A Phase 1/2, Open-Label, Prospective, Multicenter Study to Evaluate the Efficacy and Safety of the Lower Dose of Bortezomib Plus Busulfan and Melphalan As a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation: Result of Phase 1 Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1937-1937
Author(s):  
Jin Seok Kim ◽  
Chang Ki Min ◽  
Sung-Soo Yoon ◽  
Jae Hoon Lee
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Oral Mucositis ◽  
Phase 1 ◽  
Conditioning Regimen ◽  
Phase 1 Trial ◽  
Conditioning Regimens ◽  
Grade 3

Abstract Abstract 1937 Background: Despite the advantages of autologous stem cell transplantation (ASCT) over conventional chemotherapy, the results of ASCT in multiple myeloma (MM) are still unsatisfactory. Intravenous (iv) melphalan at a dose of 200 mg/m2 is the most commonly used conditioning regimen for ASCT. However, better conditioning regimens are still needed, and more intensive conditioning regimens have been investigated. We evaluated the role of bortezomib-containing regimen (escalated dose of bortezomib + iv busulfan and iv melphalan) in the MM patients who had a sensitive response to bortezomib during the induction chemotherapy. In the phase 1 trial, we assessed the MTD (maximum tolerated dose) of bortezomib. The trial is registered on National Cancer Institute website, number NCT01255527. Methods: Nine MM patients who were candidate for ASCT enrolled in this study. M:F=5:4 and median age were 59 (34–62). They were treated with escalating doses of bortezomib as a conditioning regimen (N=3/group; 0.7, 1.0, and 1.3 mg/m2 on D-6, D-3 & D+1) and a fixed dose of busulfan (3.2 mg/kg from D-5 to D-3) and melphalan (140 mg/m2 on D-2). Dose limiting toxicities (DLT) were defined as any toxicity of grade 3 or greater, with the following exceptions: vomiting, fatigue, alopecia, libido, amenorrhea, nausea, febrile neutropenia, infection, anorexia, depression, anxiety, and cytopenias. Grade 3/4 hematological toxicity was acceptable. Grade 4 of mucositis, °Ã Grade 3 diarrhea and °Ã Grade 3 cardiac toxicity were regarded as DLT. Only one patients had grade 3 oral mucositis and there were no other non hematologic toxicities of grade 3 or greater. DLT refers only to toxic events (symptomatic grade °Ã 3 toxicity) that occur until day +28 after ASCT and are attributed as possibly, probably, or definitely due to treatment. Results: Four patients had grade 3 oral mucositis (2 in 0.7 mg/m2 group, 1 in 1.0 mg/m2 group and 1 in 1.3 mg/m2 group), but no grade 4 (considered as DLT) oral mucositis. No other non hematologic toxicities of grade 3 or greater. Therefore, there were no dose limiting toxicities in this phase 1 trial and MTD of bortezomib was 1.3 mg/m2. Median times to ANC > 0.5 · 106/L and platelet > 20 · 106/L were 12 and 10 days, respectively, with no graft failures. All patients achieved at least very good partial response. Six patients (67%) achieved complete remission(CR) after ASCT. Conclusion: In the phase 1 trial, MTD of bortezomib was 1.3 mg/m2. Addition of bortezomib to busulfan and melphalan conditioning regimen shows to be safe, well-tolerated and worthy of phase 2 trial. Disclosures: No relevant conflicts of interest to declare.

High-dose lenalidomide and melphalan as conditioning for autologous stem cell transplantation in relapsed or refractory multiple myeloma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8021-8021
Author(s):  
Adriana C. Rossi ◽  
Jorge Monge ◽  
Ruben Niesvizky ◽  
Jing Mei Hsu ◽  
Tsiporah Shore ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Phase 1 ◽  
Conditioning Regimen ◽  
High Dose ◽  
Refractory Multiple Myeloma

