scholarly journals A Phase 2 Multi-Center, Open Label Study of Isatuximab Added to Standard Cybord Induction and Lenalidomide Maintenance Treatments in Newly Diagnosed, Transplant Eligible Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4767-4767
Author(s):  
Rami Kotb ◽  
Engin Gul ◽  
Donna E. Reece
Keyword(s):  
Stem Cell ◽  
Sample Size ◽  
Research Funding ◽  
Response Rate ◽  
Autologous Stem Cell Transplant ◽  
Induction Treatment ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
High Dose Melphalan

Abstract Background: Despite recent improvements, myeloma is still incurable. There is need to add new therapeutic tools. For young and fit patients, the current standard first-line therapy is a proteasome inhibitor (PI) containing induction, followed by stem cell collection, high dose Melphalan and autologous stem cell transplantation, followed by maintenance lenalidomide therapy in Canada. The anti-CD38 antibodies showed interesting activity in myeloma, and significant synergism with PI and IMiD based regimens. This CMRG-008 trial is designed to explore the benefit of adding Isatuximab to the current Canadian standard of care (CyBorD induction/Autologous SCT/Maintenance Len) in a single arm phase II trial. Design and Methods: Phase II study. Transplant eligible newly diagnosed myeloma patients (TE-NDMM) will receive Isatuximab added to four cycles of standard induction CyBorD chemotherapy (Cyclophosphamide 300 mg/m 2 PO, Bortezomib 1.5 mg/m 2 SC, and Dex 40 mg PO, all given on days 1, 8, 15 and 22 of 28-day cycles; Isatuximab 10 mg/kg IV days 1, 8, 15 and 22 of cycle 1; days 1 and 15 of cycles 2-4). After the completion of the induction treatment, subjects achieving at least stable disease will receive stem cell mobilization, collection of hematopoietic stem cells, high dose melphalan chemotherapy, and autologous stem cell transplantation. Maintenance treatment will start at 100 days (+/- 7 days) after the transplantation date (and to be continued until disease progression). The maintenance treatment will consist of Isatuximab administered in combination with Lenalidomide in 28-day cycles (Lenalidomide: 10 mg daily on days 1-21 of every cycle; Isatuximab: 10 mg/kg IV on days days 1, 8, 15 and 22 of cycle 1; days 1 & 15 of cycles 2-3; then day 1 of each subsequent cycle). The objectives: To evaluate the benefit of adding Isatuximab to CyBorD (induction = Isa + CyBorD) and Lenalidomide (maintenance = Isa + Lenalidomide) in transplant-eligible myeloma patients. Primary Endpoint: To determine the response rate (VGPR or better) defined by IMWG criteria at 100 days (+/- 7 days) after the autologous stem cell transplant (ASCT). Secondary Endpoints: A) To determine the response rate (VGPR or better) after induction treatment (before ASCT), and at 12 months, 24 months and 36 months. B) To evaluate additional efficacy outcomes including progression free survival (PFS), and overall survival (OS), time to response and duration of response. C) To confirm the feasibility, safety and tolerability of adding Isatuximab to CyBorD and to maintenance lenalidomide in transplant-eligible newly diagnosed myeloma patients. D) To determine the feasibility of autologous stem cell collection after Isa + CyBorD induction treatment. The key inclusion criteria are having a TE-NDMM with a measurable disease; adequate performance status; and adequate organ functions. The key exclusion criteria include previous exposure to anti-CD38 therapy, intolerance to CyBorD, adverse cardiac history, pulmonary disease, central nervous system disease, congenital or acquired immune suppression, and other concurrent severe or uncontrolled medical conditions. Statistics and Sample Size: Considering that the response rate (VGPR or better) after CyBorD induction therapy, high dose chemotherapy and autologous SCT is about 70-78%; and assuming a response rate (VGPR or better) to Isa-CyBorD induction and autologous stem cell transplant at 100 +/- 7 days of 88%; a sample size of 65 evaluable subjects will allow estimating the 95% confidence interval with a precision of +/- 7.9%. For the assumed rate and sample size, the lower bound of the confidence interval will be estimated to be larger than 80%. Assuming a 10% drop out rate, a total study size of 72 patients will be considered. This study is expected to open to recruitment in the third quarter of 2021. Clinicaltrials.gov #: NCT04786028. Disclosures Kotb: Janssen: Honoraria; Merck: Honoraria, Research Funding; Amgen: Honoraria; Akcea: Honoraria; Celgene: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company. Reece: BMS: Honoraria, Research Funding; GSK: Honoraria; Karyopharm: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Millennium: Research Funding; Sanofi: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

