Improved Outcome of Allogeneic Transplantation in High-Risk Multiple Myeloma Patients After Nonmyeloablative Conditioning

2002 ◽  
Vol 20 (5) ◽  
pp. 1295-1303 ◽  
Author(s):  
Ashraf Badros ◽  
Bart Barlogie ◽  
Eric Siegel ◽  
Michele Cottler-Fox ◽  
Maurizio Zangari ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Residual Disease ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
High Risk Disease ◽  
Unrelated Donors ◽  
Conditioning Regimens ◽  
N 93

PURPOSE: We present our experience with relapsed and recently diagnosed patients with high-risk multiple myeloma (MM) receiving immunosuppressive, nonmyeloablative melphalan (MEL)-based conditioning regimens (mini-allograft). PATIENTS AND METHODS: Thirty-one MM patients received allografts from HLA-matched siblings (n = 25) or unrelated donors (n = 6) using a mini-allograft. Seventeen had progressive disease (PD) and 14 had responsive disease (RD) (six with primary RD and eight with responsive relapse). Thirty patients had received one (n = 13) or two or more (n = 17) prior autologous transplantations (ATs). Median age was 56 years (range, 38 to 69 years). Twenty-one patients had chromosome 13 abnormality. Two patients were hemodialysis dependent. Blood and bone marrow grafts were administered to 28 and three patients, respectively. Donor lymphocyte infusions were given to 18 patients either to attain full donor chimerism (n = 6) or to eradicate residual disease (n = 12). RESULTS: By day 100, 25 (89%) of 28 patients were full donor chimeras, one was a mixed chimera, and two had autologous reconstitution. Acute graft-versus-host disease (GVHD) developed in 18 patients (58%), and 10 progressed to chronic GVHD (limited in six and extensive in four). At a median follow-up of 6 months, 19 (61%) of 31 patients achieved complete/near complete remission. Twelve patients (39%) have died: three of PD, three of early treatment-related mortality (TRM) (before day 100), and six of late TRM. Median overall survival (OS) was 15 months. At 1 year, there was a significantly longer event-free survival (86% v 31%, P = .01) and OS (86% v 48%, P = .04) when a mini-allograft was performed after one versus two or more prior ATs, respectively. When compared with historical MM controls (n = 93) receiving conventional allografts, early TRM was significantly lower (10% v 29%, P = .03), and OS at 1 year was better (71% v 45%; P = .08) in the mini-allograft MM patients. CONCLUSION: Mini-allograft induced excellent disease control in MM patients with high-risk disease, but is still associated with a significant GVHD.

Long-Term Follow-up of Patients With Multiple Myeloma Who Received Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2154-2154
Author(s):  
Michele L. Donato ◽  
David S Siegel ◽  
David H. Vesole ◽  
Phyllis McKiernan ◽  
Themba Nyirenda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Cumulative Incidence ◽  
Low Dose ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
Hematopoietic Stem ◽  
Unrelated Donors