8021 Background: Autologous stem cell transplantation (ASCT) remains a standard of care of eligible patients with multiple myeloma, despite the many novel therapies introduced over the past decade. High dose melphalan (HDM) is the only approved regimen to date. Lenalidomide (LEN) is an oral immunomodulatory drug which has become the backbone of myeloma therapy from induction through salvage and maintenance. Early studies noted a dose response relationship, and found myelosuppression to be the dose limiting toxicity. We previously reported on our phase 1 study of high dose lenalidomide (HDLEN) with HDM in conditioning for ASCT, where no DLT was noted up to 350mg PO daily of LEN. Here we report the phase 2 data of patients undergoing ASCT with combination conditioning regimen. Methods: 50 patients with relapsed/refractory multiple myeloma (RRMM) underwent ASCT using HDLEN+HDM conditioning. HDLEN was dosed at 350mg PO daily from day -5 to day -1 and HDM was dosed 100mg/m2 on days -2 and -1. TPatients were heavily pre-treated: 32% had prior HDM-ASCT, 96% had received prior lenalidomide, and 42% prior pomalidomide; 40% prior anti-CD38 mAB. Of note, 68% entered the study with progressive disease at time of enrollment. Results: Overall response rate was 96%, with 80% being ≥VGPR. Median progression free survival (PFS) was noted at 14.3 months, while overall survival (OS) was 68.2 months. PFS was similar when patients were stratified by prior ASCT, depth of response at enrollment, or presence of high risk FISH. Toxicities were mostly hematologic (100% neutropenia and thrombocytopenia, 90% anemia), GI (88% diarrhea, 72% nausea, 42% vomiting) and metabolic (30-96% derangement in electrolytes), and similar to historical controls receiving HDM alone. Second malignancies were noted in 2 patients. Conclusions: HDLEN/HDM is a well tolerated and effective conditioning regimen for ASCT in patients with RRMM. This regimen merits further investigation as ASCT is likely to remain an integral part of the treatment of RRMM patients, yet few advancements have been made to this modality. HDLEN may be particularly useful in patients with high risk disease and those progressing after multiple lines of therapy. HDLEN added little toxicity to HDM and SPMs were not more frequent than expected per SEER database for patients in this age range. Clinical trial information: NCT01054196. [Table: see text]

Phase 1 Trial Of Carfilzomib + High Dose Melphalan Conditioning Regimen Prior To Autologous Hematopoietic Stem Cell Transplantation (AHSCT) For Relapsed Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3329-3329 ◽  
Author(s):  
Luciano J Costa ◽  
Heather Landau ◽  
Jagadish K Venkata ◽  
Yubin Kang ◽  
Guenther Koehne ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Phase 1 ◽  
Conditioning Regimen ◽  
Phase 1 Study ◽  
Salvage Regimen ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Grade 3

