First Line Therapy With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) In Patients With AL Amyloidosis and Potentially Reversible Contraindications To Autologous Stem Cell Transplant

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1985-1985 ◽  
Author(s):  
Giovanni Palladini ◽  
Paolo Milani ◽  
Marta Vidus Rosin ◽  
Andrea Foli ◽  
Giampaolo Merlini
Keyword(s):  
Stem Cell ◽  
Partial Response ◽  
Randomized Clinical Trials ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Second Line ◽  
Hematologic Response

Abstract Two recent reports by the Mayo Clinic and UK groups showed that the combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) grants a high rate of complete response (CR) and very good partial response (VGPR) in AL amyloidosis. In the two papers a total of 30 patients who received CyBorD upfront were reported, 63% of whom achieved CR. This combination has the further advantage of sparing stem cells, allowing second-line autologous stem cell transplant (ASCT). In the present study we treated with frontline CyBorD 56 consecutive newly diagnosed patients with AL amyloidosis, diagnosed between 2010 and 2012, who were transplant candidates and refused the procedure frontline or had potentially reversible contraindications to ASCT. Main exclusion criteria from the present study were age ≥70 years, NT-proBNP >8500 ng/L, systolic blood pressure <100 mmHg, and glomerular filtration rate (eGFR) <15 mL/min. The patients received weekly cyclophosphamide 300 mg/m2, bortezomib 1.3 mg/m2, and dexamethasone (40 mg). The dose of dexamethasone was reduced to 20 mg in 13 patients (23%) who were cardiac stage 3. Starting in September 2012, bortezomib was administered subcutaneously. Hematologic response was assessed every 2 cycles. Median age was 55 years. The kidney was involved in 41 patients (73%), the heart in 39 (70%), and the liver in 5 (9%). Cardiac stage was I in 17 patients (30%), II in 26 (46%), and III in 13 (33%). Five subjects (9%) had eGFR <30 mL/min. Eleven patients (20%) experienced severe adverse events, namely fluid retention and worsening heart failure (4, 7%), cytopenia (4, 7%), worsening renal failure (2, 4%), and deep venous thrombosis (1, 2%). Additionally, 4 patients (7%) died on treatment due to progressive cardiac amyloidosis, before the first evaluation of response. Overall, 63% of patients responded (95%CI: 49-75%). Best hematologic response by intent-to-treat, was CR in 16 patients (29%), VGPR in 8 (14%), and partial response (PR) in 11 (19%). All responders achieved at least PR by cycle 2, and best response was reached by cycle 6 in all cases. Cardiac response was achieved in 13/39 subjects (33%) and in 3/41 (7%) there was a renal response. So far, 10 patients, 6 non-responders, 3 attaining PR, and 1 in VGPR with progressing proteinuria were transplanted. Response data are available for 4 of these subjects, 3 of whom responded to ASCT (1 CR, 1 VGPR, 1 PR). With a median follow-up of living patients of 15 months, 11 patients (20%) died. Median survival was not reached and 78% of patients are projected to be alive at 1 year. The main baseline determinant of patients’ outcome was cardiac stage, with 100% 1-year survival in stage I, and 70% in stage II and III patients. This is the largest study on frontline CyBorD in AL amyloidosis reported so far. In this homogeneous patient population including low/intermediate-risk subjects with potentially reversible contraindication to ASCT, 43% of patients achieved CR/VGPR and cardiac dysfunction improved in one third of cases. Second-line ASCT was feasible in subjects with suboptimal responses. Though good, the response rate to CyBorD observed in the present study was lower than that reported in the 2 previously published studies, indicating that randomized clinical trials are needed to assess the efficacy of this combination in AL amyloidosis. Disclosures: Off Label Use: Bortezomib in AL amyloidosis. Merlini:Millennium-Takeda: Honoraria; Pfizer: Honoraria.

scholarly journals Sequential response-driven bortezomib-based therapy followed by autologous stem cell transplant in AL amyloidosis

2020 ◽  
Vol 4 (17) ◽  
pp. 4175-4179
Author(s):  
Marco Basset ◽  
Paolo Milani ◽  
Mario Nuvolone ◽  
Francesca Benigna ◽  
Lara Rodigari ◽  
...  
Keyword(s):  
Stem Cell ◽  
Partial Response ◽  
Stem Cell Transplant ◽  
Complete Response ◽  
Autologous Stem Cell Transplant ◽  
Survival Duration ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Duration Of Response ◽  
Landmark Analyses