Abstract Allogeneic transplantation for multiple myeloma (mm), although seen as potentially curative, has inherent treatment-related mortality and long-term implications. Important questions remain such as the expectation for long-term survival and the role, if any, of the graft versus tumor effect. The study cohort included 56 consecutive patients (pts) with mm who received an allogeneic hematopoietic stem cell transplant (HSCT) between November 9, 2004 and June 1st 2011. Only pts who had received at least one prior autologous transplant were included in this retrospective analysis. Patients received either a non-myeloablative (NMA), a reduced intensity (RIC) or an ablative (MA) regimen. The NMA regimen consisted of low dose TBI for siblings and low dose TBI with fludarabine for unrelated donors. The RIC regimen was fludarabine melphalan, with the addition of low dose thymoglobulin for unrelated donors. The MA regimen was busulfan and melphalan, with thymoglobulin for unrelated donors. A favorable group of 26 pts received their allogeneic transplantation for consolidation after demonstrating a response (PR, VGPR, CR) to their prior autograft and without evidence of progression, leaving 30 pts in the salvage transplant group defined as pts unresponsive (less than PR) or with relapse after their prior autograft. The median age was 52.4 years (SD = 6.9 years). Twenty six (46%) pts were female. The hematopoietic cell donors were 35 siblings and 21 unrelated (URD). In the URD group, 10 (47.6%) pts had a mismatched donor. In our cohort 10 (17.9%) pts received a MA, 22 (39.3%) received a RIC and 24 (42.9%) received a NMA regimen. The median follow-up was 52 months. The related and unrelated donor cohorts were similar except for age (53.9 years versus 49.8 years p = 0.03). Overall, 32 (57.1%) pts achieved a CR. Seven (12.5%) pts had a VGPR, 13 (23.2%) had a PR and 2 (3.6%) had stable disease. At the time of analysis, 49.2% of pts were in CR. Twenty one (37.5%) pts relapsed post transplantation of whom 16 received donor lymphocytes (DLI 15 pts) or immune suppression withdrawal (1 pt), with 10 (62.5%) pts responding to this intervention. The cumulative incidence of acute GVHD (aGVHD) grade II-IV was 35.4%, 28.6% for related donors and 47.6% for URD (p = 0.16). The cumulative incidence of chronic GVHD (cGVHD) was 50%, 52% for related donors and 43% for URD (p=NS). The number of non-relapse deaths (NRM) was 13 (23.2%). The cumulative incidence of NRM at 1 year was 18.2%, and 25.5% at 5 years. In the multivariate model, number of prior autologous HSCT (1 vs >1) and grade III-IV aGVHD were significantly associated with an increased NRM. The overall survival (OS) for all 56 pts was 59% at 5 years. The OS at 5 years for the 30 pts who received transplantation as salvage (refractory to the prior autograft or relapsed after the prior autograft), was 38% compared to 82% for the consolidation group. The univariate analysis indicates that pts receiving their allogeneic transplantation as salvage, disease status prior to allogeneic HSCT, number of prior auto HSCT, aGVHD, response post allo HSCT and cGVHD were significantly associated with the risk of all cause mortality, with cGVHD being protective. Donor type (URD versus related), adverse cytogenetics, preparative regimen and age were not significant predictors of risk for all cause mortality by univariate analysis.Overall survival salvage (yes) vs consolidation group (no)Overall survival salvage (yes) vs consolidation group (no)Overall survival pts with (yes) or without (no) chronic GVHDOverall survival pts with (yes) or without (no) chronic GVHD Multivariate analysis shows OS significance for being in the salvage group (HR 4.05, p=0.0196), a GVHD (HR 2.99, p=0.034) and cGVHD (HR 0.26, p=0.012), the latter being protective. The PFS for all 56 pts was 38% at 5 years, 57% for the consolidation group and 21% for the salvage group. In conclusion, patients with multiple myeloma can have an excellent overall survival following allogeneic transplantation even in the setting of relapsed or refractory disease to a prior auto HSCT. Unrelated donors performed just as well as matched siblings. Acute GVHD was deleterious to OS, whereas chronic GVHD was significantly associated with improvement in OS supporting the role of a graft versus tumor effect in multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

Depth of response and minimal residual disease status in ultra high-risk multiple myeloma and plasma cell leukemia treated with daratumumab, bortezomib, lenalidomide, cyclophosphamide and dexamethasone (Dara-CVRd): Results of the UK optimum/MUKnine trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8001-8001
Author(s):  
Martin F. Kaiser ◽  
Andrew Hall ◽  
Katrina Walker ◽  
Ruth De Tute ◽  
Sadie Roberts ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Plasma Cell ◽  
Residual Disease ◽  
Cell Leukemia ◽  
Ultra High Risk ◽  
Grade 3 ◽  
Minimal Residual

