scholarly journals Impact of Obesity in Patients with Multiple Myeloma Receiving High-Dose Melphalan Followed By Autologous Hematopoietic Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4636-4636
Author(s):  
Justina Ofori Frimpong ◽  
Rebecca Tombleson ◽  
Melissa Alsina ◽  
Jamie Shapiro ◽  
Jongphil Kim ◽  
...  
Keyword(s):  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Hospital Length ◽  
Hospital Length Of Stay ◽  
High Dose ◽  
Obese Patients ◽  
Severely Obese ◽  
Grade 3 ◽  
Autologous Hct ◽  
High Dose Melphalan

Abstract Background: Chemotherapy administration to obese patients poses significant challenges due to the potential for augmented toxicities. There are limited guidelines and literature available on the dosing of high-dose therapy followed by autologous hematopoietic cell transplantation (HCT) in obese patients and dosing practices vary widely. We conducted a single-center, retrospective cohort study to compare outcomes and toxicities after high-dose melphalan followed by autologous HCT among non-obese (body mass index [BMI] < 30 kg/m2), obese (BMI 30-34.9 kg/m2), and severely obese (BMI ≥ 35 kg/m2) multiple myeloma patients. Patients and Methods: A total of 462 consecutive patients transplanted between January 2004 and December 2011 were included. Patients who had received a tandem transplant and those with the diagnosis of amyloidosis were excluded. The primary endpoint of the study was to compare the incidence of non-relapse mortality (NRM) and overall survival (OS) rates across all three cohorts. Secondary endpoints included progression-free survival (PFS), incidence of relapse, hospital length of stay, hospital readmission rates, engraftment and grade 3 and 4 non-hematologic toxicities. Results: All three cohorts had similar baseline characteristics except for age ≤ 65 years (yrs) (severely obese 85.3%, obese 66.7%, non-obese 63%; p = 0.001), and the use of adjusted body weight for melphalan dosing (severely obese 41.2%, obese 25.7%, non-obese 4.5%; p < 0.0001). Across all three cohorts, there were no significant differences in NRM, relapse/progression, OS, PFS, engraftment, response to transplant, hospital length of stay, 30-day readmission rates, grade 3 to 4 nausea, vomiting, enteritis, or renal toxicity. In univariate analyses, Durie-Salmon Stage (DSS) 3 was the only independent predictor of inferior OS. DSS 3 and ≥ 2 lines of therapy were significant predictors of inferior PFS. In a multivariate analysis, DSS 3 (hazard ratio [HR] 2.28, 95% confidence interval [CI]: 1.01-5.13, p = 0.05), age > 65 yrs (HR 2.13, 95%CI: 1.19-3.82, p = 0.01), serum creatinine (Cr) ≥ 1 mg/dL were associated with higher NRM, whereas actual weight (AW) dosing was associated with decreased risk of NRM (HR 0.38, 95%CI: 0.19-0.72, p = 0.003). Additionally, age ≤ 65 yrs (HR 1.32, 95%CI: 1.03-1.71, p = 0.03), baseline serum Cr ≤ 1.5 mg/dL were associated with increased risk of relapse/progression, whereas disease status ≥ partial response prior to HCT (HR 0.71, 95%CI: 0.54-0.94, p = 0.02) and BMI ≥ 35 kg/m2 (HR 0.62, 95%CI: 0.44-0.87, p = 0.01) were associated with decreased risk of relapse/progression. In a subgroup analysis evaluating only patients with AW dosing of melphalan, febrile neutropenia was more common in non-obese patients compared to obese and severely obese patients (71.4% versus 56.4% and 62.5%, respectively; p = 0.03). Conclusions: High-dose melphalan and autologous HCT can be performed safely in obese myeloma patients and BMI of ≥ 30 kg/m2 does not appear to be associated with adverse transplant outcomes. Further analysis is needed to evaluate the effect of dose adjustments on outcomes. Disclosures Alsina: Onyx: Speakers Bureau; Millenium Pharmaceuticals: Research Funding; Novartis: Research Funding; Signal Genetics: Consultancy; Onyx: Consultancy. Nishihori:Signal Genetics: Research Funding; Novartis: Research Funding.

A Phase 2 Study of High-Dose Melphalan Plus Bortezomib (Mel/Vel) Conditioning Followed By Autologous Hematopoietic Cell Transplantation in Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3987-3987
Author(s):  
Taiga Nishihori ◽  
Jose L Ochoa-Bayona ◽  
Rachid Baz ◽  
Kenneth H. Shain ◽  
Christine Simonelli ◽  
...  