Abstract Autologous stem cell transplant (ASCT) is highly effective in selected patients with light chain (AL) amyloidosis. Bortezomib, preceding or following ASCT, improves responses. Satisfactory responses, including at least a partial response, very good partial response (VGPR) with organ response, or complete response, can be observed after induction therapy alone. We report 139 patients treated upfront with cyclophosphamide/bortezomib/dexamethasone (CyBorD), followed by ASCT only if response was unsatisfactory. Only 1 treatment-related death was observed. After CyBorD, hematologic response (HR) rate was 68% (VGPR or better, 51%), with 45% satisfactory responses. Transplant was performed in 55 (40%) subjects and resulted in an 80% HR rate (65% ≥ VGPR). Five-year survival was 86% and 84% in patients treated with ASCT or CyBorD alone, respectively (P = .438). Also, 6- and 12- month landmark analyses did not show differences in survival. Duration of response was not different in the 2 groups (60 vs 49 months; P = .670). Twenty-one (15%) patients with an unsatisfactory response to CyBorD could not undergo ASCT because of ineligibility or refusal; instead, they received rescue chemotherapy, with HR in 38% of cases and 51% 5-year survival. This sequential response-driven approach, offering ASCT to patients who do not attain satisfactory response to upfront CyBorD, is very safe and effective in AL amyloidosis.

scholarly journals Delineation of the timing of second-line therapy post–autologous stem cell transplant in patients with AL amyloidosis

Blood ◽  
2017 ◽  
Vol 130 (13) ◽  
pp. 1578-1584 ◽  
Author(s):  
Yi L. Hwa ◽  
Rahma Warsame ◽  
Morie A. Gertz ◽  
Francis K. Buadi ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Key Points

Key Points Organ progression at second-line therapy predicated inferior survival. Patients relapsing from >VGPR had a longer time to develop organ progression.

Outcomes and Treatments of Relapsed AL Amyloidosis Following Stem Cell Transplant

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1858-1858 ◽  
Author(s):  
Rahma Warsame ◽  
Soo-Mee Bang ◽  
Shaji K. Kumar ◽  
Martha Q Lacy ◽  
Francis K Buadi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Treatment Options ◽  
Autologous Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Post Transplant

Abstract Abstract 1858 Systemic light chain amyloidosis (AL amyloidosis) is a condition where clonal plasma cells produce misfolded insoluble immunoglobulin light chains that deposit in various organs causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT) when eligible is the standard treatment options for patients with AL amyloidosis. There are several studies who report long term outcomes of patient post ASCT. However, there is a paucity of literature describing the outcomes of patients who have received ASCT but have relapsed. We performed a retrospective study to assess the outcomes and treatment regimens employed following relapse after ASCT. Between 1996 and 2009, 410 patients received ASCT at the Mayo Clinic as first line therapy. Of those 410 patients 42 patients died within 3 months of transplant, 64 patients died without documented relapse, 158 patients were alive without documented progression, and 146 patients had documented progression. Those 146 patients are the subject of our study. The median time to hematologic relapse was 2 years (range: 0.2–15.5 years). At relapse, 59 patients were treated with IMiD based therapy, 36 with alkylator based therapy, 24 with bortezomib, 15 with steroids, and 5 with second ASCT. The respective hematologic response rates were 58%, 33%, 50%, 53%, and 60%. The remaining six patients were not evaluable for response for one other following reasons: organ transplants; no further therapy; inevaluable disease. With a median post relapse follow up of 3.6 years, the median overall survival (OS) from the first post ASCT relapse was 4.6 years. The median post transplant follow up was 6.1 years, the median OS for these patients was 7.3 years from the time of transplant. These data provide novel information about outcomes after SCT relapse, which should be useful not only for patients and doctors but also for investigators designing studies for salvage therapies post-transplant. Disclosures: No relevant conflicts of interest to declare.

Definition of a high-risk population among patients with AL amyloidosis not undergoing autologous stem cell transplantation using bone marrow plasmacytosis and the presence of CRAB.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8516-8516
Author(s):  
Taxiarchis Kourelis ◽  
Morie Gertz ◽  
Martha Lacy ◽  
Francis Buadi ◽  
Suzanne R. Hayman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplant ◽  
Plasma Cells ◽  
Autologous Stem Cell Transplant ◽  
Bone Lesions ◽  
High Risk Population ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Beta 2 Microglobulin