8001 Background: Patients with ultra high-risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with plasma cell leukemia (PCL) continue to have dismal outcomes and are underrepresented in clinical trials. Recently, improved responses with anti-CD38 monoclonal antibody combination therapy have been reported for NDMM patients. We report here outcomes for NDMM UHiR and PCL patients treated in the OPTIMUM/MUKnine (NCT03188172) trial with daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction, augmented high-dose melphalan (HDMEL) and ASCT. With final analysis follow-up surpassed in Feb 2021, we report here early protocol defined endpoints from induction to day 100 post ASCT. Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with PCL (circulating plasmablasts > 20%) were included in OPTIMUM across 39 UK hospitals. Patients received up to 6 cycles of Dara-CVRd induction, HDMEL and ASCT augmented with bortezomib, followed by Dara-VR(d) consolidation for 18 cycles and Dara-R maintenance. Primary trial endpoints are minimal residual disease (MRD) status post ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. Data is complete but subject to further data cleaning prior to conference. Results: Median follow-up for the 107 patients in the safety population was 22.2 months (95% CI: 20.6 – 23.9). Two patients died during induction due to infection. Bone marrow aspirates suitable for MRD assessment by flow cytometry (10-5 sensitivity) were available for 81% of patients at end of induction and 78% at D100 post ASCT. Responses in the intention to treat population at end of induction were 94% ORR with 22% CR, 58% VGPR, 15% PR, 1% PD, 5% timepoint not reached (TNR; withdrew, became ineligible or died) and at D100 post ASCT 83% ORR with 47% CR, 32% VGPR, 5% PR, 7% PD, 10% TNR. MRD status was 41% MRDneg, 40% MRDpos and 19% not evaluable post induction and 64% MRDneg, 14% MRDpos and 22% not evaluable at D100 post ASCT. Responses at D100 post ASCT were lower in PCL with 22% CR, 22% VGPR, 22% PR, 22% PD, 12% TNR. Most frequent grade 3/4 AEs during induction were neutropenia (21%), thrombocytopenia (12%) and infection (12%). Grade 3 neuropathy rate was 3.7%. Conclusions: This is to our knowledge the first report on a trial for UHiR NDMM and PCL investigating Dara-CVRd induction and augmented ASCT. Response rates were high in this difficult-to-treat patient population, with toxicity comparable to other induction regimens. However, some early progressions highlight the need for innovative approaches to UHiR NDMM. Clinical trial information: NCT03188172.

Real-World Experience with Minimal Residual Disease Testing with Next Generation Flow Cytometry and Functional Imaging in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
David Böckle ◽  
Paula Tabares Gaviria ◽  
Xiang Zhou ◽  
Janin Messerschmidt ◽  
Lukas Scheller ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
High Risk ◽  
Functional Imaging ◽  
Real World ◽  
Research Funding ◽  
Residual Disease ◽  
Focal Lesions ◽  
High Risk Disease ◽  
Minimal Residual

Background: Minimal residual disease (MRD) diagnostics in multiple myeloma (MM) are gaining increasing importance to determine response depth beyond complete remission (CR) since novel agents have shown to induce high rates of deep clinical responses. Moreover, recent reports indicated combining functional imaging with next generation flow cytometry (NGF) could be beneficial in predicting clinical outcome. This applies in particular to the subset of patients suffering from relapsed/refractory multiple myeloma (RRMM) who tend to show a higher incidence of residual focal lesions despite serological response. Here, we report our institutions experience with implementing both functional imaging and NGF-guided MRD diagnostics in clinical practice. Methods: Our study included patients with newly diagnosed multiple myeloma (NDMM) and RRMM achieving VGPR, CR or sCR. Bone marrow aspirates were obtained for MRD-testing according to IMWG 2016 criteria. Samples were collected between July 2019 and July 2020 and analyzed with NGF (according to EuroFlowTM guidelines) at a sensitivity level of 10-5. Results were compared to functional imaging obtained with positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI). High-risk disease was defined as presence of deletion 17p, translocation (14;16) or (4;14). Results: We included 66 patients with NDMM (n=39) and RRMM (n=27) who achieved VGPR or better. In patients with RRMM the median number of treatment lines was 2 (range 2-11). Fifteen patients suffered from high-risk disease. Median age at NGF diagnostics was 64 years (range 31-83). Among patients achieving VGPR (n=27), CR (n=10) and sCR (n=29) seventeen (26%) were MRD-negative by NGF testing. CR or better was significantly associated NGF MRD-negativity (p=0.04). Notably, rates of NGF MRD-negativity were similar among patients with NDMM (28%) and RRMM (26%). Even some heavily pretreated patients who underwent ≥ 4 lines of therapy achieved MRD-negativity on NGF (2 of 9). Functional imaging was performed in 46 (70%) patients with DW-MRI (n=22) and PET (n=26). Median time between NGF and imaging assessment was 2 days (range 0-147). Combining results from imaging and NGF, 12 out of 46 (26%) patients were MRD-negative with both methods (neg/neg). Three patients displayed disease activity as measured with both, imaging and NGF (pos/pos). Twenty-nine of the remaining patients were MRD-positive only according to NGF (pos/neg), while two patients were positive on imaging only (neg/pos). More patients demonstrated combined MRD-negativity on NGF and imaging (neg/neg) in the NDMM setting than in RRMM (32% versus 19%). We also observed that 30% of the patients with high-risk genetics showed MRD-negativity on both imaging and NGF. Of note, none of the patients with very advanced disease (≥4 previous lines) was MRD-negative on both techniques. Conclusion In the clinical routine, MRD diagnostics could be used to tailor maintenance and consolidation approaches for patients achieving deep responses by traditional IMWG criteria. Our real-world experience highlights that MRD-negativity can be achieved in patients suffering from high-risk disease and also in late treatment lines, supporting its value as endpoint for clinical trials. However, our data also support MRD diagnostics to be combined with functional imaging at least in the RRMM setting to rule out residual focal lesions. Future studies using MRD for clinical decision-making are highly warranted. Disclosures Einsele: Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rasche:Celgene/BMS: Honoraria; GlaxoSmithKline: Honoraria; Oncopeptides: Honoraria; Skyline Dx: Research Funding; Janssen: Honoraria; Sanofi: Honoraria.

Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Survival for Patients with Chronic Myelomonocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4347-4347 ◽  
Author(s):  
Piyanuch Kongtim ◽  
Uday R. Popat ◽  
Antonio M. Jimenez ◽  
Sameh Gabella ◽  
Riad O. El Fakih ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Hypomethylating Agents ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Unrelated Donors ◽  
Conditioning Regimens

Abstract Introduction Allogeneic hematopoietic stem cell transplant (allo-SCT) is the only curative treatment modality for patients with CMML. Here we retrospectively reviewed the data for patients with CMML who received an all-SCT at our institution to identify factors associated with improved survival and determine whether treatment with hypomethylating agents (HMA) before transplant improves survival for these patients. Methods All 83 patients 18 years of age or older with a diagnosis of CMML confirmed at The University of Texas MD Anderson Cancer Center who underwent allo-SCT between April 1991 and December 2013 were identified through review of the institutionÕs medical records and included in this analysis. Forty, 7, and 36 patients had CMML-1, CMML-2 and CMML that had progressed to AML (CMML/AML) respectively. The median age was 57 years. CMML specific cytogenetic risk at diagnosis (Such E, hematologica, 2011) was good, intermediate, and high risk in 46, 19, and 18 patients respectively. Seventy-eight patients received induction treatment before transplant, 37 receiving HMA (either 5-azacytidine or decitabine) for at least 3 courses and 41 receiving 1-2 courses of cytotoxic chemotherapy. Among the patients who received induction therapy, 15 patients in HMA group and 9 patients in convention chemotherapy group achieved a complete remission before transplant. Thirty, 47 and 6 patients received transplants from matched related donors (MRD), matched unrelated donors (MUD), and mismatched related or unrelated donors (MMD), respectively. The sources of hematopoietic stem cells were peripheral blood for 48 patients (57.8%) and bone marrow for 35 patients (42.2%). Conditioning regimens varied; most patients received either fludarabine in combination with busulfan or fludarabine combined with melphalan. Sixty-four patients received myeloablative and 19 patients received reduced intensity conditioning regimens. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Patient and transplant characteristics did not significantly differ between the patients treated with HMA and the patients treated with conventional chemotherapy or given supportive care alone. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), Treatment related mortality (TRM), relapse incidence through last follow-up and incidences of acute GVHD and chronic GVHD. All of these outcomes were measured from the time of allo-SCT. Results Median follow up duration for 29 survivors was 48 months. Seventy-five patients engrafted (90.4%) with median time to neutrophil and platelet engraftment of 13 and 15 days respectively. Patients treated with a HMA had a significantly lower cumulative incidence (CI) of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; p=0.03), whereas TRM at 1 year post-transplantdid not significantly differ between the groups (27% and 30%, respectively; p=0.84). Acute GVHD all grades and grade 2-4 were seen in 28.2% versus 35.8% (p=0.05) and 12.8% versus 11.3% (p=0.72) in patients who received a HMA compared to those who treated with other agents respectively. CI of chronic GVHD was 35% in patients treated with a HMA versus 19.2% in those treated with other agents (p=0.36) while CI of chronic extensive GVHD was seen in only 26.7% versus 19.2% respectively (p=0.64). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a HMA (43%) than in those who received other treatments (27%; p=0.04) (Figure 1). However, therapy with HMA before transplant did not significantly influence the 3-year OS rate (45% in those treated with HMA and 39% in those treated with other agents; p=0.22). The independent prognostic factors for PFS were a blast count of < 5% before transplant (HR 0.36, 95%CI 0.14-0.78), treatment with a HMA (HR 0.44, 95% CI 0.23-0.86), a transplant from an MRD (HR 0.41, 95% CI 0.22-0.94), development of grade 2-4 acute GVHD (HR 2.7, 95% CI 1.27-5.77), and development of chronic GVHD (HR 0.15, 95% CI 0.05-0.45). Conclusion We conclude that treatment with hypomethylating agents before allo-SCT may improve survival in patients with CMML. Figure 1. Progression free survival Figure 1. Progression free survival Disclosures Alousi: Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy.

