Transplant Outcomes after Topotecan-Melphalan-Cyclophosphamide (TMC) Conditioning for Autologous Stem Cell Transplantation for Multiple Myeloma. Comparison to Melphalan 200 mg/M2 (MEL200).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1177-1177
Author(s):  
Michele Donato ◽  
Ana Aleman ◽  
Donna Weber ◽  
Michael Wang ◽  
Muzaffer Qazilbasch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Conditioning Regimen ◽  
Patient Characteristics ◽  
High Dose ◽  
Transplant Outcomes ◽  
Transplant Program ◽  
Preparative Regimen

Abstract Background: Topotecan at modest doses has activity in multiple myeloma (MM). The combination of high-dose topotecan, melphalan, and cyclophosphamide (TMC) has been used as a conditioning regimen for autologous SCT in patients with MM. We report the results of a phase II trial with this combination and perform a retrospective analysis comparing TMC to a standard preparative regimen of melphalan 200 mg/m2 (MEL200). Patients and Methods: Between 10/99 and 3/04, 55 patients with newly diagnosed MM were treated on a Phase II trial of topotecan 3.5 mg/m2 daily for 5 days in combination with cyclophoshamide 1 gm/m2 daily for 3 days, and melphalan 70 mg/m2 daily for 2 days followed by autologous SCT. Patient characteristics are summarized in table 1. In brief, median age was 55 (range, 37–67), median time to transplant was 6 months (range, 2-59); median B2M @diagnosis 3.3 (range, 1.4–17.2); 76% of patients had chemosensitive disease prior to transplant. Results: No treatment related deaths were observed, the regimen was well tolerated with grade 2 Bearman mucositis and diarrhea the most common toxicities, and no grade 3 or 4 toxicities observed. When compared to a group of patients who received MEL 200 the overall response rate was lower 75% vs 82% and a lower CR rate 11% vs 36%, but a similar median time to disease progression (14 m vs 13 m), with a trend towards a better 3 yr overall survival (87% vs 77%; p=.05) (Table 2 and Figure 1). Conclusion: TMC is a well tolerated conditioning regimen for myeloma, our results suggests that although no more effective than MEL200 as a single preparative regimen for MM, it warrants exploring as part of a tandem transplant program. Patient Characteristics TMC MEL200 N 55 157 Median Age (range) 55(37-67) 56(29-75) Median B2M @Dx 3.3 (1.4 - 17.2) 4 (0.5 - 49.8) % Abn Cytogenetics 15% 22% CR/PR @ SCT 4%/73% 10%/89% % 1ry Refractory 24% 27% Transplant Outcomes TMC MEL200 p ORR/CR conversion 75%/11% 82%/36% Non Relapse Mortality 0 2 Median OS NR 52 months .05 Figure Figure

Mycophenolate Mofetil (MMF) with or without Tracolimus (FK506) as a Second Line Treatment for Steroid-Resistant Acute Graft-Versus-Host Disease. The Experience of Saint Louis Hospital.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2892-2892
Author(s):  
Gustavo Fisher ◽  
Vanderson Rocha ◽  
Moema dos Santos ◽  
Agnes Devergie ◽  
Marie Robin ◽  
...  
Keyword(s):  
Median Time ◽  
Phase Ii ◽  
Acute Gvhd ◽  
Phase Ii Trial ◽  
Conditioning Regimen ◽  
High Dose ◽  
Line Treatment ◽  
Second Line ◽  
Steroid Resistant ◽  
Gvhd Prophylaxis