Keyword(s):  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Autologous Hct ◽  
High Dose Melphalan ◽  
Autologous Hematopoietic Cell Transplantation

Abstract Background: High-dose melphalan followed by autologous hematopoietic cell transplantation (HCT) remains the integral component of multiple myeloma (MM) therapy in the era of novel agents. We published our prior study with the use of high-dose melphalan + bortezomib (Mel/Vel) conditioning regimen for tandem transplants in refractory MM patients (Nishihori, et al. Br J Haematol 2012). We designed a phase 2 trial using MelVel conditioning followed by autologous HCT in patients with newly diagnosed chemosensitive MM (NCT 00948922). Methods: Sixty seven newly diagnosed MM patients who achieved ≥ partial response (PR) to induction therapy with ≤grade 1 peripheral neuropathy (PN) were enrolled from 12/2009 to 06/2014. Patients received high-dose melphalan at 100 mg/m2 IV for 2 days, immediately followed by 1 dose of bortezomib at 1.3 mg/m2 (Mel/Vel conditioning). Maintenance therapy was not prescribed by design. The protocol later was modified to include maintenance bortezomib subcutaneously (started at 3 months after HCT) at 1.3 mg/m2 weekly x4, every 8 weeks, for a total of 6 cycles. Progression-free and overall survival (PFS and OS) estimates were calculated using Kaplan-Meier method. Results: A total of 67 patients received autologous HCT. The median age was 58 (25 - 73) years with the following disease characteristics: Durie-Salmon stage, 3A (72%) and 3B (10%); IgG (55%), IgA (21%), IgD (1%), and light chain (22%). High-risk cytogenetics/FISH were seen in 28% of patients. The median beta-2 microglobulin was 3.3 (range, 1.3 – 34.8). Induction regimens were bortezomib-based in 39%, lenalidomide-based in 19% and, both bortezomib and lenalidomide in 42%. Median time from initiation of induction to HCT was 204 days (range, 101 - 664). Responses prior to HCT were stringent CR (sCR) 21%, CR 12%, very good partial response (VGPR) 34%, and PR 33%. Neutrophil engraftment was achieved after a median of 11 days (range, 10 – 14) and platelet engraftment occurred after a median of 15 days (range, 11 – 22). Median CD34 cell dose was 3.8 x 106/kg (range, 2 – 20.08). Responses at 3 months after HCT (in 64 evaluable patients) were sCR 47%, CR 14%, VGPR 20%, PR 16% and progressive disease 3%. Bortezomib maintenance was prescribed to 31 patients (46%). Prevalence of grade 1 PN before (n=67) and at 3 months (n=64) after HCT were 37% and 38%, respectively. Two patients withdrew consent to initiate maintenance and 1 patient was unable to initiate maintenance due to grade 1 PN (baseline PN of 0). At the time of review, a median number of maintenance delivered was 4 (range, 1-6) and only one patient required dose reduction. The 2-year PFS and OS estimates are 62% (95% CI 0.47 – 0.75) and 90% (95% CI 0.80 – 0.97) with a median follow-up of 21 months (range, 2 – 54). The 1-year PFS estimates were 85% (95% CI 0.65 – 0.97) for bortezomib maintenance vs. 81% (95% CI 0.66 – 0.92) for no maintenance (p=0.6). There were no significant differences in PFS or OS stratified by cytogenetic/FISH risk status. There was no transplant related mortality. Conclusions: The combination of bortezomib and high-dose melphalan (Mel/Vel) as conditioning regimen for autologous HCT is well tolerated and appears to improve responses after HCT. Weekly x4 post HCT bortezomib maintenance given every 8 weeks appears to be well tolerated and is a promising strategy for eligible patients. Longer follow up is required to assess the benefit of post HCT maintenance strategy. Disclosures Baz: Millennium: Research Funding. Alsina:Millennium: Consultancy, Research Funding.