Myeloablative Versus Nonmyeloablative Hemopoietic Cell Transplantation (HCT) for Patients with Myelodysplasia (MDS) or AML with Multilineage Dysplasia Following MDS (tAML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2320-2320
Author(s):  
Bart L. Scott ◽  
Michael Maris ◽  
Brenda Sandmaier ◽  
Barry Storer ◽  
Thomas Chauncey ◽  
...  
Keyword(s):  
High Risk ◽  
Retrospective Review ◽  
Conditioning Regimen ◽  
Refractory Anemia ◽  
High Risk Disease ◽  
Significant Difference ◽  
Unrelated Donors ◽  
Conditioning Regimens ◽  
Conditioning Intensity ◽  
Cmv Status

Abstract The median age at diagnosis of MDS is 72 years (yrs), and conventional HCT is not an option for many patients (pts). The primary benefit of nonmyeloablative conditioning regimens is a reduction in acute post-HCT morbidity and mortality. However, this benefit may be offset by an increase in post-HCT relapse. To address these issues, we performed a retrospective review of data from 172 pts over age 40 yrs with a diagnosis of MDS or tAML as determined by WHO criteria who underwent HCT between January 1998 and December 2003. Data were analyzed as of July 28, 2004. One hundred thirty two pts were conditioned with a myeloablative regimen of targeted (800–900 ng/ml) busulfan (starting dose 1mg/kg every 6 hours for 16 doses) and cyclophosphamide (120mg/kg) with or without thymoglobulin. Forty pts selected for a nonmyeloablative regimen because of age or comorbid illnesses were conditioned with 2 Gy TBI with or without fludarabine, 30mg/m2/day for three days. The median age was 52 (40–65) yrs for the myeloablative group, and 62 (40–73) yrs for the nonmyeloablative group. The majority of pts in the nonmyeloablative group had progressed to tAML (55%) and had high risk disease by IPSS (55%). The WHO distribution (highest at any time) was as follows: myeloablative/nonmyeloablative- 34%/55% with tAML, 29%/22% with refractory anemia with excess blasts (RAEB-1/2), and 37%/22% with refractory anemia with or without ringed sideroblasts (RA/RARS). The IPSS distribution (highest at any time) was as follows: myeloablative/nonmyeloablative-26%/55% high, 23%/30% int-2, 41%/15% int-1, and 11%/0% low risk. All pts received HCT from HLA-matched related (50% of myeloablative, 65% of nonmyeloablative) or unrelated donors. There were no differences between the two groups with regards to gender distribution, donor CMV status, recipient CMV status, duration of disease prior to HCT, primary or secondary etiology of MDS, or source of stem cells. Overall survival (OS) [46%/31%], relapse free survival (RFS) [40%/28%], and non-relapse mortality [37%/37%] did not differ significantly between myeloablative/nonmyeloablative pts. There was a trend towards improved RFS in pts with RA/RARS (p=0.16) who received myeloablative HCT, and a trend towards improved RFS in pts with tAML who received nonmyeloablative HCT (p=0.14). Among pts with more advanced disease (RAEB-1/2 or tAML) given myeloablative/nonmyeloablative HCT there were 39%/87% who received induction chemotherapy (IC) pre-HCT and 59%/85% given IC achieved a CR. Post-HCT OS and RFS were similar for pts who achieved CR following IC regardless of conditioning regimen used. Thus, while there was a trend towards superior survival with myeloablative HCT in pts with RA/RARS and with nonmyeloablative HCT in pts with tAML, in this retrospective review there were no significant differences between results obtained with myeloablative and nonmyeloablative conditioning regimens. Furthermore, even though most nonmyeloablative pts had high risk disease, there was no significant difference in RFS between the two groups suggesting that a graft vs. tumor effect was more important than conditioning intensity in preventing relapse in pts with high risk MDS or tAML in CR after IC. This raises the question of whether nonmyeloablative HCT should be considered in all pts with high risk MDS or tAML who achieve a CR with IC.