8516 Background: There is consensus that light chain amyloidosis (AL) patients with CRAB criteria (abnormal calcium or renal function, anemia or lytic bone lesions) also have multiple myeloma (MM). These patients are typically excluded from AL trials; however, AL patients with >= 10% bone marrow plasma cells (BMPC) in the absence of CRAB are included in trials along with AL with < 10% BMPC. We postulated that the currently used dichotomy may be incorrect and examined the spectrum of AL with and without MM. Methods: We identified 1,272 patients with AL seen within 90 days of diagnosis, between January 1, 2000, and December 31, 2010. We defined the population of patients with coexisting MM based on the existence of CRAB (AL-CRAB-MM). Patients without CRAB were divided into two groups, AL-only (<10% BMPC) and AL-PC-MM (>=10% BMPC). Results: Among the 1,272 patients, 117 (9%) had AL-CRAB-MM, 476 (37%) had AL-PC-MM, and 679 (53%) had AL only. Their respective median overall survivals (OS) were 16.2, 15.8, and 28.4 months (p<0.0001). Autologous stem cell transplant (ASCT) was performed in 203 (30%), 138 (29%) and 23 (20%) patients respectively. Since the outcomes of AL-CRAB-MM and AL-PC-MM were similar, they were pooled for univariate and multivariate analyses. On multivariate analysis, AL-CRAB-MM and AL-PC-MM retained negative prognostic value independent of age, cardiac stage, prior autologous stem cell transplant (ASCT), beta 2 microglobulin, and dFLC. We next considered whether patients received ASCT as part of their treatment. For those patients who never received ASCT, the 5-year OS were 19%, 14%, and 31%, p<0.001, for AL-CRAB-MM, AL-PC-MM, and AL only respectively. In contrast, for those patients who received ASCT, the respective 5-year OS were 46%, 56%, and 73%, p<0.001. Conclusions: AL patients with >=10% BMPCs have a poor prognosis similar to patients with AL-CRAB-MM and should therefore be considered as AL with MM.

scholarly journals Patterns of Relapse after Upfront Therapy in AL Amyloidosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2140-2140 ◽  
Author(s):  
Paolo Milani ◽  
Marco Basset ◽  
Francesca Russo ◽  
Andrea Foli ◽  
Giovanni Palladini ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Partial Response ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Second Line ◽  
Second Line Therapy ◽  
Prolonged Time ◽  
Hematologic Response ◽  
Line Therapy ◽  
Upfront Therapy

Abstract Introduction. In the last few years a major international effort allowed establishing baseline staging systems and response criteria in AL amyloidosis. However, we still lack validated progression criteria. This is acutely relevant for reporting progression free survival in clinical trials and because novel agents are first tested in the relapsed/refractory setting. We studied the patterns of relapse and outcome of 259 consecutive patients with AL amyloidosis who attained hematologic response after upfront therapy. Methods. The prospectively maintained database of the Pavia Amyloidosis Research and Treatment Center, including 1069 treatment-naïve patients with AL amyloidosis diagnosed between 2004 and 2015, was searched for patients who achieved at least partial response (PR) after upfront treatment, and did not require second-line therapy for at least 6 months. Relapse was defined as the initiation of second-line therapy. Results. A total of 259 consecutive patients were identified. Their median age was 66 years (range 39-84 years). The heart was involved in 184 patients (71%) and the kidney in 179 (69%) of subjects. Cardiac stage was I in 29% of patients, II in 46%, IIIa in 18%, and IIIb in 7%. Renal stage was I in 48% of patients, II in 39%, and III in 13%. Upfront treatment was melphalan and dexamethasone (MDex) in 129 patients (50%), cyclophosphamide, bortezomib and dexamethasone (CyBorD) in 71 (27%), bortezomib plus MDex (BMDex) in 46 (18%), bortezomib and dexamethasone in 10 (4%) in 3 subjects (1%) with IgM-AL amyloidosis. Best hematologic response after upfront therapy was CR in 82 patients (32%), very good partial response (VGPR) in 134 (52%), and partial response (PR) in 43 (16%). Cardiac response was achieved in 38% of patients and renal response in 27%. All patients in whom treatment was discontinued in PR had also achieved organ response. After a median follow-up of living patients of 41 months, 92 patients (35%) needed second line therapy (relapsed). At time of relapse, dFLC (difference between amyloidogenic - involved - and uninvolved free light chains) increased in 86 patients (93%), reaching a median of 60 mg/L [interquartile (IQR) range 26-108 mg/L], corresponding to 41% (IQR 19-84%) of baseline value, with 44 patients (48%) whose dFLC at relapse remained below the threshold of "measurable disease" (50 mg/L) generally required for enrollment in clinical trials. Progression of NT-proBNP was observed in 20 patients, and was preceded by a dFLC increase (to a median of 50% of baseline value; IQR: 20-83%) in 20 (91%). A >50% increase in proteinuria was observed in 24 patients (26%), 2 of whom maintained VGPR with no increase in dFLC. In 11 patients (12%) estimated glomerular filtration rate decreased by >25%, with dFLC increase in all cases. Overall, 70 patients (76%) had signs of cardiac or renal progression at time of second line therapy initiation. Median time to second line therapy was 57 months. The variables significantly associated with prolonged time to relapse were baseline dFLC <60 mg/L (11% vs 32% relapsing at 3 years, P=0.004), quality of hematologic response (21%, 35%, and 54% relapsing at 3 years, among patients in CR, VGPR, and PR, respectively; CR vs. VGPR: P=0.003, VGPR vs. PR: P=0.028), and treatment with BMDex [27% relapsing at 3 years, compared with 38% with CyBorD (P=0.014), and 39% with MDex (P=0.023)]. A multivariate analysis stratified by achievement of CR showed that treatment with BMDex independently prolonged time to second line therapy (HR=0.28, P=0.016), while dFLC <60 at diagnosis retained borderline significance (HR=0.15, P=0.067). Thirty-two patients died, and median survival after relapse was 58 months. Progression of NT-proBNP was associated with shorter survival (median 17 vs. 62 months, P=0.001). Conclusion. Low dFLC burden at diagnosis and treatment with the combination of bortezomib, melphalan and dexamethasone are associated with more durable responses. An increase in NT-proBNP should not be awaited to start treatment, because it is associated with poorer survival. However, cardiac progression is preceded by a dFLC increase in >90% of cases. Increases in dFLC (>20%) should trigger second-line therapy in patients with cardiac involvement. Disclosures Palladini: Prothena: Honoraria. Merlini:Pfizer: Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy; Millennium Takeda: Consultancy; Prothena: Honoraria.