Abstract Acute GVHD remains a major problem following allogeneic HSCT. Use of steroids is the first line to treat aGVHD, with an overall improvement of 55%, but durable responses of 35%. Recently, results of a randomized trial testing ATG in patients non-responding to steroids have been disappointing. Drugs such as MMF or FK506 have been used as GVHD prophylaxis, but few data is available as a second line treatment of steroid-resistant aGVHD. We conducted a prospective phase II trial in our unit to test the role of MMF associated or not to FK506 in steroid-resistant aGVHD in 53 patients. Four criteria of steroid-resistant aGVHD were defined: A) no improvement of signs of skin GVHD after 1 week of treatment with prednisolone 2mg/kg; B) signs of skin progression or no response of visceral (gut or liver) GVHD 3 days after treatment; C) visceral signs of progression 2 days after treatment; D) progression to organ stage 4 (Gluksberg classification) 1 day after treatment. Response of signs of aGVHD to MMF (30 mg/kg day) or FK506 (0.05mg/kg/day) was defined as complete remission (CR) (all organs); partial remission (PR) or failure (progression even in one organ). HSCT were performed from 1999 to 2004 for patients with hematological malignancies (73%) or aplastic syndromes (27%). The median age was 29 y (5–58) (34% of children) and the median follow-up time was 24 mo (1–54). The donor was HLA identical in 23 (43%) and unrelated in 30 (57%) (including 18 cases of HLA mismatched). Myeloablative conditioning regimen was used in 77%. As GVHD prophylaxis CsA+MTX was used in 26 patients (68%), CsA alone in 14 (26%) and in 3 patients CsA+ steroids. Bone Marrow cells were used in 62% of the cases, PB in 25% and CB in 13%. Treatment of aGVHD consisted in prednisolone 2mg/kg IV in all patients associated to CsA. Once criteria of resistance were established, CsA was stopped and replaced by MMF and/or FK506. FK was not added if renal insufficiency was observed. Criteria of steroid-resistant aGVHD were A in 7 patients; B in 26; C in 19, and D in 1 patient. Steroid resistant acute GVHD grade I was observed in 9 patients (17%); II in 26 (49%); III in 19 (36%) and IV in 3 (6%). MMF was used in 15 patients (28%) and associated to FK506 in 38 (72%). Median time to start second line treatment was 16 days (7 to 100). Complete response in skin was observed in 74% of the patients, 66% in gut and 75% in liver. However, overall CR was observed in 21 patients (40%), partial response in 5 (9%) and failure in 27 (51%). Median time to obtain CR or PR was 8 days (2–20) after starting second line treatment. Cumulative incidence of CR at one year was 39%. Recipient’s age, CMV serology, source of stem cells, conditioning regimen, HLA incompatibility were not associated with CR; there was not statistical difference of CR if MMF was used alone or associated to FK. For those patients with aGVHD in progression, third line treatment consisted most frequently in the use of high dose steroids or ATG/ALG. Overall survival at 1y was 35±7%; it was 74±10% for patients achieving CR (n=21), 5±4% for non-responders (n=27) and 4 out of 5 patients with PR died. Cause of death was commonly associated to infections. In conclusion, in this phase II trial, use of MMF and/or FK506 is an option to treat steroid resistant GVHD but did not result in 1-y survival rate that would justify to set-up a larger randomized study.

A Randomized Phase II Trial of High-Dose Melphalan, Ascorbic Acid and Arsenic Trioxide with or without Bortezomib in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2309-2309
Author(s):  
Manish Sharma ◽  
Peter Thall ◽  
Xuemei Wang ◽  
Chitra Hosing ◽  
Floralyn L Mendoza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
High Dose ◽  
Randomized Phase Ii ◽  
Preparative Regimen ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Abstract 2309 Poster Board II-286 Background There is a role for novel preparative regimens in multiple myeloma to improve the outcome after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto HCT). Bortezomib is an active agent in newly diagnosed or relapsed multiple myeloma, and has synergistic activity with melphalan. We conducted a randomized phase II trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA) and melphalan. Methods auto HCT, with preparative regimen melphalan 100 mg/m2 IV on days -4 and -3, AA 1000 mg/day IV on days -9 to -3 and ATO 0.25 mg/kg IV on days -9 to -3. Patients were randomized to 3 arms; no bortezomib (arm 1), bortezomib 1 mg/m2 on days -9, -6 and -3(arm 2), and bortezomib 1.5 mg/m2 on days -9, -6 and -3 (arm 3). Primary endpoints were complete response (CR), NCI grade 4 toxicity, and overall survival (OS). Results In arms 1, 2 and 3, median intervals between diagnosis and auto HCT were 12.2, 9.6 and 8.8 months; median follow up in all surviving patients was 20 months (range 10 to 31). CR+near CR rates in arms 1, 2 and 3 were 35%, 30% and 25%. Grade 3–4 toxicity was seen in 6 patients in arm 1 (mucositis 3, dyspnea 1, acute renal failure 1, pleural effusion 1), 6 patients in arm 2 (mucositis 3, diarrhea 1, pneumonia 1 and hydronephrosis 1) and 6 patients in arm 3 (pulmonary edema 2, mucositis 1, intestinal obstruction 1, low back pain 1, elevated transaminases 1). The most common adverse events were nausea, diarrhea and pedal edema. Grade 1–2 weight gain due to fluid retention was seen in 84%, 70% and 95% of patients in arms 1, 2 and 3. Median time to neutrophil engraftment (ANC >500/dl) was 10 days in each arm. Median OS has not been reached in any of the 3 arms. Median progression-free survival (PFS) times were18.6, 13.2 and 17.5 months. OS was significantly shorter in patients with relapsed disease (0.00001) and cytogenetic abnormalities at auto HCT (0.0002). Conclusions Adding bortezomib to a preparative regimen of ATO, AA and high dose melphalan is safe and well tolerated in patients with multiple myeloma. There was no significant impact of adding bortezomib at either dose on the CR rate, grade 3-4 toxicity or OS. Disclosures: Shah: Celgene, Amgen, Novartis, Elan: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Qazilbash:Cephalon: Speakers Bureau.