A Phase 2 Study of Bortezomib Plus High-Dose Melphalan (Mel/Vel) Conditioning for Autologous Hematopoietic Cell Transplantation In Multiple Myeloma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4158-4158 ◽  
Author(s):  
Taiga Nishihori ◽  
Leonel Ochoa ◽  
Joseph Pidala ◽  
Kenneth H. Shain ◽  
Rachid Baz ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Autologous Hct ◽  
One Year ◽  
High Dose Melphalan

Abstract Abstract 4158 Background: High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) is a preferred primary treatment approach for those patients who have adequate organ function and performance status. We previously reported the use of melphalan + bortezomib conditioning regimen for tandem transplants in a different group of patients with refractory myeloma (Alekshun, et al. ASH 2007). In this study, we examine the effects of adding bortezomib to standard high-dose melphalan in patients with newly diagnosed myeloma who have chemosensitive disease. Methods: Thirty five newly diagnosed multiple myeloma patients with responsive disease (partial response (PR) or better) to induction therapy were enrolled to the study from January 2010 to June 2011. Patients received high-dose melphalan conditioning at 100 mg/m2 IV for 2 days, immediately followed by 1 dose of bortezomib at 1.3 mg/m2 (Mel/Vel). Those patients who achieved PR post induction were considered for tandem autologous transplant with Mel/Vel conditioning. Results: To date, 35 patients received autologous HCT conditioned with Mel/Vel, and 32 are evaluable for response. Median age is 56 years (range, 25 – 72) with the following disease characteristics: IgG (n=21), IgA (n=8), IgD (n=1), light chain (n=5). High-risk cytogenetics/FISH were seen in 13 patients (37%). Median beta-2 microglobulin was 3.5 (range, 1.3 – 34.8). Sixteen patients received bortezomib-based induction, 9 patients received lenalidomide-based therapy and 10 received both bortezomib and lenalidomide. Median time from initiation of induction to transplant was 221 days (range, 134 – 664). Responses to induction therapy were stringent CR (n=10), CR (n=4), very good partial response (VGPR) (n=13), and PR (n=8). Median CD34 cell dose is 4.86 × 106/kg (range, 2 – 20.08). Neutrophil engraftment was achieved after a median of 11 days (range, 10 – 14) and platelet engraftment occurred after a median of 16 days (range, 11 – 19). Two patients received tandem HCT. Best responses post transplant were sCR (n=19), CR (n=3), VGPR (n=7), PR (n=1) and progressive disease (n=2). The one year progression-free survival (PFS) estimate is 77% (95% CI 0.59 – 0.95) and one year overall survival (OS) estimate is 96% (95% CI 0.88 – 1.00) with a median follow-up of 279 days (range, 47 – 515). We did not detect significant differences in OS (p=0.69) stratified by cytogenetic/FISH risk status. Conclusions: The combination of bortezomib and high-dose melphalan (Mel/Vel) as conditioning regimen for autologous HCT is well tolerated and appears to improve responses post transplant. This early result is encouraging and the regimen will be examined in expanded cohort of patients. Disclosures: Baz: Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding.

scholarly journals Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2154-2154
Author(s):  
Noa Biran ◽  
Shijia Zhang ◽  
Scott D. Rowley ◽  
David H. Vesole ◽  
Michele L. Donato ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Conditioning Regimen ◽  
High Dose ◽  
Advisory Committees ◽  
Common Grade ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Background: A regimen of escalating doses of thalidomide, in combination with bortezomib and high dose melphalan (Mel/Vel/Thal) was evaluated as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM) in a phase I/II study. Methods: Patients received Mel/Vel/Thal as a second of tandem ASCT if they achieved <CR to their first ASCT (tandem), or as conditioning for a salvage ASCT (salvage). Exclusion criteria were dose-intense therapy within 56 days, uncontrolled infections, severe organ dysfunction, Karnofsky score <70%, or painful grade 2 or greater peripheral neuropathy. Conditioning consisted of Vel 1.6 mg/m2 intravenously on days -4 and -1 with Mel 200 mg/m2 on day -2. Thal was given on days -5 through -1 and was administered in a planned step-wise dose escalation of 600, 800 and 1000 mg (in cohorts of 3 pts). Dexamethasone (Dex) 10-20 mg was given prior to Vel and Mel. All pts received G-CSF every other day starting day +3 until engraftment. Serious adverse events (SAEs) were graded according to CTCAE version 3. Results: Twenty-nine pts were enrolled: 9 in the phase 1 dose-escalation phase and an additional 20 pts in phase 2. In the phase I portion, all pts experienced somnolence, with grade 3 occurring in 1 pt at the 800 mg/day dose. Subsequently, Dex 40 mg was given with first dose of Thal at the 1000 mg level with decreased severity of somnolence. No dose limiting toxicities defined as ≥ grade 4 non-hematological SAEs occurred in the phase I portion, allowing full dose escalation with 9 pts enrolled. The maximum tolerated dose for Thal was not reached and the 1000 mg dose was chosen for the phase 2 dose expansion. No regimen related mortality occurred in either phase I or phase II portion of the study. All SAEs except lethargy and dizziness occurred after ASCT and were not attributed to Thal. The most common grade 1 and 2 non-hematologic toxicities included nausea (65.5%), mucositis (51.7%), diarrhea (48.3%), somnolence (48.3%), lethargy (27.6%), and vomiting (17.2%). The most common grade 3 non-hematologic adverse events (AEs) were neutropenic fever (58.6%), mucositis (6.9%), and somnolence (13.8%), which increased risk of falls. SAEs included somnolence (13.8%), tumor lysis syndrome (3.4%), and engraftment syndrome (3.4%). All transplant-related SAEs resolved by day +28 after ASCT. All pts achieved prompt hematological recovery with the median time to ANC >500/uL 