkage ◽  
First Line ◽  
Free Survival ◽  
Depth Of Response ◽  
Early Tumor Shrinkage ◽  
Early Tumor

Early tumor shrinkage (ETS) and depth of response (DoR) predict favorable outcomes in metastatic colorectal cancer. We aim to evaluate their prognostic role in metastatic pancreatic cancer (PC) patients treated with first-line modified-FOLFIRINOX (FOLFOXIRI) or Gemcitabine + Nab-paclitaxel (GemNab). Hence, 138 patients were tested for ETS, defined as a ≥20% reduction in the sum of target lesions’ longest diameters (SLD) after 6–8 weeks from baseline, and DoR, i.e., the maximum percentage shrinkage in the SLD from baseline. Association of ETS and DoR with progression-free survival (PFS) and overall survival (OS) was assessed. ETS was reached in 49 patients (39.5% in the FOLFOXIRI, 29.8% in the GemNab group; p = 0.280). In the overall population, ETS was significantly associated with better PFS (8.0 vs. 4.8 months, p < 0.001) and OS (13.2 vs. 9.7 months, p = 0.001). Median DoR was −27.5% (−29.4% with FOLFOXIRI and −21.4% with GemNab, p = 0.016): DoR was significantly associated with better PFS (9.0 vs. 6.7 months, p < 0.001) and OS (14.3 vs. 11.1 months, p = 0.031). Multivariate analysis confirmed both ETS and DoR are independently associated with PFS and OS. In conclusion, our study added evidence on the role of ETS and DoR in the prediction of outcome of PC patients treated with first-line combination chemotherapy.

scholarly journals Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials

2017 ◽  
Vol 35 (25) ◽  
pp. 2900-2910 ◽  
Author(s):  
Juan-Jose Lahuerta ◽  
Bruno Paiva ◽  
Maria-Belen Vidriales ◽  
Lourdes Cordón ◽  
Maria-Teresa Cedena ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Bone Marrow Involvement ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Pooled Analysis ◽  
Disease Stage ◽  
Cox Models ◽  
Depth Of Response ◽  
The Impact

Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of “operational cure” was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM.

scholarly journals Pursuing a Curative Approach in Multiple Myeloma: A Review of New Therapeutic Strategies

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2015 ◽  
Author(s):  
Mattia D'Agostino ◽  
Luca Bertamini ◽  
Stefania Oliva ◽  
Mario Boccadoro ◽  
Francesca Gay
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Hematologic Cancer ◽  
Focus On Results ◽  
Individualize Treatment ◽  
New Generation ◽  
Effective Drugs

Multiple myeloma (MM) is still considered an incurable hematologic cancer and, in the last decades, the treatment goal has been to obtain a long-lasting disease control. However, the recent availability of new effective drugs has led to unprecedented high-quality responses and prolonged progression-free survival and overall survival. The improvement of response rates has prompted the development of new, very sensitive methods to measure residual disease, even when monoclonal components become undetectable in patients’ serum and urine. Several scientific efforts have been made to develop reliable and validated techniques to measure minimal residual disease (MRD), both within and outside the bone marrow. With the newest multidrug combinations, a good proportion of MM patients can achieve MRD negativity. Long-lasting MRD negativity may prove to be a marker of “operational cure”, although the follow-up of the currently ongoing studies is still too short to draw conclusions. In this article, we focus on results obtained with new-generation multidrug combinations in the treatment of high-risk smoldering MM and newly diagnosed MM, including the potential role of MRD and MRD-driven treatment strategies in clinical trials, in order to optimize and individualize treatment.

scholarly journals Cyclophosphamide–bortezomib– dexamethasone compared with bortezomib–dexamethasone in transplantation-eligible patients with newly diagnosed multiple myeloma

2019 ◽  
Vol 27 (2) ◽  
Author(s):  
A. Figueiredo ◽  
H. Atkins ◽  
R. Mallick ◽  
N. Kekre ◽  
A. Kew ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Tertiary Centre ◽  
Depth Of Response ◽  
Cell Mobilization ◽  
Stimulating Factor ◽  
Good Partial Response