Response-Adapted Therapy for Newly Diagnosed Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3606-3606
Author(s):  
Frederic J. Reu ◽  
Tomas Radivoyevitch ◽  
Jason Valent ◽  
Chad Cummings ◽  
Katherine Tullio ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Research Funding ◽  
Response Rate ◽  
Response Assessment ◽  
Second Primary ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Minor Response ◽  
High Dose Melphalan

Abstract Background: Before SWOG S0777 (Durie BGM at al. ASH 2015, abstract #25) it was not clear whether standard upfront regimens VRd (bortezomib, lenalidomide, dexamethasone) or Rd (lenalidomide, dexamethasone) yield different survival outcomes for newly diagnosed myeloma patients (pts.) but it was known that the higher response rate of VRd comes at a higher risk for severe peripheral neuropathy. Since no test predicts who requires the more toxic regimen to avoid adverse myeloma effects we designed a carepath that tailors therapy according to early response endpoints. Methods: Newly diagnosed symptomatic MM patients (pts) with measurable disease who were not eligible for or elected against a clinical trial were advised to begin a 2-drug regimen of lenalidomide (R) and weekly dexamethasone (d) or, if cast nephropathy suspected or R copay too high, bortezomib (V) and dexamethasone (D). Depending on response assessment per IMWG 2011 criteria after each cycle, treatment intensity was to be increased with sequential addition of agents (R or V, cyclophosphamide, and then liposomal doxorubicin) when there was not at least minor response (MR) after the first, or at least partial response (PR) after the second cycle of an administered combination. Once PR was reached, pts. were evaluated for high dose melphalan (HDM) and ASCT or consolidation with their induction regimen followed in either case by lenalidomide or bortezomib maintenance. After IRB approval, pts treated on carepath were identified through our registry and electronic medical records were reviewed. Results: From Oct 2012 to Dec 2015 the carepath was used in 91 pts. Their median age at treatment start was 64 years (34-84), 40 (44%) were ≥ 65, 11 (12%) ≥ 75 years old; at least one cytogenetic risk study (MyPRS®, FISH panel, karyotype analysis) was obtained in 81 (89%) and of them 23 (28.4%) had high risk features (MyPRS® score > 45.2, del17p, 1q amp, t4;14, t;14;16 and non-hyperdiploid karyotype abnormalities), 33 (36%) had ISS stage III and 21 (23%) had serum creatinine ≥ 2mg/dL, 6 (7%) were on dialysis. At median follow up of 20.5 months (1.7-44.6), at least PR was achieved in 84 pts (92%), at least very good partial remission (VGPR) in 63 (69%), with negative immunofixation in blood and urine in 24 (26%) and complete remission (CR) documented by bone marrow exam in 6 (7%). Only one pt (1%) had progressive disease as best response, stable disease and MR were seen in 3 pts. (3%) each. Induction required 2, 3, 4 and 5 drugs in 49 (54%), 33 (36%), 8 (9%), 1 (1%) pts, respectively, and was followed by high dose melphalan and autologous stem cell transplant in 19 (21%). Sixty-three pts. (69%) remain on carepath treatment without progression, while 28 (31%) have experienced progression with skeletal events in 4 (4%) and ARF in 2 pts. (2%). Nine pts. (10%) have died, 4 while in remission of whom 3 suffered a bleed while anticoagulated for DVT or pre-existing A-fib and died 1 after transition to hospice; the remaining 5 died after progression, of infection (3), secondary plasma cell leukemia (1), or after transition to hospice (2). No patient developed shingles or second primary malignancies so far; mild peripheral neuropathy (PNP) occurred in 27 pts (30%), severe or painful PNP in 4 (4%) and 8 pts. (9%) suffered venous thromboembolism (9%) on DVT prophylaxis with aspirin. Conclusions: Carepath therapy required only two drugs during induction in over 50% of patients to achieve an overall response rate of 92% with ≥ VGPR in 69% in a real-world setting without exclusion of patients on dialysis. Reduction in costs and side effects compared to upfront use of VRd for everyone were accompanied by promising early Kaplan-Meier estimates for progression-free and overall survival (Fig. 1) supporting the carepath principle and future randomized comparison of response-adapted therapy to fixed regimens like the new SWOG S0777 defined standard triplet VRd. Disclosures Reu: Novartis: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Signal Genetics: Consultancy. Valent:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Faiman:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Takeda: Consultancy. Hamilton:Takeda: Speakers Bureau. Smith:Celgene: Honoraria; Spectrum: Honoraria; Genentech: Honoraria; Abbvie: Research Funding.