10 days (range, 8-14 days), and platelet >20,000 12 days (range 9-26 days). All pts received at least one ASCT prior to enrolling on the study. Seventeen pts (59%) had interim salvage chemotherapy between their upfront and Mel/Vel/Thal ASCT (i.e. received a salvage ASCT), with median time from first to salvage ASCT 29 months. The remaining 12 (41%) went directly from an upfront ASCT Mel-based ASCT to the Mel/Vel/Thal ASCT (tandem ASCT) within 6 months of the first ASCT. Twenty-seven (93%) were Durie-Salmon stage III, and 13 (44%) had >2 prior lines of therapy. Of those who had Mel/Vel/Thal as a salvage ASCT, 70% had ≥3 prior lines of therapy. The overall response rate (ORR) was 69% with 38% complete remission. ORR for Mel/Vel/Thal compared to upfront Mel ASCT was 69% versus 62% with 11 patients achieving CR with Mel/Vel/Thal compared to 5 patients with Mel alone (Figure 1). Ten of 27 evaluable patients (37%) had an upgrade in response in the Mel/Vel/Thal salvage ASCT compared to their upfront ASCT: 2 pts (7%) went from PD to PR, 1 (4%) from SD to CR, 1 (4%) from PR to VGPR; 3 (11%) from PR to CR and 2 (7%) from VGPR to CR. Median PFS and OS were 9.3 and 65.4 months, respectively, with a median follow-up of 17.8 months. Of those who underwent tandem Mel followed by Mel/Vel/Thal ASCT the median PFS was 14.9 months with a median OS not yet reached at time of analysis. For the 17 patients who received a salvage Mel/Vel/Thal ASCT, median PFS from their upfront ASCT was 11.9 months, compared to 9.1 months with the salvage Mel/Vel/Thal ASCT. Conclusions: High-dose Thal up to 1000 mg daily for 5 days can be safely combined with Vel and dose-intense Mel as an ASCT conditioning regimen with acceptable toxicities. Confirmation of potential synergistic effects of this combination regimen will require an appropriately designed phase III study. Figure 1 Figure 1. Disclosures Biran: BMS: Research Funding; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Siegel:Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Cryotherapy Reduces Mucositis in Multiple Myeloma Patients Receiving High-Dose Melphalan Conditioning Prior to Autologous Stem Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4265-4265 ◽  
Author(s):  
Mabel Rodriguez ◽  
Nelly G. Adel ◽  
Sean Devlin ◽  
Sergio A Giralt ◽  
Heather Landau
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Research Funding ◽  
High Dose ◽  
Cell Transplant ◽  
Grade 3 ◽  
High Dose Melphalan ◽  
Hospital Days ◽  
Severe Mucositis

Abstract Abstract 4265 Background: High-dose melphalan (MEL) followed by autologous stem cell support has been an integral component of multiple myeloma (MM) therapy since the 1980's. In general, high-dose melphalan is well-tolerated however grade 3 and 4 mucositis has been reported in up to 75% of patients (Lilleby et al. Bone Marrow Transpl, 2006). The efficacy of cryotherapy in preventing mucositis was initially documented in patients receiving infusional 5- fluorouracil (Rubenstein et al. Cancer, 2004). It is presumed that vasoconstriction reduces exposure of the oral mucosa to chemotherapy. Due to similar pharmacokinetic properties of melphalan including its short half life, cryotherapy has been used in MM patients undergoing MEL and stem cell transplant (SCT) with small series and one randomized trial supporting its use (Lilleby et al. Bone Marrow Transpl, 2006). At Memorial Sloan-Kettering Cancer Center, ice chips administered for 30 minutes before, during and after melphalan administration was adopted in March 2011 for all MM patients receiving MEL (≥ 140 mg/m2). In this study we sought to determine if the incidence of mucositis has been reduced since instituting cryotherapy into our standard practice. Methods: We retrospectively identified MM patients who received MEL 140 or 200 mg/m2 prior to SCT between January 1, 2009 and June 12, 2012 using our pharmacy database and electronic medical record. We analyzed two groups of patients by date of SCT and confirmed that patients transplanted prior to 3/2011 did not receive cryotherapy while all others did. Mucositis grade was recorded as documented by medical staff or determined by the investigators using the CTCAE version 4 criteria. Disease and treatment characteristics were collected in addition to narcotic use, total parenteral nutrition (TPN) requirement, and days of hospitalization. Fisher's exact test was used to compare the proportion of patients with mucositis, severe mucositis (defined as grade 3 or higher) and those requiring patient controlled analgesia (PCA), by cryotherapy use. Logistic regression was used to adjust for prior radiation and the number of prior lines of therapy. The number of hospital days was compared using a t-test. Results: During the study period, 214 patients underwent one or more autologous SCTs for MM; for patients who had more than one, only the initial SCT was included in this analysis. Of 214 patients, 85 (40%) received cryotherapy of whom 34% developed mucositis compared to 47% who did not receive cryotherapy (P = 0.08). Grade 3 mucositis was seen in 2% and 16% of patients who did and did not receive cryotherapy respectively (P = 0.004). No patient in either group developed grade 4 mucositis. After adjusting for radiation and lines of prior therapy the association between grade 3 mucositis and cryotherapy remained significant (OR: 0.13 (0.02, 0.47); P = 0.01). PCA use was lower in patients who received cryotherapy (19%) compared to those who did not (37%) (P = 0.01), with the median duration of use being 5 days in both groups. TPN was not required for any patient. Hospital days were similar in both groups (P = 0.88). Conclusion: Cryotherapy administration at the time of high-dose melphalan reduces the incidence of severe mucositis and PCA use. Cryotherapy is readily available and should be offered to all MM patients receiving ≥ 140 mg/m2 of melphalan. Disclosures: Landau: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.