scholarly journals Heavy and Light Chain Monitoring in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1852-1852
Author(s):  
Noemi Puig ◽  
Teresa Contreras ◽  
Bruno Paiva ◽  
María Teresa Cedena ◽  
José J Pérez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Response Assessment ◽  
Advisory Committees ◽  
Minimal Residual

Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of bone marrow minimal residual disease (MRD) negativity. However, other methods of disease evaluation in serum such as heavy+light chain (HLC) assessment, with a potential complementary value to the IMWG response criteria, have also been tested. Aim: To evaluate the performance of HLC assay in HRsMM pts at diagnosis and after consolidation, comparing the results with standard serological methods and Next Generation Flow (NGF) for the assessment of bone marrow MRD. Patients and Methods: Ninety HRsMM pts included in the GEM-CESAR trial received six 4-weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and 2 further cycles of consolidation with the same regimen. All pts received maintenance treatment with lenalidomide for up to 2 years. SPEP and IFE were performed using standard procedures. Serum IgGk, IgGl, IgAk and IgAl HLC concentrations were measured using Hevylite (The Binding Site Group Ltd, Birmingham, UK) on a SPA PLUS turbidimeter. HLC concentrations and ratios were considered abnormal if they were outside the 95% reference ranges provided by the manufacturer. MRD was analyzed by flow cytometry following EuroFlow recommendations (sensitivity, 2x10-6). Standard response assignment was carried out as per the IMWG guidelines. Hevylite responses were assigned and HLC-pair suppression was defined as in Michalet et al (Leukemia 2018). Results: Out of 90 HRsMM pts, 75 had monoclonal intact immunoglobulin and samples available at diagnosis (50 IgG and 25 IgA). HLC ratio was abnormal in 98% of IgG pts and in 100% of IgA pts. Response assessment by Hevylite and standard IMWG criteria were available in 62 pts post-consolidation (Table 1). A good agreement was found between the two methods (kappa quadratic weighting = 0,6327 (0,4016 - 0,8638)). Among 46 pts with assigned CR as per the IMWG response criteria, there were 3 and 8 pts in PR and VGPR according to the Hevylite method, respectively. In 62 cases, paired Hevylite and MRD assessment data were available. Concordant results were found in 72.5% of cases (45/62; HLC+/NGF+ in 15 and HLC-/NGF- in 30 cases) while in the remaining 27.4% of cases results were discordant (17/62; HLC-/NGF+ in 6 and HLC+/NGF- in 11 cases). Post-consolidation, 24, 25.8 and 42.3% of the 62 samples were positive by SPEP, NGF and Hevylite, respectively. HLC-pair suppression was identified in 13/62 pts; 10 had severe HLC-pair suppression at the end of consolidation. After a median follow-up of 32 months (8-128), 93% of pts remain alive and progression-free. Three patients that have already progressed had their responses assessed post-consolidation. The first pt was assigned VGPR by the standard IMWG criteria and PR by Hevylite and was MRD positive by NGF; the second pt was assigned CR by IMWG criteria and Hevylite but had severe HLC-pair immunosuppression and was MRD positive by NGF; the third pt was in CR by IMWG and HLC criteria and was MRD positive by MFC. Conclusions: Moderate agreement was found between response assessment by Hevylite and the standard IMWG methods as well as between Hevylite and MRD assessment by NGF. Most discordances were a result of Hevylite detecting disease in samples negative by the standard methods, but longer follow-up is needed to ascertain its clinical value. HLC assessment could have anticipated the progression noted in 2 (out of 3) patients. Disclosures Puig: Takeda, Amgen: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Sanofi and Takeda: Consultancy. Rodriguez Otero:Kite Pharma: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy. Oriol:Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Rios:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; AbbVie: Consultancy. De Arriba:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria. Ocio:Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; BMS: Honoraria; Novartis: Consultancy, Honoraria; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Mundipharma: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy; Janssen: Consultancy, Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2574-2579 ◽  
Author(s):  
Ashraf Badros ◽  
Bart Barlogie ◽  
Christopher Morris ◽  
Raman Desikan ◽  
Sara R. Martin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
High Response Rate ◽  
Cell Transplant ◽  
Poor Risk ◽  
Heavily Pretreated ◽  
Donor Lymphocyte Infusions