Introduction Cyclophosphamide–bortezomib–dexamethasone (CyBorD) is considered a standard induction regimen for transplant-eligible patients with newly diagnosed multiple myeloma (mm). It has not been prospectively compared with bortezomib–dexamethasone (Bor-Dex). We aimed to compare the efficacy of CyBorD and Bor-Dex induction in transplant-eligible patients. Methods In a retrospective observational study at a single tertiary centre, all patients with transplant-eligible mm who received induction with CyBorD or Bor-Dex between March 2008 and April 2016 were enrolled. Progression-free survival (pfs), response, and stem-cell collection for a first autologous stem-cell transplantation (ahsct) were compared. Results Of 155 patients enrolled, 78 (50.3%) had received CyBorD, and 77 (49.7%), Bor-Dex. The patients in the Bor-Dex cohort were younger than those in the CyBorD cohort (median: 57 years vs. 62 years; p = 0.0002) and more likely to have had treatment held, reduced, or discontinued (26% vs. 14.5%, p = 0.11). The stem-cell mobilization regimen for both cohorts was predominantly cyclophosphamide and granulocyte colony–stimulating factor (gcsf). Plerixafor was used more often for the CyBorD cohort (p = 0.009), and more collection failures occurred in the CyBorD cohort (p = 0.08). In patients receiving Bor-Dex, more cells were collected (9.9×106 cells/kg vs. 7.7×106cells/kg, p = 0.007). At day +100, a very good partial response or better was achieved in 75% of the CyBorD cohort and in 73% of the Bor-Dex cohort (p = 0.77). Median pfs was 3.2 years in the Bor-Dex cohort and 3.7 years in the CyBorD cohort (p = 0.56). Conclusions Overall efficacy was similar in our patients receiving CyBorD and Bor-Dex. After ahsct, no difference in depth of response or pfs was observed. Cyclophosphamide–gcsf seems to increase collection failures and hospitalizations in patients receiving CyBorD. Prospective studies are required to examine that relationship.

Maintenance Therapy for Myeloma: How Much, How Long, and at What Cost?

2012 ◽  
pp. 515-522 ◽  
Author(s):  
Michel Attal ◽  
Murielle Roussel
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Second Primary ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy

Overview: Maintenance therapy in multiple myeloma has been under investigation for more than 3 decades and has been without evidence of clear advantage in terms of progression-free survival (PFS) until the mid-2000s. Neither conventional chemotherapy, prednisone, nor interferon-based maintenance regimens offered any benefit after conventional or high-dose therapy. Thalidomide was the first drug, mainly given as maintenance after high dose therapy, to demonstrate clinical benefits in terms of PFS and, in some studies, of overall survival (OS). The role of other novel agents such as lenalidomide and bortezomib as maintenance therapy is emerging. Lenalidomide has been shown to reduce the risk of relapse with longer follow-up needed to see if this will translate into a survival benefit. At present, a number of key questions remain unanswered. What are the optimal dose and duration of those treatments? Is the risk of toxicity and second primary malignancies acceptable? Will the disease be more aggressive at time of relapse? Is the clinical benefit predicted by initial prognostic factors and response to previous therapy? Does maintenance therapy work by further eradication of minimal residual disease or by immunological control of the malignant clone? Ongoing randomized trials are evaluating lenalidomide and bortezomib, both in the transplant and nontransplant settings, to better define the role of these drugs as maintenance in multiple myeloma.

scholarly journals Case series: MRD negativity assessment using 11C-Acetate PET with 3-weekly daratumumab-based quadruplet induction in newly diagnosed multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110303
Author(s):  
Cheong Ngai ◽  
Shaji Kumar ◽  
Garrett Chi-lai Ho ◽  
Sirong Chen ◽  
Chor-sang Chim
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Case Series ◽  
Progression Free Survival ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Positron Emission ◽  
Pet Ct ◽  
Subsequent Relapse