scholarly journals Phase I/II Study of Lenalidomide and High Dose Melphalan As Preparative Regimen in Autologous Transplant in Myeloma: Report of Phase II Efficacy and Safety Data

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3193-3193 ◽  
Author(s):  
Attaya Suvannasankha ◽  
Sherif Farag ◽  
Rebecca Silbermann ◽  
Mary Cangany ◽  
Anita Rush-Taylor ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
High Dose ◽  
Disease Response ◽  
Preparative Regimen ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Background: High-dose melphalan and autologous hematopoietic stem cell transplantat (auto-HCT) is a standard consolidation therapy for eligible multiple myeloma (MM) patients due to superior survival outcome as compared to chemotherapy alone. However, patients remain at continuous risk of disease relapse following auto-HCT. Lenalidomide is active in newly diagnosed and relapsed MM and has synergistic activity with melphalan, but has not previously been incorporated into preparative regimen for auto-HCT. While high dose lenalidomide induces myelosuppression, the anti-tumor activity of lenalidomide is dose-dependent. Methods: We conducted a single center, phase I/II study of lenalidomide and melphalan in patients with MM undergoing auto-HCT. The phase I portion included MM patients at all disease stages, including patients undergoing auto-SCT as salvage therapy. The phase II portion enrolled patients undergoing a first auto-SCT after achieving at least stable disease following their induction regimen. Phase I objectives included determination of side effect profile and recommended phase II dose (RP2D). Phase II objectives were disease response at day +100 and toxicity. Treatment: All patients received a standard melphalan dose of 200 mg/m2 (100 mg/m2 IV days -1 and -2). Phase I lenalidomide dose was escalated from 50 mg, 75mg, 100 mg, and 150 mg and administered orally daily from days -7 to +2. Phase I data were previously reported (Blood (ASH Annual Meeting Abstracts), Nov 2012; 120: 3146). Thirteen patients were treated and no MTD was reached. The RP2D lenalidomide dose (150 mg orally daily days -7 to +2) was further explored in the phase II portion of this study. Post-transplant lenalidomide maintenance therapy was started between days +100 and +120 in all responders. We now report the planned interim analysis of the efficacy and safety profile of the phase II study. Results: From 5/1/12 to 7/9/15, forty seven subjects were enrolled to the phase II portion of the study. Study accrual is complete. We report below on the 37 patients with at least 100 days follow-up (median duration of follow-up of 12 months). 36 patients were assessable for response. Responses are as followed: stringent CR 8 (22%), CR 3 (8%), VGPR 20 (54%), PR 3 (8%), progressive disease 2 (5%). Among responders, 34 were able to start maintenance lenalidomide on days +100 to +110 (two withdrew from the study to pursue tandem stem cell transplant). To date, 21 patients remain on the treatment. Of 13 who discontinued the therapy; 4 was due to progression, 4 due to physician/patient preference, 2 due to toxicities and 3 from other reasons. Median progression free survival has not been reached. Toxicities were considered treatment related if they occur after the initiation of study drugs. DLTs are defined as any AEs occurring from days -7 to -2 that cause delay or prevent subjects from proceeding to auto-SCTs, grade 3 or more non-hematologic toxicities that do not resolve to a grade 2 or less by day 30 after auto-SCT, or engraftment failure. No DLTs were observed. The median time for ANC and platelet engraftment was 12 and 15 days and no delayed engraftment was observed. Toxicities and posttransplant hematopoietic recovery rates were similar to historical data observed with single agent high dose melphalan. Lenalidomide related toxicities occurred more commonly during the maintenance phase. Common toxicities occurring in more than 10% of patients were diarrhea (24%), peripheral neuropathy (21%) and fatigue (10%). Grade 3-4 toxicities occurred in 16% percent of patients: fatigue (5%), neutropenia (5%) neuropathy (3%), and thrombocytopenia (3%). Conclusion The use of high dose lenalidomide in combination with high-dose melphalan as a preparative regiment for auto-SCT is well tolerated. High VGPR or better disease response rates, compared to historical control, suggest that the preparative combination regimen may improve the depth of response. Stem cell rescue likely overcome lenalidomide induced myelosuppression. The study is now closed to accrual. Updated data on primary endpoints from all subjects will be reported at the meeting. Disclosures Suvannasankha: Celgene: Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Farag:Bristol Myers: Speakers Bureau; Millennium: Speakers Bureau; Teva: Research Funding; Celgene: Speakers Bureau. Silbermann:Amgen: Consultancy; Celgene: Research Funding. Abonour:Celgene: Research Funding, Speakers Bureau.