Abstract Standard allogeneic stem cell transplant (allo-SCT) regimens have been associated with a high transplant-related mortality (TRM) in multiple myeloma (MM). Nonmyeloablative therapy can establish stable engraftment after allo-SCT and maintain the antitumor effect with less toxicity, which is important in heavily pretreated and elderly patients. We report on 16 poor-risk MM patients receiving allo-SCT from an HLA-matched (n = 14) or mismatched (n = 2) sibling following conditioning with melphalan 100 mg/m2 (MEL-100). Ten patients had refractory relapse, 4 responsive relapse, and 2 patients were in near complete remission (nCR) with poor-prognosis disease. Patients had received 1 (n = 9) or 2 (n = 7) prior autotransplants. Donor lymphocyte infusions (DLIs) were given to 14 patients with no clinical evidence of graft versus host disease (GVHD) either to attain full donor chimerism (n = 4) or to eradicate residual disease (n = 10). Fifteen patients showed myeloid engraftment, and 12 patients were full donor chimeras at day +21. No TRM was observed during the first 100 days. Acute GVHD developed in 10 patients; 1 had fatal grade IV GVHD. Seven progressed to chronic GVHD, limited in 3 and extensive in 4 patients. At a median follow-up of 1 year, 5 patients achieved and sustained CR, 3 nCR, and 4 partial remission. Of 4 patients progressing after transplantation, 3 achieved a remission following further chemotherapy and DLI. Remarkable graft versus myeloma responses were seen in chemotherapy-refractory patients. Two patients died of progressive disease, and 3 died of GVHD complications without active disease. GVHD remains a major problem with this procedure.

Haploidentical Hematopoietic Cell Transplantation (HCT) Compared with Matched HCT from Family Donors: report of 216 cases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5160-5160
Author(s):  
Daopei Lu ◽  
Wei Han ◽  
Lujia Dong ◽  
Xiaojun Huang ◽  
Kaiyan Liu ◽  
...  
Keyword(s):  
High Risk ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Great Majority ◽  
Post Transplant ◽  
Unrelated Donors ◽  
Haploidentical Hematopoietic Cell Transplantation ◽  
First Time ◽  
Related Mortality