scholarly journals A Single Autologous Stem Cell Transplant (ASCT) Followed By Two Years of Post-Transplant Therapy in Recently Diagnosed Elderly Multiple Myeloma (MM) Patients. Safety and Response Results from the Prospective Phase II Trial (NCT01849783)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2153-2153 ◽  
Author(s):  
Kalyan Nadiminti ◽  
Christopher Strouse ◽  
Praveen Vikas ◽  
Lindsay Dozeman ◽  
Allyson Schultz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Maintenance Therapy ◽  
Median Time ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Conditioning Regimen ◽  
Safety And Efficacy

Abstract Introduction : Melphalan 200mg/m2 has been the standard conditioning regimen for ASCT for multiple myeloma. Novel agents in combination with high dose melphan are being evaluated in clinical trials to improve outcomes. We previously reported results of early ASCT ( < 12 months from diagnosis) using VDT (Bortezomib, Thalidomide, Dexamethasone) plus Melphalan 200mg/m2 conditioning chemotherapy followed by combination maintenance therapy in younger MM patients (Age <65). This current prospective study evaluates the tolerance, safety and efficacy of early ASCT and maintenance therapy in MM patients who are ≥65 of age. Methods and patients: A total of 41 eligible patients with newly diagnosed multiple myeloma age ≥ 65 were prospectively enrolled in the IRB approved phase II trial beginning in June 2013. After an induction chemotherapy and stem cell collection, ASCT was performed with a preparative chemotherapy consisting of VDT-Melphalan 200mg/m2. The patients were considered to have high risk cytogenetics if they had 17p deletion, t(14;16), amp 1q, or t(4;14) by FISH on CD-138 sorted plasma cells. After engraftment and recovery, patients were started on maintenance therapy for 2 years. Planned regimen for the first year was a combination of VDT as 28 day cycles and year 2 therapy consisted of bortezomib, cyclophosphamide and dexamethasone( VCD) as 28 day cycles. Alternate regimens were used in case of toxicities. Primary end points include PFS, frequency of severe toxicities, ICU admissions, and percentage of patients able to complete the full course of maintenance. Responses were evaluated according to IMWG consensus criteria and adverse events were recorded according to CTCAE v 4.03. Results: 37 of the 41 patients enrolled received single ASCT between 2013 to 2016 of which 35 patients went to receive triple maintenance therapy and were included in this analysis. Median age was 68 (range: 65 to 75y). 12 (59%) and 15(40%) had standard risk and high risk cytogenetics by FISH, respectively. Median follow up was 27 months (3 months - 5 years). Major non-hematologic toxicities ≥ grade 3 were related to infections (25%), diarrhea (16%) and mucositis (11%). Median time to ANC and platelet engraftment was 11 and 17 days, respectively. There was one death within day 100 related to candida sepsis. Only 2 patients were re-hospitalized within 100 days but none required ICU admission. Median time to start post-transplant therapy was 73 days (range: 47 to 185 days). Best responses noted prior to initiation of maintenance were 17 sCR(47.2%), 3CR(8%), 10 VGPR(27%) and 6 PR(17%). 18 patients completed 2 years of maintenance therapy thus far and responses at the time of this analysis include sCR in 16 and CR in 2 patients. A total of 3 patients died during maintenance phase due to progressive disease. Median PFS and OS were not reached and 3 year PFS and OS were around 82 and 90%, respectively. Conclusions: This is the first trial to prospectively evaluate the safety and efficacy of early ASCT in elderly MM patients using a novel agent conditioning regimen followed by an intensive 2 year maintenance therapy. These results from the median follow up of 27 months indicate that the regimen is safe and tolerated without any increased mortality, and results in higher rates of deep and sustained responses. Major non hematologic toxicities included infections and GI related. No increased hospitalizations or ICU admissions were noted. Further follow up will determine the long term effects of the combination maintenance regimen, disease responses and survival in this group of elderly MM patients. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Impact of Holmium-DOTMP on Transplant Outcomes. Results of a Retrospective Single Institution Analysis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 426-426
Author(s):  
Anna Christoforidou ◽  
Patricia Williams ◽  
Linda Roden ◽  
Ana Aleman ◽  
Donna Weber ◽  
...  
Keyword(s):  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Patient Characteristics ◽  
Phase Iii ◽  
High Dose ◽  
Free Survival ◽  
Transplant Outcomes ◽  
Phase Iii Trials ◽  
Total Body ◽  
High Dose Melphalan