scholarly journals Addition of Bortezomib to High Dose Melphalan As Conditioning Regimen for Autologous Stem Cell Transplantation Improves the Response Rate in Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4647-4647 ◽  
Author(s):  
Benedetta Dalla Palma ◽  
Lucia Prezioso ◽  
Fabrizio Accardi ◽  
Stefano Bisbano ◽  
Federica De Luca ◽  
...  
Keyword(s):  
Stem Cell ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rate ◽  
Conditioning Regimen ◽  
Median Number ◽  
High Dose ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
High Dose Melphalan

Abstract High-dose Melphalan (HDM) is the most commonly used conditioning regimen for autologous stem cell transplantation (ASCT) in newly diagnosed transplant-eligible Multiple Myeloma (MM) patients. Recent evidence suggests that the depth of response after induction therapy influences progression free survival (PFS) and, in most studies, overall survival (OS). Actually the effect of the inclusion of new drugs in the conditioning regimen for ASCT is still unknown. Phase I-II clinical study showed that the addition of Bortezomib (Bor) to HDM is safe and a promising conditioning regimen. Thus, in this study we analyzed a single center experience on the use of Bor in combination with HDM (Bor-HDM) as conditioning regimen before ASCT as frontline treatment in MM patients in order to evaluate the safety and the response rates of this combination regimen. We analyzed a total cohort of 48 newly diagnosed MM patients (25 females and 23 males; median age 60 years, range 42-70) admitted consecutively to our Bone Marrow Transplantation Center from 2008 to 2014. Regarding prognostic stratification, 25% of patients were classified as stage III according to International Staging System (ISS), and 12% exhibited high-risk cytogenetic features (defined by presence of del(17p) and/or t(4;14) and/or t(14;16)). All patients with the exception of three underwent to 3-drugs Bor-based induction therapy including Bor (median cumulative dose: 28.9 mg/m2), Thalidomide and Dexamethasone (VTD). After induction therapy and stem cell collection 28 out of 48 patients were treated with Bor-HDM, whereas 20 patients with HDM alone as conditioning regimen before ASCT. HDM was administered on day -2 (median dose: 200 mg/m2), and a single-dose Bortezomib at the dosage of 1.3 mg/m2 was administered on day -1 in the Bor-HDM group. Stem cells were reinfused on day 0 (median number of CD34+ infused: 3.3x106/Kg, range 1.86-6x106/Kg). Responses were evaluated at day 100 after ASCT, and definitions of response were used according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for MM. Quantitative variables were compared by non-parametric Kruskal-Wallis and Mann-Whitney tests as appropriate and categorical variables were analyzed by Chi-square and Fisher's exact test. pvalue of <0.05 was considered significant. Any significant difference was not observed between Bor-HDM group vs HDM group, regarding age at diagnosis (p=0.77), sex (p=0.24), cumulative induction dose of Bortezomib (p=0.42), dose of Melphalan used for conditioning (p=0.16) and the median number of CD34+ cells infused (p=0.12). Distribution of ISS stage was similar in the two groups (p=0.14), as well as that of high-risk cytogenetic (p=0.14). Moreover the response rates after the induction therapy was not statistically different in the two groups of patients analyzed (sCR + CR: 19% in Bor-HDM group vs 26% in HDM group; VGPR: 33% vs 48%; PR: 48% vs 26%, p=0.22). Any significant difference on hematopoietic recovery rates was not observed in Bor-HDM as compared to HDM alone with a mean time to neutrophil recovery of 12 days (range 9-18) and to platelet recovery of 12 days (range 9-21) in both groups. Bor-HDM conditioning was well tolerated, without increase of neuropathy occurrence. Then we analyzed the response rate after ASCT, showing that the overall response rate (ORR) was significantly higher in Bor-HDM group as compared to HDM (sCR+CR: 56% in Bor-HDM vs 17% in HDM; VGPR 30% vs 28%; PR: 15% vs 56%, p=0.0072) with a higher number of "good quality" response (sCR + CR + VGPR: 86% vs 45%; p=0.0075). The number of sCR was also significantly higher in Bor-HDM as compared to HDM alone (23% vs 0%, p=0.067). Moreover an improvement of the response rate after ABMT was seen more frequently in the Bor-HDM group as compared to the HDM group (p=0.0063). We then observed that the number of patients that underwent tandem ASCT was higher in the HDM group (66% vs 41%), even not reaching a statistical significance. In conclusion, this retrospective analysis suggests that BOR-HDM is safe as conditioning regimen with a higher response rate after ASCT as compared to the standard HDM regimen giving the rational design for randomized studies needed to assess whether this conditioning regimen is superior to HDM alone. Disclosures Giuliani: Celgene: Research Funding; Janssen: Research Funding.