Abstract A total of 216 cases of matched and mismatched-haploidentical HCT from family donors have been performed since May 2002 in our Institute. The purpose of this analysis is to compare the GvHD, relapse rate and their risk factors for complications and survival. The feasibility of the present regimen can then be evaluated. In the arm of mismatched-haploidentical HCT, GIAC regimen (G-CSF priming hematopoietic cells collection; immunosuppression intensified and prolonged; ATG being used; combination use of BM + PB) was used for the first time. It was developed for patients without HLA matched related or unrelated donors. However, in HLA matched HCT, ATG was not used. The two groups were comparable in disease diagnoses, sex, and prophylaxis of GvHD, number of MNC/kg and use of G-CSF post-transplant. The great majority of recruited patients had hematological malignancies. A few were cases of SAA. There were significantly more patients in advanced stage or in high-risk status in mismatched-haploidentical HCT group. After median value of 9(2–260 months follow up, the results are shown in Table 1. Table 1. Survival and causes of Death (2-year Kaplan-Meire Estimates) Characteristics and Outcomes Matched Mismatched-haploidentical No. Of Patients 116 100 Age (yr.) 37 (12–62) 23 (3–52) Status of Patients Standard Risk 86 (74.8%) 44 (44%) High Risk 30 (25.2%) 56 (56%) Days post-transplant ANC>0.5x109/L 16.4 12 Platelets>20x109/L 16.9 17 Acute GvHD <100 days 0-I 48.6% 52% II 38.6% 35% III-IV 12.8% 13% Chronic GvHD 62.5% 63.3% Extensive 18.7% 18.3% Overall survival for 1 year 81.2% 72% Relapse related mortality 5.17% 6% Non-relapse related mortality 11.2% 16% In summary, compared to matched HCT, GIAC regimen for mismatche-haploidentical HCT is sufficiently safe for patients.

Early Bortezomib Following Allogeneic Stem Cell Transplantation (SCT) for Multiple Myeloma To Enhance or Maintain Remission Status.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2010-2010
Author(s):  
Nicolaus Kroeger ◽  
Tatjana Zabelina ◽  
Francis Ayuk ◽  
Djordje Atanackovic ◽  
Heike Schieder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Residual Disease ◽  
Chronic Gvhd ◽  
Donor Lymphocyte Infusion ◽  
Bortezomib Treatment ◽  
Major Toxicity ◽  
Stem Cell Graft ◽  
Unrelated Donors ◽  
Low Toxicity

Abstract We investigated the toxicity and efficacy of early administration of bortezomib in 14 patients with residual disease (n=9) or complete remission (immunofixation-negative) (n=5) after a median of 383 days (range, 47–1317) after melphalan/fludarabine-based dose-reduced allogeneic SCT for multiple myeloma. The median age was 49 years (range, 32–62), and stem cell graft was from HLA-identical siblings (n=2) or unrelated donors (n=12). Three patients had received prior Thalidomide and donor lymphocyte infusion, and 2 of them still received low dose thalidomide (50 mg) during bortezomib treatment. The study consisted of two cycles bortezomib (1.3 mg/m2) given intravenously on day 1, 4, 8 and 14 (q21d). In case of response and low toxicity, two further cycles were applied. Eleven patients completed two cycles, and 4 patients completed four cycles. Two patients stopped after three cycles due to side-effects; 3 patients could not complete the proposed two cycles and stopped either after the first injection (n=1) of the first cycle, or after the second (n=1) or third (n=1) injection of the second cycle due to neurotoxicity. Major toxicity was thrombocytopenia grade IV (> 75 % reduction) which was seen in 6 patients (43 %), but none required platelet support. Neutropenia grade IV was seen in 2 patients (14 %), neurotoxicity grade III and IV was observed in 3 patients (21 %) while mild grade I-II neuropathy was seen in 10 patients (71 %). Other toxicity was fatigue grade I (85 %), nausea grade I (50 %), diarrhea grade I-II (93 %). Two patients with acute or chronic GvHD of the skin experienced deterioration of the manifestation, which could be treated succesfully with corticosteroids. A significant decrease during bortezomib-therapy was observed for CD3+ cells (p=0.02), while no effect was seen for B-cells (CD19+) (p=0.4). Two patients who received bortezomib on day 125 and 201 after allogeneic SCT experienced Herpes zoster infection during and 2 weeks after bortezomib treatment, respectively. All 9 patients with persistent disease showed further regression of the paraprotein including negative immunofixation in 5 patients. We conclude that early bortezomib after allogeneic SCT for patients with multiple myeloma is active and can induce further regression of the paraprotein. The toxicity is considerable especially if given early after allo SCT.

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