Abstract Background:166Holmium-DOTMP is a beta emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Phase I/II trials have shown feasibility and tolerability when combined with a standard conditioning regimen of melphalan with or without total-body irradiation (TBI) in pts with multiple myeloma (MM) undergoing autologous stem cell transplantation (SCT). Purpose: To define the potential impact of 166Holmium-DOTMP (HO) in combination with melphalan when compared to a standard conditioning regimen of melphalan 200 mg/m2 (M200) in MM patients undergoing auto SCT. Methods: We performed a retrospective review of transplant outcomes among patients with MM who received an auto SCT between 1/98-12/01 with either M200 or a melphalan-HO combination and were in a 1ry refractory or 1st remission consolidation state. Univariate analysis was performed for response, survival and event free survival. Results: 104 pts were identified. Patient characteristics are summarized in Table 1. In brief the HO group had a higher percentage of patients with IgA disease, otherwise there were no siginificant differences in prognostic factors among the groups. Transplant outcomes are summarized in Table 2. The HO group had a trend towards a higher conversion to CR rate (51% vs 32%) for all patients, (23% vs 12.5%) for 1ry refractory patients and similar OS rates and a higher NRM rate of 12% vs 3% when compared to MEL200. When the analysis was limited to patients receiving &lt;2400 mCi the HO group had a trend towards longer PFS (33 months vs 24 months) with no difference in NRM rates. The OS rate at 5 yrs was 54% for the HO group vs 43% for the MEL200 group, among the 21 patients in the HO group receiving &lt;2400 mCi the 5 yr OS was 61% (Figure 1). Conclusion: 166Holmium-DOTMP in combination with high dose melphalan can result in higher CR rates than melphalan 200 mg/m2 alone, when given in optimal doses (&lt;2400 mCi) the results seem to be superior and the toxicities are minimal. Targeted skeletal radiotherapy with 166Holmium-DOTMP in combination with melphalan 200 mg/m2 is safe and effective and should be further studied in Phase III trials in all patients with MM undergoing autologous SCT, based on these data other methods of targeted skeletal radiotherapy should also be pursued. Patient Characteristics HO &lt;2400 mCi HO ≥ 2400 mCi Melphalan 200 p MEL200 vs HO N 21 20 63 Median Age 52 (45–61) 53 (36–64) 55 (35–69) NS IgA Type 33% 40% 14% .03 Median B2M @ Dx 3.15 3.15 3.5 NS Durie Salmon III 43% 55% 67% NS Number with Δ13 0 0 3 NS CR/PR @ SCT 5%/57% 5%/70% 6%/68% NS 1ry Refractory 38% 25% 25% NS Transplant Outcomes HO &lt;2400 mCi HO ≥ 2400 mCi MEL200 MEL 200 vs HO ORR/CR conversion 95%/55% 90%/48% 92%/32% NS/.06 NRM 5% 20% 3% .07 Median OS NR 31 months 52 months NS Median EFS 30 months 23 months 19 months .3