scholarly journals Utilization of Autologous Stem Cell Transplantation in Older Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5701-5701
Author(s):  
Justin King ◽  
Mark A. Fiala ◽  
Scott R. Goldsmith ◽  
Keith E. Stockerl-Goldstein ◽  
Mark A. Schroeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Older Patients ◽  
Research Funding ◽  
Small Sample ◽  
Poor Performance Status ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Equity Ownership

Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

Phase II Study of Combination of the Hypercvad Regimen with Dasatinib in the Front Line Therapy of Patients with Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 837-837 ◽  
Author(s):  
Farhad Ravandi ◽  
Hagop M. Kantarjian ◽  
Deborah A. Thomas ◽  
Stefan Faderl ◽  
Dan Jones ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Allogeneic Stem Cell Transplant ◽  
Median Response ◽  
Platelet Recovery

Abstract Abstract 837 Background: Combination therapy with cytotoxic chemotherapy and tyrosine kinase inhibitors has improved the outcome for patients with Ph+ ALL with durable remissions in some patients even without an allogeneic stem cell transplant. The dual Src and Abl inhibitor dasatinib has ∼325 times more potent in vitro kinase inhibition than imatinib against BCR-ABL with significant clinical activity in patients with imatinib-resistant lymphoid blast phase CML (CML-LB) and Ph+ ALL. Aim: To determine the efficacy and safety of combining chemotherapy with dasatinib for treating patients with Ph+ ALL. Methods: In this phase II trial, patients with newly diagnosed Ph+ ALL receive dasatinib 50 mg po bid (or 100 mg daily) for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Patients in CR continue to receive maintenance dasatinib 50 mg po bid (or 100 mg daily) and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. Results: We have enrolled in the study 34 patients with untreated Ph+ ALL and 7 patients with 1 prior cycle of chemotherapy (before Ph+/BCR-ABL+ status was known). Patients younger than 50 years old have received a median of 6 cycles (range 2-8) and patients 50 years and older have received a median of 6 cycles (range 1-8). 20 patients are receiving maintenance in CR and two have completed the entire treatment regimen. Median age is 51 years (range 21 – 79); 22 patients were older than 50 years, Median WBC at diagnosis was 13.6 × 109/L (range, 1-276 × 109/L). 12 patients had CNS involvement at presentation. All patients are evaluable for assessment of response to induction; 39 (95%) achieved CR after first cycle or were CR at start. Two patients died before response assessment from infections. Thirty-one of 39 (79%) evaluable patients achieved cytogenetic (CG) CR after 1 cycle; 4 had a major CG response (3 had 5% and one had 15% Ph+), 2 had insufficient metaphases, and 2 are unknown (no CG exam on day 21 marrow). To date, 22 patients (56%) have achieved complete molecular remission (CMR) and another 8 (21%) have achieved a major (but not complete) molecular response (MMR) at a median of 14 weeks from initiation of treatment (range 2 – 59 weeks). Minimal residual disease assessment by flow cytometry is negative in 35 (90%) patients at a median of 3 weeks (range, 2-18 weeks). The median time to neutrophil and platelet recovery for cycle 1 is 18 and 23 days and for subsequent cycles is 15 and 20 days. Grade 3 and 4 adverse events have included bleeding (GI, GU, soft tissue and subdural hematomas)(18), pleural effusions (9), pericardial effusion (1), reversible rise in creatinine (10), deep vein thromboses (6), pulmonary emboli (3), as well as diarrhea, infections, hypophosphatemia, hypokalemia, hypocalcemia, hyperglycemia, and elevated transaminases. With a median follow up of 13 months (range 1-33), 29 patients (71%) are alive and 27 (66%) are in CR; 4 patients died in CR; 1 from an unrelated cardiac event and 3 from infections. Three patients have undergone an allogeneic stem cell transplant. The median disease free survival is 48+ weeks (range,1 to 140+) and the median overall survival is 52+ weeks (range, 3 to 143+). Eight patients have relapsed with a median response duration of 51 weeks (range 23-73) and 6 of them have died. In 5 patients morphological relapse was preceded by flow and molecular relapse. Five relapsed patients had ABL mutations (3 T315I, 1 F359V, and 1 V299L). Conclusion: Combination of chemotherapy with dasatinib is effective in achieving long term remissions in patients with newly diagnosed Ph+ ALL. Disclosures: Ravandi: Bristol Myers Squibb: Honoraria, Research Funding. Kantarjian:Bristol Myers Squibb: Research Funding. Wierda:Genzyme: Research Funding; Genentech: Consultancy, Honoraria. Cortes:Bristol Myers Squibb: Research Funding. O'Brien:Bristol Myers Squibb: Research Funding.