Role of autologous stem cell transplant after induction therapy with bortezomib-lenolidomide or bortezomib-thalidomide in newly diagnosed multiple myeloma patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8596-8596
Author(s):  
N. Shah ◽  
D. Weber ◽  
R. Orlowski ◽  
M. Wang ◽  
S. K. Thomas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Partial Response ◽  
Induction Therapy ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Highly Active

8596 Background: The introduction of novel therapeutic options with bortezomib and immunomodulatory agents in the up-front management of multiple myeloma (MM) has significantly improved induction response rates. However, the role of high dose chemotherapy and autologous stem cell transplant (ASCT) after induction with these highly active agents is not known, especially in patients with only a partial response to induction therapy. Methods: We conducted a retrospective review of 95 newly diagnosed MM patients treated with induction bortezomib-lenolidomide-dexamethasone (BLD) or bortezomib-thalidomide-dexamethasone (BTD) prior to ASCT. Responses were graded according to IMWG criteria. Results: 19 patients received BLD and 76 patients received BTD. All patients were conditioned with a melphalan-based regimen. Of the 19 patients who underwent induction with BLD, complete response (CR), very good partial response (VGPR) and partial response (PR) were achieved in 2 (11%), 8 (42%) and 9 (47%) respectively for an overall response rate (ORR) of 19/19 (100%). After ASCT, CR, VGPR and PR were achieved in 9 (47%), 5 (26%) and 5 (26%) respectively for a continued ORR of 21/21 (100%). Notably, 4/8 (50%) of patients with a VGPR after induction therapy with BLD improved to a CR after ASCT. 3/9 (33%) of patients with an initial PR to BLD improved to a CR and 1/9 (11%) with a PR improved to VGPR after ASCT. Of the 76 patients who underwent induction with BTD, CR, VGPR and PR were achieved in 6 (8%), 37 (49%) and 31(41%) respectively for an ORR of 74/76 (97%). 1 patient had stable disease and 1 patient had progressive disease. After ASCT, 27/76 (36%) achieved a CR, 30/76 (39%) a VGPR and 18/76 (24%) a PR for an ORR of 75/76 (99%). Of the patients who initially had a VGPR to BTD 16/37 (43%) improved to a CR while 5/32(16%)of PR patients improved to a CR and 9/32 (28%) of PR patients improved to a VGPR. Conclusions: Of the 40 patients who only achieved a PR after induction therapy with BLD or BTD, 16 (40%) had further improvement to a CR or VGPR after ASCT. Thus there is a significant benefit of ASCT in these patients who initially demonstrate relative resistance to induction therapy with highly active regimens. [Table: see text]