Weekly bortezomib in the treatment of patients (pts) with previously treated multiple myeloma: A phase II trial of the Minnie Pearl Cancer Research Network

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7547-7547 ◽  
Author(s):  
F. A. Greco ◽  
D. R. Spigel ◽  
J. H. Barton ◽  
C. Farley ◽  
M. T. Schreeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Research Network ◽  
High Dose ◽  
Weekly Schedule ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Previously Treated ◽  
Grade 3

7547 Background: Bortezomib, administered on a twice-weekly schedule, is now a standard part of treatment for patients with multiple myeloma. Weekly bortezomib schedules have shown activity in other cancer types, and are more convenient than twice weekly schedules. In this multicenter, community-based phase II trial, we evaluate the feasibility, toxicity, and efficacy of weekly bortezomib in pts with previously treated multiple myeloma. Methods: Eligibility criteria included a diagnosis of multiple myeloma treated with 1 or 2 previous systemic regimens (only 1 if first-line therapy included high-dose therapy); ECOG PS 0–2; creatinine < 2.0 mg/dL; WBC ≥ 3000/μL; ANC > 1000/μL; platelets ≥ 50,000/μL; no peripheral neuropathy > grade 1; informed consent. All pts received bortezomib 1.6mg/m2 IV on days 1, 8, 15, and 22 of each 5-week cycle. Pts were reevaluated at 10-week intervals; treatment continued for 8 cycles (40 weeks) or until myeloma progression. Results: Between 5/04 and 12/05, 37 pts entered this trial. Pt characteristics: median age 70 years; male/female, 20/17; 24 pts (65%) had received 2 previous regimens (previous high dose therapy, 2 pts); elevated β-2 microglobulin, 27 pts (73%). Of 26 pts evaluated, 13 pts (50%) had major responses, 11 pts (42%) stable disease, and 2 pts (8%) had progression. After a median follow-up of 7 months, projected median PFS is 9.6 months; overall survival at 1 year is 81%. Weekly bortezomib was well tolerated by most pts. Grade 3/4 toxicities included fatigue (21%), diarrhea (11%), neutropenia (7%), thrombocytopenia (4%), all others < 5%. No grade 3/4 neuropathy occurred. Only 1 pt required bortezomib dose reduction during treatment, and 2 pts discontinued treatment because of toxicity (myelosuppression, 1; fatigue/dehydration, 1). Conclusions: Weekly bortezomib is a convenient, well tolerated treatment for pts with previously treated multiple myeloma. Overall response rates with this schedule are similar to those previously reported with the standard twice-weekly schedule. Further followup is necessary to better evaluate the duration of response and the incidence of cumulative toxicities. [Table: see text]

Beneficial Prophylactic Antimicrobial Use Against Infectious Complications during Autologous Stem Cell Transplantation: A Result of Randomized Phase II Study in Multiple Myeloma and Non-Hodgkin’s Lymphoma Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5477-5477 ◽  
Author(s):  
Shin Kim ◽  
Yang Hee Cho ◽  
Ock Bae Ko ◽  
Ja Eun Koo ◽  
Danbi Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Median Time ◽  
Phase Ii ◽  
High Dose Chemotherapy ◽  
Control Group ◽  
High Dose ◽  
Prophylaxis Group ◽  
Randomized Phase Ii