Abstract Background The alkylating agent melphalan, given at the myeloablative dose of 200mg/m2 preceding autologous hematopoietic stem cell transplantation (AHSCT), is part of the upfront management of patients with multiple myeloma (MM) and has been used in the salvage setting, often as second transplant. Proteasome inhibitors (PI) have been shown in vitro to impair the fanconi/BRCA pathway of DNA repair and increase DNA fragmentation and apoptosis induced by alkylating agents in MM cells. We hypothesized that combining carfilzomib, a second generation PI, with melphalan would result in more effective anti myeloma activity. We herein performed a phase 1 study to identify the maximal tolerated dose (MTD) of carfilzomib when used in combination with myeloablative doses of melphalan as conditioning regimen for patients with relapsed MM and describe toxicity and preliminary activity profile for the combination. Methods Phase 1, multicentric, dose escalation trial with traditional 3+3 design. Eligible subjects had symptomatic MM, relapsed after at least one line of therapy, with evaluable disease and having obtained at least a minimal response (MR) after the most recent salvage regimen. Subjects were also required to have at least 2 x 106 CD34+ cells/kg in storage for transplant and additional 2 x 106 CD34+ cells/kg as “back up”. Treatment consisted of two doses of carfilzomib administered IV over 30 minutes on days -3 and -2. The day -2 dose was administered one hour prior to administration of melphalan200mg/m2. Carfilzomib dose consisted of 20(day-3)/27 (day -2) mg/m2 (cohort 0), 27/27 (cohort 1), 27/36 (cohort 2), 27/45 (cohort 3) and 27/56 mg/m2 (cohort 4). All subjects received pegfilgrastim 6 mg subcutaneously on day +1. Dose limiting toxicities (DLT, non-hematologic grade 4 and selected grade 3 toxicities) were evaluated during the first 30 days after transplantation. Disease response was assessed 100 days after transplantation. Results Enrolment of cohort 4 (last) is ongoing. Twelve subjects were accrued in cohorts 0-3 with no DLT being identified. Median age was 56 (range 45-68). Median number of prior lines of therapy was 3 (range 2-6) and 5 subjects had previously received AHSCT. There was no acute toxicity associated with carfilzomib infusion. Median CD34+ dose infused was 4.15 x 106/kg (range 2.21-9.34). Neutrophil engraftment occurred after a median of 11 days (range 8-15) and platelet engraftment after a median of 17.5 days (range 11-24). There were no non-hematologic grade 4 toxicities. The most frequent grade 3 toxicity was infection in 7/12 subjects consisting of 1 episode of pneumonia, 1 episode of bacteremia, 1 episode of urinary tract infection and 4 episodes of febrile neutropenia. Other grade 3 toxicities were rash (n=2), hypertension (n=1), hypophosphatemia (n=1) and hypocalcemia (n=1). Nine subjects, from cohorts 0, 1 and 2, have reached day +100 response assessment. Prior to transplant the responses to salvage regimen were MR in 1/9, partial response (PR) in 6/9, very good partial response (VGPR) in 1/9 and complete response (CR) in 1/9 subjects. At day +100 cumulative responses were PR in 3/9, VGPR in 3/9 and CR in 3/9 subjects. Pharmacodynamic studies in peripheral blood mononuclear cells revealed that carfilzomib precluded melphalan-induced increase in FANCD2 and FANCI mRNA. Conclusion Conditioning with carfilzomib and melphalan prior to AHSCT is well tolerated in patients with relapsed MM. Final results of this phase 1 study will be presented at the meeting. The MTD cohort (or cohort 4 if no MTD is found) will be subsequently expanded for better determination of this regimen’s activity. Disclosures: Costa: Onyx: Research Funding. Off Label Use: Carfilzomib in conditioning regimen for stem cell transplantation.

Bendamustine Plus Melphalan As Conditioning Regimen for Second Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: Single Centre Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2516-2516 ◽  
Author(s):  
Massimo Martino ◽  
Giuseppe Messina ◽  
Tiziana Moscato ◽  
Roberta Fedele ◽  
Giuseppe Console ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Median Time ◽  
Autologous Stem Cell Transplantation ◽  
Conflicts Of Interest ◽  
Phase 1 ◽  
Conditioning Regimen ◽  
First Line