Induction Therapy with Bortezomib and Dexamethasone Followed By Autologous Stem Cell Transplantation for Systemic Light Chain Amyloidosis: Our Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5907-5907
Author(s):  
Sandeep Jain ◽  
Luciano J Costa ◽  
Robert K Stuart ◽  
Saurabh Chhabra ◽  
Alice Mims ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cardiac Involvement ◽  
Stem Cell Transplant ◽  
Patient Characteristics ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
High Dose Melphalan

Abstract Introduction: The optimal treatment approach for systemic AL amyloidosis remains unclear. Autologous stem cell transplant (ASCT) is the only modality associated with long term survival, but failure to show survival benefit in randomized clinical trial raises doubts about its efficacy 1, 2. Outcomes after ASCT are better in patients who achieve complete hematologic response after the ASCT3. One report has shown improved outcomes with combining one dose of the proteasome inhibitor bortezomib with high dose melphalan as part of conditioning regimen 4. Preliminary data from a recent study suggest that the outcome of treating AL amyloidosis with two cycles of bortezomib and dexamethasone followed by ASCT was superior to the outcome of the ASCT alone5. We describe our experience with giving 4-6 cycles of bortezomib and dexamethasone induction prior to high dose melphalan and ASCT in patients with systemic AL amyloidosis. Patients and methods: We included all patients who underwent autologous transplant for symptomatic systemic AL amyloidosis at our institution from October 2010 till June 2014. Five patients were included in the analysis and patient characteristics are described in table 1. All patient received 4 -6 cycles of induction with bortezomib and dexamethasone followed by autologous stem cell transplant using high dose melphalan (200 mg/m2). One patient also received six cycles of lenalidomide and dexamethasone prior to bortezomib based induction for lack of response. Hematologic and organ response were assessed using the definitions from the 10th International symposium on Amyloid and Amyloidosis. Overall survival was calculated by Kaplan Meyer’s method using Graphpad Prism 6.0 software. Results: There was no transplant related mortality. After median follow up of 13 months (12-25 months) all patient are alive. Toxicities from the ASCT were mostly cytopenias in the immediate post-transplant period which were managed as per the standard of care. Two patients achieved hematological complete response while one more had very good partial response and other two achieved partial response. Of the four patients with nephrotic range proteinuria, two patients had > 95% reduction in proteinuria, one had > 75% reduction in proteinuria and another patient had > 50% reduction in proteinuria. One patient had Liver involvement with elevated alkaline phosphatase which normalized post-transplant (table 2). The responses were maintained on last follow up and none of the patient had hematological or organ relapses. Discussion: Bortezomib alone and in combination with steroids has shown efficacy in AL amyloidosis, but its role in induction prior to high dose melphalan/ASCT to help achieve deeper hematological response is unknown. Our experience shows that this combination may be highly efficacious without significant toxicity. Limitations of our study include the small number of patients and absence of any patients with cardiac involvement, which is a worse prognostic marker. We conclude that the bortezomib and dexamethasone induction followed by high dose melphalan/ASCT for AL amyloidosis should be studied in prospective trials. Table 1.Patient Characteristics n=5Age, years 51.2 (44-62)Race (Caucasian)4 (80%)Gender ( female)3 (60%)Cardiac involvement 0 (0)Renal involvement 4 (80%)Serum creatinine ≥ 2.5 0 (0)Organ involvement ≥21 (20%)BM plasma cells > 10%1 (20%)Hgb ≤ 10 g/dl0 (0)LVEF <50%0 (0)Induction therapy Bortezomib/dexamethasone only4 (80%)Lenalidomide/dexamethasone + Bortezomib/dexamethasone1 (20%) Table 2. Outcomes n=5 Baseline After ASCT Hematologic response n=5 M protein 0.772 gm/dl 0.096 gm/dl 2 CR, 1 VGPR, 2 PR Renal response n=4 24 hours proteinuria 3.13 gm 0.432 gm 2 > 95% reduction, 1 >75% reduction, 1 >50 % reduction. Liver response n=1 Alkaline phosphatase 700 IU/L 62 IU/L Disclosures No relevant conflicts of interest to declare.

scholarly journals Sequential Therapy with Cyclophosphamide, Bortezomib and Dexamethasone Followed By Autologous Stem Cell Transplant Is Safe and Highly Effective in AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3312-3312
Author(s):  
Marco Basset ◽  
Paolo Milani ◽  
Andrea Foli ◽  
Mario Nuvolone ◽  
Jessica Ripepi ◽  
...  
Keyword(s):  
Stem Cell Transplant ◽  
Response Rate ◽  
Autologous Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Eligibility Criteria ◽  
Satisfactory Response ◽  
Hematologic Response ◽  
Significant Difference ◽  
Travel Grant