Complete response (CR) is an important favorable factor for survival in multiple myeloma (MM). However, CR patients continue to relapse, especially in the presence of minimal residual disease (MRD). Bone marrow (BM) MRD is predictive of progression-free survival (PFS) in MM. However, myeloma outside the BM aspiration site may result in subsequent relapse despite MRD-negativity. Therefore, positron emission tomography-computed tomography (PET-CT) based on F-fluorodeoxyglucose (FDG) is a complementary tool to monitor residual disease in MM. However, FDG may miss myeloma lesions that are not FDG-avid. On the other hand, 11C-Acetate (ACT) has been found to be a more sensitive and specific tracer than FDG in MM. Recently, the addition of daratumumab to bortezomib, thalidomide, dexamethasone (VTd) or bortezomib, lenalidomide, dexamethasone (VRd) backbone has been proven to improve outcomes. Herein, we report three newly-diagnosed MM patients achieving deep responses with imaging CR using ACT PET in addition to conventional immunofixation CR and MRD-negative CR after a 3-weekly daratumumab-based quadruplet induction regimen.

Minimal residual disease (MRD) status pre- and post- high-dose therapy/autologous stem (HDC/ASCT) cell transplantation for multiple myeloma (MM) in the era of novel agents.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8605-8605
Author(s):  
Adetola Kassim ◽  
Jeremy Scott McDuffie ◽  
Claudio A Mosse ◽  
Bipin N. Savani ◽  
John P. Greer ◽  
...  
Keyword(s):  
Residual Disease ◽  
Prognostic Significance ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Novel Agents ◽  
Disease Stage ◽  
High Dose ◽  
Free Survival ◽  
Depth Of Response ◽  
The Impact

8605 Background: MRD assayed by multi-parameter flow cytometer (MFC), has prognostic significance after HDT/ASCT for MM (Paiva et. al. 2008). The frequency of MRD negativity (-) after induction therapy using novel agents such as immunomodulatory drugs like lenalidomide (IMiDs), and proteasome inhibitors like bortezomib, is unknown. The impact of HDT/ASCT on MRD status in this patient group has not been studied. Methods: We performed a retrospective study of all MM patients undergoing HDT/ASCT (January 2010 - December 2012) in our institution. No restrictions on inclusion were made based on the International Myeloma Working Group response criteria. All patients had novel agents as part of their initial induction regimen. Statistical analysis was by SPSS software (V 12.0). MRD status was determined by MFC on bone marrow samples pre- HDC/ASCT [M1] and post- HDC/ASCT (D100 [M2] and I year [M3]). MFC was done with antibodies against CD45, CD19, CD138, CD38, CD20, CD56, and anti-k and l cytoplasmic antibodies. Results: MRD status was available on 91 patients pre-transplant. Of these patients, 80 had MFC recorded at M2 and 17 patients had MFC recorded at M3. Fifty-eight percent were male and 76% were Caucasian. Forty percent received IMiDs, while 60% got proteasome based therapies. Of the 91 patients with MRD pre-HDC/ASCT, 58% (53/91) were MRD (-), and of these patients 89% (41/46) remained MRD (-) at M2. 48 patients were MRD positive (+) pre-HDC/ASCT, 58% (20/34) became MRD (-) at M2. Age, cytogenetic risk, disease stage, number of chemotherapy cycles or immunofixation status had no impact on MRD status. There were only 6 relapses in the cohort, thus the impact of MRD status on progression-free survival could not be studied. Conclusions: Novel agents improve depth of response pre-transplant. HDC/ASCT increases MRD negativity post-transplant. MRD status could aid better timing of HDC/ASCT or adoption of a risk-adapted strategy for high-risk patients. MRD status validation in a prospective cohort is underway at our center (NCT01215344). With future follow-up, the impact of MRD on progression-free survival in the era of novel agents will be determined.

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