Effect of Obesity on Outcomes after Autologous Hematopoietic Stem Cell Transplantation (Auto HCT) for Multiple Myeloma (MM): An Analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3333-3333
Author(s):  
Dan T. Vogl ◽  
Waleska S. Peréz ◽  
Tao Wang ◽  
Edward A. Stadtmauer ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Body Weight ◽  
Multivariate Analyses ◽  
Autologous Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
Obese Patients ◽  
Hematopoietic Stem ◽  
Severely Obese ◽  
High Dose Melphalan ◽  
Univariate Analyses

Abstract Background: Obesity is increasing in prevalence worldwide and has potential implications on chemotherapy dosing and selection of patients for therapy. Auto HCT improves outcomes for patients with MM, but optimal chemotherapy dosing for obese patients is poorly defined. Methods: We identified 1087 patients reported to the CIBMTR between 1995 and 2003 who underwent auto HCT for MM as part of initial therapy, defined as within 18 months of diagnosis, and received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal (18.5– 24.9), overweight (25–29.9), obese (30–34.9), or severely obese (≥35). Underweight patients (BMI <18.5, N=9) were excluded from analysis. We analyzed overall survival (OS) and progression-free survival (PFS) from date of transplant, using Kaplan-Meier curves and the log-rank test for univariate analyses and using Cox proportional hazards models for multivariate analyses. Results: Cases were reported from 114 centers in 10 countries. There were 292 patients of normal weight (27%); 472 were overweight (43%), 198 were obese (18%), and 125 severely obese (11%). Median follow-up of survivors was 63, 61, 60 and 59 months, respectively. Significant baseline differences among BMI groups indicate that obese patients selected for transplant were younger (median age 58, 58, 56, and 55 years, respectively, p=0.005) and had less severe disease at diagnosis, with lower bone marrow plasmacytosis and less frequent renal failure, hypercalcemia, and severe anemia. Obese patients received higher total melphalan doses but lower doses per square meter of body surface area (calculated based on actual body weight). Univariate analyses show no significant effect of BMI category on either OS or PFS. However, among patients who received TBI as part of conditioning, multivariable analyses show a significant effect of BMI on PFS (p-value for interaction 0.006). In this subgroup, a higher BMI was associated with longer PFS (p=0.006, Figure 1). Among patients who received melphalan alone, no effect of BMI was apparent (Figure 2). The difference in PFS for patients receiving melphalan/TBI was due to a decreased risk of relapse among obese patients. Pairwise comparisons of conditioning regimen (TBI vs. no TBI) within BMI categories showed significant reduction in risk of treatment failure for obese (HR=0.54, p=0.04) and severely obese (HR=0.32, p=0.001) patients who received TBI. No differences in OS were apparent in multivariate analyses. Relative risks (RR) for PFS from a multivariable model adjusting for possible confounders are shown below: TBI No TBI n RR (95% CI) P n RR (95% CI) P Normal 44 1.00 Poverall=0.006 248 1.00 Poverall=0.18 Overweight 62 0.92 (0.60–1.40) 0.69 405 0.90 (0.75–1.08) 0.24 Obese 21 0.49 (0.27–0.90) 0.021 177 0.85 (0.68–1.07) 0.16 Severely obese 22 0.39 (0.20–0.76) 0.005 100 1.12 (0.86–1.45) 0.42 Conclusion: Obesity, when measured by BMI, has no statistically significant effect on OS among patients with myeloma receiving high-dose melphalan. Among patients receiving melphalan with TBI, a higher BMI is associated with improved PFS. The reason for the restriction of this effect to TBI-containing conditioning regimens requires further investigation. The current common strategy of reducing melphalan doses (i.e. calculating based on ideal or adjusted body weight) does not appear to impair outcomes for obese patients. Obesity should not exclude patients from consideration of autologous transplantation. Figure Figure

Velcade, Intravenous Cyclophosphamide and Dexamethasone (VCD) Induction for Previously Untreated Multiple Myeloma (German DSMM XIa Trial).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 131-131 ◽  
Author(s):  
Hermann Einsele ◽  
Peter Liebisch ◽  
Christian Langer ◽  
Martin Kropff ◽  
Hannes Wandt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rate ◽  
Induction Treatment ◽  
High Dose ◽  
Prognostic Impact ◽  