Introduction: Autologous stem cell transplant (ASCT) is a very effective treatment in AL amyloidosis. However, its role is challenged by novel, powerful, non-transplant therapy, also due to the potentially high treatment-related mortality (TRM) that requires an extremely careful patient selection. Bortezomib-based induction and consolidation preceding and following ASCT have been proposed to improve patient outcomes. Here we report the outcome of 139 patients treated with bortezomib-based induction followed by ASCT in case of unsatisfactory response. Methods: Starting in 2009 we offered upfront therapy with cyclophosphamide (300 mg/m2), bortezomib (1.3 mg/m2) and dexamethasone (40 mg) weekly (CyBorD) to all patients with AL amyloidosis who met the eligibility criteria for transplantation at our institution. Eligibility criteria for ASCT were: age < 65 years, NT-proBNP <5000 ng/L, eGFR >50 mL/min per 1.73 m2, NYHA class >3, PS-ECOG, ≤2, left ventricular EF >45%, DLCO >50% (Palladini and Merlini, Blood 2016). Patients who did not achieve a satisfactory response after CyBorD proceeded to ASCT (with melphalan 200 mg/m2), if still eligible. A satisfactory response was defined as complete response (CR), very good partial response (VGPR) with organ response (OR), or partial response (PR) with OR. Patients with overt multiple myeloma were excluded. We assessed response rates (by intent-to-treat), overall survival (OS) and time to next line of treatment or death (TNTD). Results: Between 2009 and 2018, 139 consecutive newly diagnosed patients were eligible for ASCT and received CyBorD as first line treatment. They represented 15% of all patients diagnosed at our center during the study period. Patients' characteristics are reported in Table 1. Treatment with CyBorD continued for 2 cycles in 44 patients (32%), 4 cycles in 64 (46%), 6 cycles in 20 (14%) and 8 cycles in 11 (8%) patients. Only one patient (stage IIIa) died within 100 days from CyBorD initiation due to sudden death. After CyBorD treatment, 26 (20%) patients achieved CR, 45 (32%) VGPR, and 24 (17%) PR (overall hematologic response rate 69%). Sixty-three patients (45%) achieved a satisfactory response after CyBorD and did not proceed to ASCT. Twenty-one patients (15%) who did not reach a satisfactory response after CyBorD did not proceed to ASCT because of organ progression that made them no longer eligible (16 subjects, 12%) or patient refusal (5 cases, 4%). The remaining 55 subjects (40%) received ASCT. No patients died within 100 days from ASCT. Hematologic response after ASCT was obtained in 80% of patients, with CR in 21 subjects (38%), VGPR in 15 (27%) and PR in 8 (15%). In the overall cohort, the hematologic response rate after CyBorD or CyBorD followed by ASCT was 77%, with 47 subjects (34%) attaining CR, 40 (29%) VGPR, and 19 (14%) PR. After a median follow-up of living patients of 48 months, 27 subjects died. In the whole study cohort, overall median survival (OS) was not reached and projected OS was 78% at 4 years and 69% at 10 years. In patients who proceeded to ASCT, median OS was not reached, and projected survival was 90% at 4 years and 77% at 10 years. In patients who achieved a satisfactory response after CyBorD and did not proceed to ASCT, median OS was not reached as well, and projected survival was 84% at 4 years and 72% at 10 years (P=0.438 compared to ASCT). In patients who did not proceed to ASCT despite having failed to achieve a satisfactory response after CyBorD, median survival was 47 months (P<0.001 compared to the 2 other groups). We then compared OS in patients who achieved VGPR or CR after CyBorD alone or after CyBorD followed by ASCT and found no significant difference (Figure 1). Finally, we evaluated TNTD in patients who attained CR and found no significant difference between subjects treated with CyBorD alone and those who received ASCT after CyBorD (relapsed or dead at 4 years 36% vs. 20%, P=0.737). This is in agreement with the median time to relapse from CR of 4.3 years reported by the Boston University group (Browning, et al. Blood 2017). Conclusion: This sequential treatment approach granted a high rate of profound hematologic responses and prolonged survival with minimal TRM (<1%) that occurred during the induction phase. In patients who attained profound hematologic response (CR or VGPR), OS and durability of response were similar in subjects who responded to initial CyBorD and in those who proceeded to ASCT. Figure 1 Disclosures Milani: Janssen: Honoraria; Pfizef: Honoraria. Palladini:Sebia: Honoraria; Celgene: Other: Travel grant; Janssen-Cilag: Other: Travel grant; Janssen-Cilag: Honoraria. OffLabel Disclosure: Bortezomib in AL amyloidosis

scholarly journals Efficacy of Daratumumab Containing Regimens Post Lenalidomide Maintenance in Transplant Eligible Patients: Real-World Experience from the Canadian Myeloma Research Group Database