Outcome of High Dose Melphalan with Autologous Hematopoietic Stem Cell Transplant In Myeloma Associated with AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2400-2400
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
High Dose Melphalan

Abstract Abstract 2400 Background: Approximately 10% of patients with multiple myeloma (MM) have clinically overt primary systemic light-chain (AL) amyloidosis, and about 30% have concurrent occult AL amyloidosis. The impact of concurrent AL amyloidosis on the prognosis of myeloma is not well known. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) has shown significant activity in both MM and AL amyloidosis. Methods: We performed a retrospective analysis of patients who had concurrent MM and AL amyloidosis and underwent auto HSCT with high dose Melphalan at MDACC between 01/1998 to 05/2010. We identified 41 patients with concurrent MM and AL amyloidosis. Patient characteristics are summarized in Table 1. Twenty -six patients had occult AL amyloid, while 15 had clinically overt disease. Results: Median age at auto HSCT was 56 years (39-77), 58.5% being male with median follow up of 58.7 months from the time of diagnosis and 42.5 months from auto HCT. The median time from diagnosis to auto HCT was 8.9 mos (2.7-102.4 mos). 39% had Salmon Durie Stage III disease and 36.6% had more than one involved site at the time of transplant.Cytogenetic abnormalities were detected in 24.4% of patients. Post transplant hematologic responses were as follows: ≥CR=10 (24%), ≥VGPR=16 (39%), >PR=33 (80.5%), ≥stable disease= 40 (97.6%). Among the patients with overt organ involvement, one had early death. Of the 15 evaluable patients, organ responses were scored using the published consensus guidelines for amyloidosis and were as follows: PR=5 (33.3%), ≥SD=7 (46.7%). No correlation was seen between organ response and hematologic response. The 100-day treatment related mortality (TRM) was 0 and 1-year TRM of 2.4% which is comparable to patients transplanted for MM alone at our center. The median progression-free (PFS) and overall survival (OS) from auto HCT were 33.8 and 58.3 months, respectively.The median PFS and OS from diagnosis were 49.8 and 96 mos, respectively. In multivariate analysis, creatinine ≥ 2mg/dl was associated with a shorter PFS (p=0.043) and hemoglobin <10g/dl showed a trend towards a shorter PFS (p=0.093). None of these variables (Hb <10g/dl, Age>60yrs, Creatinine≥2mg/dl, B2M >3.5mg/l, BM plasma cells>30%) emerged as significant predictors of OS. There was no significant difference in outcome between patients with occult or symptomatic AL amyloidosis for OS (p=0.24) or PFS (P=0.9) Conclusion: In this analysis the outcome of patients with concurrent MM and AL amyloidosis was comparable to patients with MM alone. We believe these patients are acceptable candidates for auto HCT. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Weber: novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Orlowski: Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.