Abstract Background: Bendamustine has a proved activity in hematological malignancies including both first line and relapsed multiple myeloma (MM). Moreover Bendamustine is generally well tolerated, with the majority of adverse events mainly limited to myelosuppression. Recently Mark et al published a phase I trial adding escalating doses of Bendamustine to the current standard conditioning of Melphalan 200 mg/m2 (HDM) in patients with MM at their first transplant. No transplant related mortality (TRM) was observed and the regimen was well tolerated. Recently was stated that double autologous stem cell transplantation (ASCT) improve the outcome of patients achieving a poor response after first ASCT. Although HDM is the standard for conditioning in MM, in some cases the CR rate is lower than expected. In this trial we evaluate feasibility and efficacy of the association of Bendamustine and Melphalan (BM) as conditioning regimen to second ASCT in patients with MM. Methods: This study was approved by local ethic committee.Between January and June 2014, 12 patients with MM underwent second ASCT following BM as conditioning regimen. The median age was of 56 years (range 40-66), 8 male and 4 female with a diagnosis of MM, stage IIIA (n=7), IIIB (n=4) and IIA (n=1). All patients received a bortezomib-containing regimen as first-line induction therapy and received Melphalan 200 mg/m2 as conditioning regimen before the first ASCT. All patients urderwent second ASCT following Bendamustine (100 mg/m2 days -4 and -3) and Melphalan (140 mg/m2 day -2) as conditioning regimen. G-CSF were given at day 5 after transplant. Results: A median number of 4.9x106/kg of CD34+ cells (range: 4-6.2) was infused. All patients engrafted, with median time to reach neutrophil>500/µl and platelet >20.000/µl of 12 days (range, 11 to 15) and 14 (range, 11 to 19), respectively. Overall, the BM regimen was well tolerated. Almost all patients experienced mucositis, nausea and diarrhea but all events were of grade 1 or 2 (grade 3 diarrhea occurred in only 1 patient). Four patients (33%) had fever (grade 1 or 2) that was clinically identified in 2 cases (pneumonia and cystitis). The median time of duration of fever was 4 days (range, 2-6). No TRM occurred after at least day + 90 after transplant. Overall, no added toxicity were observed between the first and second ASCT. At day + 90 after first and second transplant response rate was respectively: 1 CR, 10 VGPR, 1 PR and 4 CR, 5 VGPR, 1 PR, 2 too early. Three patients in VGPR after first transplant converted to CR after second ASCT. Conclusion: Bendamustine plus Melphalan is feasible as conditioning regimen for second ASCT in patients with MM. The regimen was well tolerated and the toxicity profile of ASCT with conditioning regimens BM or Melphalan is comparable. Longer follow-up is needed to evaluate conversion rate and survival. References: Mark TM et al. A phase 1 study of bendamustine and melphalan conditioning for autologous stem cell transplantation in multiple myeloma. Biol Blood Marrow Transplant. 2013 May;19(5):831-7. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prospective Analysis of Bortezomib, Fludarabine and Melphalan As Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation for Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1020-1020
Author(s):  
Phyllis McKiernan ◽  
David S Siegel ◽  
David H. Vesole ◽  
Tracy Andrews ◽  
Noa Biran ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Advisory Committees ◽  
Significant Difference ◽  
Grade 3