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Hira S Mian ◽  
Christine Eisfeld ◽  
Christopher P. Venner ◽  
Victor Jimenez-Zepeda ◽  
Cyrus Khandanpour ◽  
...  
Keyword(s):  
Stem Cell ◽  
Real World ◽  
Research Group ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
P Value ◽  
Cell Transplant ◽  
Second Line

Introduction Lenalidomide maintenance following autologous stem cell transplant (ASCT) remains a standard of care among transplant eligible patients with newly diagnosed multiple myeloma (NDMM). Many previous clinical trials done in patients following one prior line of therapy either excluded patients progressing on lenalidomide or included a very small proportion of these patients. Given the paucity of data in this setting, the optimal management of patients progressing on lenalidomide maintenance remains unknown. Daratumumab-containing triplet regimens have recently been introduced for these patients, typically in combination with pomalidomide (DPd), lenalidomide (DRd), or bortezomib (DVd). To our knowledge, there is no prospective data to allow comparison of the efficacy of these three regimens in patients progressing on lenalidomide maintenance, which is an increasingly common clinical scenario. Understanding the comparative efficacy, tolerability and toxicity of these regimens in patients progressing on lenalidomide maintenance in the 'real-world' is needed in order to help clinicians make appropriate decisions and guide future studies. Methods The Canadian Myeloma Research Group Database (formerly known as the Myeloma Canada Research Network Database, MCRN-DB) is a prospectively maintained disease specific database with over 7000 patients enrolled from 14 academic sites across Canada with legacy data collected from 2007. The Munster Myeloma database collects myeloma specific information in a German academic center and currently contains data from 800 patients collected from 2005. All consecutive patients treated with daratumumab based regimens in second line following relapse on lenalidomide maintenance were included in the analysis from the two databases analyzed up to 30/06/2020. Results A total of 1380 NDMM patients on lenalidomide maintenance post autologous stem cell transplant were identified in the two databases. From them, 73 patients were included in this analysis as they were treated with daratumumab containing regimen in second line. Specifically, 18 (24.7%) of these patients were treated with DPd, 32 (43.8%) patients with DRd, and 23 (31.5%) patients with DVd. The baseline characteristics, maintenance details, post-maintenance response rates and toxicity for each regimen are shown in Table 1. The median follow-up for the cohort from the time of daratumumab initiation was 8.3 months (range 0.4 - 40.0). Although, a higher proportion of patients in the DPd arm obtained a CR/VGPR compared to DRd or DVd, it did not reach statistical significance (p-value 0.06). The median PFS of the entire cohort was 16.96 months (95% CI 11.47-23.44). The median PFS of the individual regimens was as follows: DPd 17.65 months, DRd not reached and DVd 11.47 months as demonstrated in Figure 1 (p-value =0.46). Conclusion In summary, our results show that daratumumab-based regimens are effective among patients progressing on lenalidomide maintenance in the real world. Despite the small sample size, the results presented here are in line with recent sub-analyses of phase III studies examining the common daratumumab-based regimens used in this setting (CASTOR with median PFS of DVd between 7.8 months in all lenalidomide refractory patients and 27 months in all patients in first relapse; MM014 with median PFS of DPd after lenalidomide refractoriness of 21.8 months). The efficacy of DRd, in which daratumumab is added to an increased dose of lenalidomide, is notable and warrants further evaluation to identify which patients are most likely to benefit. Additional studies with longer follow-up are required to assess the optimal daratumumab-based regimen to be used in this growing population of patients relapsing after lenalidomide maintenance. Disclosures Mian: Janssen: Consultancy, Honoraria; Celgene: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. McCurdy:Sanofi: Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Song:Celgene: Research Funding; Celgene, Janssen, Amgen, Takeda: Honoraria. Leblanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. White:Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Stakiw:Roche: Research Funding; Celgene: Honoraria; Lundbeck: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria. Louzada:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kotb:Karyopharm: Current equity holder in publicly-traded company; Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Merck: Honoraria, Research Funding; Sanofi: Research Funding. Reece:Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Amgen: Consultancy, Honoraria; Millenium: Research Funding; BMS: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding.