Short Period ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Abstract 131 Introduction. Autologous stem cell transplantation (ASCT) after cytoreductive induction is considered standard of care for younger patients (pts) with multiple myeloma (MM). The previous standard of induction, the Vincristin-Adriamycin-Dexamethasone (VAD) combination, achieves inferior results compared with induction regimens which combine the proteasome inhibitor Velcade (V = Bortezomib) with Dexamethasone (D)(=VD) and a cytostatic drug such as Doxorubicin (PAD = VD plus Doxorubicin). Velcade-based induction therapy was shown to translate into better myeloma control after high dose melphalan and to lead to prolonged progression-free survival. In order to find a more efficacious and safer drug combination for induction therapy in MM, we tested the combination of Velcade with Cyclophosphamide and Dexamethasone (VCD). Methods. This trial was designed as an open, prospective, multi-center, uncontrolled, combined phase II/III study. As previously reported (Kropff M et al., Ann Hematol 2009), in the first 30 pts the optimal dose of iv Cyclophosphamide in combination with V and D was defined as 900 mg/m2 on d1. Between 03/2006 and 03/2009 we enrolled an additional 370 pts up to 60 years of age with untreated MM to receive three 3-week cycles of induction treatment with V 1.3 mg/m2 iv d1,4,8,11; D 40 mg/d orally d1,2,4,5,8,9,11,12; and C 900mg/m2 iv d1 before scheduled high dose melphalan and ASCT. The primary endpoint of the study is response rate on day 63 after 3 cycles of VCD according to EBMT and IMWG criteria. Results. Final data from 400 pts from 39 German centers will be presented at the meeting. In the currently evaluable 300 pts (mean age 52.3 years; 1.7% stage I, 21.3% stage II, 77.0% stage III) molecular cytogenetic analysis showed a prevalence of 13q- in 38%, of t[4;14] in 13% and of 17p- in 12% of pts (no changes in 35%). All 300 pts (88.3% of whom completed three cycles) were included in the intent-to-treat analysis. Overall response rate (ORR = CR+PR) was 84%, with 10% CR and 74% PR, 5.7% MR, 7.3% NC and 2.3% PD. The negative prognostic impact of 13q- or t[4;14] was abrogated (ORR normal 87.3%, 13q- 83.7%, t[4;14] 90.0%), the unfavorable influence of p53 loss in the 17p- subgroup was still detectable (ORR 69.2%) but this did not reach statistical significance. VGPR rates will be reported at the meeting. Serious adverse events were documented in 78/300 (26.0%) patients. Death rate was remarkably low (1.3%, of which one was not related to the trial medication). 155/300 (52%) of pts experienced grade 3/4 non-serious AEs and of these leucopenia (93/300 pts= 31%), thrombocytopenia (7%), neutropenia (6%), anaemia (5%) were the most frequent events. 80 AEs grade 3 or 4 and 45 SAEs were of infectious origin and occurred in 47/300 pts. 80/130 SAEs (61.5%) were at least possibly related to Velcade. 101/300 pts (34%) developed episodes of peripheral neuropathy. PNP was grade 1 in 62/300 pt (20.7%), grade 2 in 31/300 pt (10.3%) and grade 3 in 7/300 pts (2.3%). Conclusion. This analysis demonstrates that proteasome inhibition by Velcade in combination with Dexamethasone and iv Cyclophosphamide (VCD) is an induction regimen for newly diagnosed MM which is highly effective in a short period of time, has a rather low toxicity profile and is feasible for administration in an outpatient setting. Based on these characteristics, VCD qualifies to become a new standard for MM induction therapy. Disclosures: Einsele: OrthioBiotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Bortezomib is licensed as monotherapy for use in relapsed/refractory MM and in combination with melphalan/Prednisone in the first-line treatment of MM pts ineligible for HD-MEL and ASCT. . Liebisch:OrthoBiotech: Consultancy, Honoraria. Langer:OrthoBiotech: Consultancy. Kropff:OrthoBiotech: Consultancy, Honoraria. Kröger:OrthoBiotech: Honoraria. Ostermann:OrthoBiotech: Honoraria. Mügge:OrthoBiotech: Honoraria. Wolf:OrthoBiotech: Honoraria. Gramatzki:OrthoBiotech: Consultancy, Honoraria. Maschmeyer:OrthoBiotech: Travel Grant. Sezer:OrthoBiotech: Consultancy, Honoraria. Heidemann:OrthoBiotech: Honoraria. Jäger:OrthoBiotech: Honoraria. Dechow:Celgene: Research Funding. Simon:OrthoBiotech: Honoraria. Straka:OrthoBiotech: Consultancy, Honoraria, Research Funding. Fingerle-Rowson:orthoBiotech: Employment. Knop:OrthoBiotech: Honoraria.