scholarly journals Bortezomib Maintenance Therapy after Induction with R-CHOP, ARA-C and Autologous Stem Cell Transplantation in Newly Diagnosed MCL Patients, Results of a Multicenter Phase II HOVON Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 339-339 ◽  
Author(s):  
Jeanette K Doorduijn ◽  
Monique C. Minnema ◽  
Marie Jose Kersten ◽  
Pieternella J Lugtenburg ◽  
Martin R. Schipperus ◽  
...  
Keyword(s):  
Stem Cell ◽  
Maintenance Therapy ◽  
Phase Ii ◽  
Research Funding ◽  
Progressive Disease ◽  
Induction Treatment ◽  
High Dose ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Introduction. The standard first-line treatment of young and fit mantle cell lymphoma (MCL) patients consists of a rituximab containing induction of CHOP and high dose ARA-C, followed by high dose consolidation and autologous stem cell transplant (ASCT). Thus far, almost all patients relapse after ASCT. Bortezomib is a proteasome inhibitor with activity in MCL. We investigated in a randomized phase II study whether there was any indication that maintenance therapy with bortezomib after ASCT could improve the outcome of treatment, measured as event free survival (EFS). Methods. Patients 18-65 years with newly diagnosed MCL were treated with 3 cycles of R-CHOP and 2 cycles of ARA-C (2 x 2 g/m2 iv d1-4) and rituximab (375 mg/m2, iv d11). Patients in PR or CR continued with ASCT after BEAM conditioning. Patients with a PR or CR after ASCT, with a neutrophil count > 0.5 x 109/l and platelets > 80 x 109/l were randomized between bortezomib and no further treatment. Bortezomib 1.3 mg/m2 iv was given once every two weeks, for 2 years, starting between 6 - 12 weeks after transplantation. Results . Between October 2007 and February 2012, 140 patients aged 34-66 years (median 57) were registered. Five patients were not eligible. The MIPI score was low, intermediate, high or unknown in 57%, 32%, 10% and 1% respectively. All eligible patients started induction treatment with R-CHOP. Two patients did not receive the first ARA-C cycle, because of progressive disease and physician decision. Hundred-fifteen patients (85%) received the BEAM and ASCT. Reasons to stop protocol treatment before ASCT were: progressive disease (PD) (n=6), inadequate stem cell harvest (n=3), excessive toxicity (n=3), other reasons (n=8). The response after ASCT was CR/CRu in 99 patients (86%), PR in 15 (13%), unknown in 1 (1%). Only 62 patients (45%), aged 34-65 years (median 56) were randomized between bortezomib maintenance and no further treatment. Two patients were randomized, but not eligible. Reasons for no randomization were: not eligible (n=30), patient refusal (n=14), excessive toxicity (n=2, and other reasons (n=7). In each treatment arm 30 patients were included. The patient characteristics were well balanced, except the MIPI score. In the no maintenance arm 21 patients (70%) had a low MIPI, compared to 15 patients (50%) in the bortezomib arm, and 6 (20%) versus 11 (37%) patients had an intermediate MIPI score. In both arms 3 patients (10%) had a high MIPI. Fifteen patients (50%) in the maintenance group continued bortezomib for 2 years. Reasons to stop earlier were excessive toxicity (n=6), PD/relapse (n=4), patients refusal (n=3) and other (n=2). The main adverse events during maintenance therapy were neurologic (CTC grade 2: 14%, grade 3: 4%), and infectious (grade 2: 11%, grade 3: 7%). Three patients developed a secondary malignancy: a basal cell carcinoma in the no maintenance group, a melanoma and a prostate carcinoma in the bortezomib group. With a median follow-up of the patients still alive of 50.9 months EFS at 4 years for all patients is 61%, and the overall survival (OS) 78%. The median follow-up of the randomized patients still alive is 42.9 months. The EFS at 4 years is 72% without maintenance versus 71% in the patients randomized for bortezomib maintenance. The OS at 4 years also shows no significant difference between the groups, 90% versus 93% respectively. Conclusion. There is no indication that bortezomib iv maintenance in a frequency of once every 2 weeks does improve the EFS of newly diagnosed MCL patients after intensive induction treatment with R-CHOP, double ARA-C and BEAM followed by ASCT. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Doorduijn: Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Off Label Use: bortezomib maintenance in MCL. Minnema:Celgene: Consultancy; Jansen Cilag: Consultancy; Amgen: Consultancy. Kersten:janssen: Honoraria, Research Funding; takeda millennium: Research Funding; roche: Honoraria, Research Funding. Lugtenburg:Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Celgene: Consultancy; Roche: Consultancy. Schipperus:Novartis: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy.

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