Improved Stem Cell Transplant Related Mortality for AL Amyloidosis At a Single Transplant Center

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2016-2016
Author(s):  
Zandra K. Klippel ◽  
Barry Storer ◽  
William I. Bensinger ◽  
Leona Holmberg ◽  
Pamela S Becker ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Risk Stratification ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Entire Cohort

Abstract Abstract 2016 The role of AHSCT in AL amyloidosis is controversial. There is evidence that AHSCT offers long term disease control with high organ response rates, however, the only randomized phase III trial comparing transplant with conventional melphalan and dexamethasone therapy deemed transplant inferior. Better understanding of risk stratification for SCT candidacy has resulted in TRM rates are as low as 5.6% in some series. The goal of the current study was to evaluate the TRM rate for all consecutive patients who have undergone AHSCT for AL amyloidosis at institution. Special attention in evaluation of any detectable differences in TRM over the time period of this review was a major goal of this project. Retrospective review was performed of all patients with primary AL amyloidosis who have undergone AHSCT at our institution. The database captured patients from December 2001 and our study includes patients through February 2012. Patients who were diagnosed with secondary amyloidosis by the stem cell transplant service and/or referring oncologist were excluded. TRM was defined as death from any cause within 100 days post stem cell infusion. We then evaluated data from the entire cohort and divided it into two different time periods: 2001–2006 and 2007–2012. Thirty-nine patients had an initial AHSCT during the study period. Nine patients were enrolled in the SWOG 0115 trial which comprised tandem autoSCT using 100 mg/m2 of melphalan conditioning 3–6 months apart. Of those, 6/9 (66%) had both transplants. For purposes of this abstract we report on the data resulting from first transplantation only for patients in the SWOG 0115 trial. The median age at transplant for the entire cohort was 57.6 years old (39–74). Males represent 64% of the patients. Most of the patients had symptomatic involvement of one organ (48.7%) with 23% having more than 2 organs involved. There were 14 patients transplanted in the 2001–2006 period and 25 patients in the 2007–2012 period. Overall TRM for 2001–2012 was 5.1%. During the 2001–2006 period TRM was 14% (2/14 patients). No TRM occurred for patients transplanted from 2007–2012. Overall survival (OS) improved when separately comparing the two study periods. Overall survival was 64% at 3 years in the 2001–2006 cohort and 92% at 3 years in the 2007–2012 cohort. Patients in the 2007–2012 cohort include all patients enrolled to SWOG 0115. Sixty percent of patients reported for that period received <200mg/m2 melphalan for transplant conditioning. Eight of nine patients enrolled in SWOG 0115 received 100 mg/m2, one received 140mg/m2. Six patients treated on our institution's standard amylodosis SCT protocol received 140mg/m2 conditioning. The remaining ten patients received 200mg/m2 melphalan. Patients in the 2007–2012 period were more likely to receive induction treatment prior to transplant with novel regimens (72% vs 21% p=0.003). In addition, these patients were more frequently diagnosed with amyloid cardiac involvement. For purposes of this abstract amyloid cardiac involvement is defined according to whether or not the SCT team concluded on the basis of history, physical examination and available ancillary data (including echocardiography) that the patient had amyloidotic cardiac disease (40% vs 14% p=0.15). All patients had echocardiography pre-AHSCT. The mean Inter Ventricular Septum (mIVS) thickness was 14.5 mm in the 2007–2012 period vs. 11.7 mm in the 2001–2006 one p=0.004. Univariate analysis of risk factors affecting improved OS identified year of transplant (>2006; p=0.03), number of treatments pre-transplant (>1; p=0.04), and time from diagnosis to transplant (>4mo; p=0.05) as factors associated with improved survival. Number of organs involved (>1; p=0.06) showed a trend towards worse survival. In conclusion, our single institution data demonstrates a reduction in TRM over the past 5 years. Reasons for improvement in TRM are under investigation and may include better risk stratification, better supportive care (including frequent hospitalization for cardiac monitoring in high-risk patients) and improvement in pre-AHSCT performance status for those patients receiving induction therapy with novel agents. Figure: Comparison of overall survival of patients with AL amyloidosis after autologous stem cell transplant based on year of transplant. Figure:. Comparison of overall survival of patients with AL amyloidosis after autologous stem cell transplant based on year of transplant. Disclosures: Holmberg: Millenium: Research Funding; Otsuka: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Sanofi: Research Funding.

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