Abstract The benefit of using prophylactic antimicrobials in autologous stem cell transplantation (ASCT) is controversial. A prospective randomized phase II comparison study was therefore performed to assess the benefit of prophylactic antimicrobials. Forty consecutive patients with multiple myeloma (MM, 28 patients) or non-Hodgkin’s lymphoma (NHL, 12 patients) were enrolled. After stratification by disease, patients were randomly allocated into control group with no prophylactic antimicrobials (19 patients) or prophylaxis group receiving prophylactic antimicrobials (21 patients) just before the administration of high-dose chemotherapy. Prophylactic antimicrobials comprised domly allocated into apyylactic lacticiprofloxacin 500 mg po bid, fluconazole 100 mg po bid and acyclovir 200 mg po tid; started one day before high-dose chemotherapy initiation and stopped when absolute neutrophil count reached 500/mm3 after nadir or infection occurred. High-dose chemotherapy was high-dose melphalan for MM and BEAM for NHL. Lenograstim 5 μg/kg/day was given from day 1 of ASCT. At least one episode of fever was present in 15/19 (79%) patients in control group much more frequent than 12/21 (57%) patients in prophylaxis group but with no statistically significance (p=0.13) probably due to small sample size of current study. Microbiologically or clinically documented infections occurred in 4 patients (21%) from control group and in no patient from prophylaxis group, with statistically significant difference (p=0.04). Documented infections of patients from control group included 3 staphylococcal bacteremias (1 methycillin-sensitive Staphylococcus aureus, 1 Staphylococcus epidermidis, 1 Methycillin-resistant coagulase-negative staphylococcus) and 1 herpes skin infection. No death, invasive fungal infection, or serious adverse events occurred in either group. The median duration of fever (12 days in control group and16 days in prophylaxis group), therapeutic antimicrobial therapy (9 days in control group and 11 days in prophylaxis group), and hospital stay after ASCT (19 days in both groups) were not different between groups. Median time to neutrophil engraftment was 10 days and median time to platelet engraftment was 11 days in both groups. In conclusion, this small-sized randomized phase II comparison shows that use of prophylactic antimicrobials as current study diminishes microbiologically or clinically documented infection during ASCT significantly.

Bortezomib in Combination with Pegylated Liposomal Doxorubicin and Thalidomide (VDT), An Effective Steroid Independent Regimen for Previously Untreated Multiple Myeloma Patients: Final Result of a Phase II Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 618-618
Author(s):  
Taimur Sher ◽  
Kena C Miller ◽  
Sikander Ailawadhi ◽  
Debbie Manfredi ◽  
Margaret Wood ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Phase Ii Study ◽  
Pegylated Liposomal Doxorubicin ◽  
High Dose ◽  
Advisory Committees ◽  
Significant Toxicity ◽  
Grade 3