Abstract Background: Despite advances in novel myeloma treatments and autologous hematopoietic stem cell transplantation (ASCT), allogeneic HSCT (alloSCT) remains the only curative option for patients (pts) with multiple myeloma (MM). Questions remain as to the timing of alloSCT, toxicity risks and optimal conditioning regimen. The addition of bortezomib (Vel) to fludarabine (Flu) and melphalan (Mel) for conditioning prior to alloSCT is based on the demonstrated safety of Vel in combination with melphalan prior to ASCT, the synergistic effect of Vel with Mel, and the ability of Vel to selectively eliminate allo-reactive T-cells. Methods: We present a prospective Phase II study using Flu/Mel/Vel (FMV) as a conditioning regimen for alloSCT. The primary endpoint is overall survival (OS), and secondary endpoints include progression free survival (PFS), incidence of graft-versus-host disease (GVHD) and transplant related mortality (TRM). For related donors, the conditioning regimen was Flu 30 mg/m2 days -5, -4, -3, -2, Vel 1.6 mg/m2 days -4, -1, Mel 140 mg/m2 day -2. For unrelated donors, rabbit ATG 4 mg/kg was given in divided doses days -3, -2, -1. GVHD prophylaxis consisted of methotrexate and tacrolimus. We compared pts receiving FMV to historical controls of pts receiving FM at the same dose and schedule without Vel. We also compared pts receiving FMV to all pts with MM treated with alloSCT including all regimens and donor types. The response criteria from the IMWG and M-Smart criteria were used to determine response and risk, respectively. Chi-square tests of association and Wilcoxon rank sum tests were performed to test for differences across groups. OS/PFS probabilities were calculated using the Kaplan-Meier product limit estimator with log rank-tests. Multivariate Cox proportional hazard models examined factors associated with OS/PFS. Results: Of the 54 pts who received FMV, 35 (65%) were male and the median age was 56 years. Twenty-seven pts had an HLA matched sibling donor and 27 had an unrelated donor. At the time of alloSCT, 5 pts were in a CR, 27 in a VGPR, 13 in a PR, 9 had < PR. Twenty eight pts (52%) had high risk disease. Twenty-nine pts (53%) received alloSCT as salvage, defined as relapsed or refractory to ASCT, and 25 pts (46%) as consolidation after ASCT. OS was 42% at 10 years. While 32 pts developed aGVHD, only 2 had ≥ Grade 3. Of the 31 pts who developed cGVHD, 23 were graded as extensive. TRM was 5% at day 100, and 15% over 10 years. Pts in the control groups had similar baseline characteristics to the FMV group. The only significant difference was 47 pts (72%) who received FM were transplanted as salvage, and 18 (28%) as consolidation after ASCT (p=0.035). The total number of pts who did not receive FMV (non FMV) was 121, with 66 pts receiving FM. Compared to pts who received FMV, there was no difference in OS for pts who received FM or the non FMV group, 35% (p=0.55) and 48% (p=0.855) respectively. There was no difference in pts who developed aGVHD, however 9 pts (13%) had ≥ grade 3 aGVHD in the FM group (p=0.004) and 15 (12%) in the non FMV group (p=0.006). The cumulative incidence of cGVHD was similar with 51% for pts receiving FM and 60% for FMV pts (p=0.32). TRM was similar to pts who had received FMV; 18% for FM and 17% for non FMV. There were no differences between the 3 groups across disease risk, donor type, or disease status at the time of alloSCT. Multivariate analysis of the 3 groups, shows achieving a CR after alloSCT (p=0.0006) or having cGVHD (p=0.0004) predicts for improved OS, while severe aGVHD (p=0.0002) predicts for decreased OS. Discussion: While FMV was associated with a lower incidence of severe aGVHD, the addition of bortezomib to the FM backbone did not improve PFS or OS. Day 100 TRM was low for all regimens, and the addition of Vel did not impact overall TRM. For all 175 pts, those who achieve a CR after alloSCT had a significantly improved OS. This prompts the question of whether strategies should be employed post alloSCT to maximize response to a CR, and the role of achieving MRD negativity after alloSCT also needs to be elucidated. Figure Figure. Disclosures Siegel: BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Biran:Amgen: Consultancy, Speakers Bureau; BMS: Research Funding; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Skarbnik:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2684-2691 ◽  
Author(s):  
Sergio Giralt ◽  
William Bensinger ◽  
Mark Goodman ◽  
Donald Podoloff ◽  
Janet Eary ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Phase 1 ◽  
High Dose ◽  
Two Phase ◽  
Hematopoietic Stem

Abstract Holmium-166 1, 4, 7, 10-tetraazcyclododecane-1, 4, 7, 10-tetramethylenephosphonate (166Ho-DOTMP) is a radiotherapeutic that localizes specifically to the skeleton and can deliver high-dose radiation to the bone and bone marrow. In patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation two phase 1/2 dose-escalation studies of high-dose 166Ho-DOTMP plus melphalan were conducted. Patients received a 30 mCi (1.110 Gbq) tracer dose of 166Ho-DOTMP to assess skeletal uptake and to calculate a patient-specific therapeutic dose to deliver a nominal radiation dose of 20, 30, or 40 Gy to the bone marrow. A total of 83 patients received a therapeutic dose of 166Ho-DOTMP followed by autologous hematopoietic stem cell transplantation 6 to 10 days later. Of the patients, 81 had rapid and sustained hematologic recovery, and 2 died from infection before day 60. No grades 3 to 4 nonhematologic toxicities were reported within the first 60 days. There were 27 patients who experienced grades 2 to 3 hemorrhagic cystitis, only 1 of whom had received continuous bladder irrigation. There were 7 patients who experienced complications considered to be caused by severe thrombotic microangiopathy (TMA). No cases of severe TMA were reported in patients receiving in 166Ho-DOMTP doses lower than 30 Gy. Approximately 30% of patients experienced grades 2 to 4 renal toxicity, usually at doses targeting more than 40 Gy to the bone marrow. Complete remission was achieved in 29 (35%) of evaluable patients. With a minimum follow-up of 23 months, the median survival had not been reached and the median event-free survival was 22 months. 166Ho-DOTMP is a promising therapy for patients with multiple myeloma and merits further evaluation. (Blood. 2003;102:2684-2691)

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