Abstract Abstract 618 Introduction: Steroids have been an important component of multiple myeloma (MM) therapeutics. High doses steroids as used in MM are associated with significant toxicity and morbidity. Development of steroid independent or steroid-lite regimens remains an important area of investigation in MM. Orlowski et al combined Doxil (D) with bortezomib (V) and showed enhanced anti-myeloma activity. In a phase II study in relapsed refractory MM patients, we observed further improvement in clinical efficacy with addition of thalidomide (T) to VD combination (VDT regimen). Encouraged by high response rates of this steroid sparing novel combination we investigated VDT regimen in treatment naïve MM patients. Final results of this phase II trial are reported here. Methods: Patients with previously untreated MM were eligible for this phase II trial. VDT regimen (V 1.3mg/m2 on days 1, 4,15,18; D 20mg/m2 on days 1,15 and T 200 mg daily continuously) given on a 4-week cycle for a maximum of 8 cycles. Acyclovir (400 mg BID) and weight adjusted low-dose warfarin (1 or 2mg for absolute body weight <70kg or ≥70kg, respectively) was given for prophylaxis of herpes zoster and deep vein thrombosis (DVT), respectively. Response was assessed using the modified Blade criteria. Results: Forty patients (26 males, 14 females; median age 60.5, range 40-80 yrs) were enrolled on this study. Among these 58%(n=23) had stage III (Durie-Salmon) disease with a median b2 microglobulin of 3.7 (range 1.6-16.5 mg/L) and median LDH of 443 (range 152-129 IU/L). Thirty-nine patients are eligible for response evaluation (1 too early for assessment). Overall response rate (CR/nCR+PR) was 79.4% (n=31) with 38% (n=15) patients achieving CR/nCR. The median progression free (PFS) and overall survival (OS) has not been reached. At 1 year the PFS and OS is 81% and 97%, respectively (1 patient died from disease progression to leukemic phase). Toxicity: Neutropenia was the most significant hematological toxicity with grade 3 and 4 neutropenia observed in 22.5% and 2.5% of the patients, respectively. Only 1 (2.2%) patient had febrile neutropenia. Clinically significant neuropathy (grade ≥2) was seen in 20% while grade ≥2 palmer planter erythrodysesthesia was seen in 15% (n=6) of the patients. Other grade 3 non-hematological toxicities included pneumonia (20%), pleural effusion (10%), pulmonary embolism (2%), DVT (2%), congestive heart failure (5%) and interstitial pneumonitis (2%). Conclusion Although effective, steroid based treatment regimen can be associated with significant toxicity especially among patients with concurrent co morbid conditions such as hypertension and diabetes mellitus. Furthermore, recent investigations demonstrate that decreasing steroid doses may actually improve PFS and OS despite a comparatively low initial ORR. In this clinical trial we hypothesized that rational combination of novel myeloma agents may actually preclude the need to rely on high-dose steroids without significantly compromising ORR. Consistent with our expectations, the VDT regimen has ORR comparable to some of the steroid-inclusive triple drug combinations. The toxicity profile of this combination was acceptable and the regimen was well tolerated. Thus we note that VDT is an effective and well tolerated steroid-independent induction regimen for MM patients. Disclosures: Off Label Use: A Phase II study of a novel combination in newly diagnosed myeloma patients. Miller:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Czuczman:Centocor Ortho Biotech: Research Funding. Sood:Celgene: Stock. Chanan-Khan:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Intravenous (i.v.) busulfan (Bu) plus melphalan (Mel) is a well-tolerated preparative regimen for stem cell transplantation (SCT) in patients (pts) with advanced lymphoid malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6548-6548
Author(s):  
P. Kebriaei ◽  
T. Madden ◽  
N. Thapar ◽  
E. Shpall ◽  
C. Hosing ◽  
...  
Keyword(s):  
Conditioning Regimen ◽  
Test Dose ◽  
Patient Characteristics ◽  
High Dose Chemotherapy ◽  
Fixed Dose ◽  
High Dose ◽  
Lymphoid Malignancies ◽  
Gvhd Prophylaxis ◽  
Preparative Regimen ◽  
Low Toxicity

6548 Background: High dose chemotherapy and SCT is an accepted treatment option for pts with relapsed lymphoid malignancies. However, relapse remains a significant problem. A double alkylating regimen of Bu and Mel has been suggested as an effective and myeloablative pre-transplant conditioning regimen. Historically, oral Bu was used and the combination resulted in considerable mucositis and VOD. An i.v. formulation of Bu has been developed that has less pharmacokinetic variability. We are investigating i.v. Bu-Mel in pts with lymphoid malignancies undergoing auto- or allo-SCT. Patients and Methods: The conditioning regimen consists of i.v. Bu 130 mg/m2 over 3 hr daily for 4 days, either as a fixed dose per BSA, or to target an average daily AUC of 5,000 μMol-min ± 12% determined by a test dose of i.v. Bu at 32 mg/m2 given 48 hours prior to the high dose regimen. After the 4 daily Bu doses, there is a rest day, followed by 2 daily doses of Mel at 70mg/m2. Stem cells are infused the following day. Dilantin is given for seizure prophylaxis. GVHD prophylaxis is tacrolimus and methotrexate for pts receiving allo-SCT. Results: Patient characteristics, engraftment, and regimen-related toxicities are listed below: Grade I or II mucositis was the most common regimen-related toxicity. There were no cases of VOD; reversible hyperbilirubinemia was observed in 3 pts receiving allo-SCT. No grade IV toxicity was noted, and there were no regimen-related deaths with longest follow-up of 10 months. All allo-SCT pts had 100% donor chimerism by day 30. 27 pts had i.v. Bu delivered per test dose guidance; 6 pts received fixed dose Bu at 130 mg/m2. The median daily systemic Bu exposure was 4867 μMol-min. Conclusion: Intravenous Bu-Mel is well tolerated, and enables prompt neutrophil and platelet engraftment. Individualized PK-directed dosing of i.v. Bu is feasible, and likely contributes to the low toxicity profile of this regimen. Longer time is needed to assess disease control. [Table: see text] No significant financial relationships to disclose.

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