Busulfan / Melphalan / Bortezomib (Bu-Mel-Vel) Vs. High Dose Melphalan As Conditioning Regimen For Autologous Hematopoietic Cell Transplantation In Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3357-3357 ◽  
Author(s):  
Tulio E. Rodriguez ◽  
Parameswaran Hari ◽  
Patrick J Stiff ◽  
Xiaobo Zhong ◽  
Danielle Sterrenberg ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Maintenance Therapy ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
High Dose Melphalan ◽  
Autologous Hematopoietic Cell Transplantation

Abstract Background High dose melphalan (MEL) preceding autologous hematopoietic cell transplantation (HCT) for MM continues to be the standard of care. No regimen has been clearly proven superior to MEL 200 mg/m2 (MEL 200). The combination of Busulfan (Bu) and MEL was shown to improve progression free survival (PFS) (Lahuerta, et al; Haematologica. 2010 Nov; 95 (11):1913-20). The combination of bortezomib (Vel) with MEL also demonstrated superior PFS vs. MEL alone using historical controls (Roussel et al; Blood. 2010; 115:32-7). We studied a conditioning regimen combining Bu, MEL and Vel (BuMelVel) in an open label phase II study aimed at improving PFS after HCT for MM. To assess the potential value of this novel regimen, we performed a comparative analysis between BuMelVel and a cohort of patients conditioned with MEL 200 from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Methods Between July 2009 and May 2012, 43 eligible patients received BuMelVel conditioning followed by HCT. Bu was administered daily intravenous (IV) for a total of 4 days with the first 2 days (day -6, -5) at fixed dose of 130 mg/m2 over 3 hours and the subsequent 2 doses (day -4, -3) adjusted to achieve a target area under the concentration-time curve (AUC) total of 20,000 mM* min by performing pharmacokinetic (PK) analysis after the first dose of IV Bu. Mel 140 mg/m2 and Vel 1.6 mg/m2 were administered IV on Day-2 and Day -1 respectively. Outcomes were compared with a contemporaneous North American cohort (n=162) receiving single agent MEL 200 conditioning from the CIBMTR database. Controls were matched on age, sex, Karnofsky performance status (KPS), stage and interval from diagnosis to HCT. Multivariate analysis of Relapse, PFS, and overall survival (OS) was performed. Median follow up of survivors was 25 months. Planned maintenance therapy was not used. Results Age, gender, KPS, isotype, and stage were similar between groups (Table 1.). The MEL 200 cohort had more standard risk patients per Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) (78% vs. 40% in BuMelVel, p <0.0001) and more patients with only 1 prior line of therapy pre-HCT (67% vs. 47%, p = 0.02). Platelet and neutrophil engraftment kinetics were similar. Veno-occlusive disease (VOD) was not observed in the BuMelVel group and there was no non-relapse mortality (NRM). The incidence of relapse and PFS at 1 year were superior in the BuMelVel cohort (Table 1.). OS was similar between the cohorts. In multivariate analysis, PFS was superior in the BuMelVel cohort (HR for relapse/death in MEL 200 =1.87, p=0.04). Lack of a very good partial response or higher (≥VGPR) prior to HCT was associated with inferior PFS whereas lower KPS (<80) and higher international stage were associated with mortality. Conclusion PK directed dosing of Bu can be safely combined with Mel 140 followed by bortezomib without higher risk of VOD or NRM and in the absence of maintenance therapy. Within the constraints of a short follow up and uncontrolled post-transplant salvage therapies on both groups, no difference in OS has yet been observed. This novel conditioning regimen is safe and was associated with superior PFS compared with similarly matched controls and warrants further testing. Disclosures: Rodriguez: Otsuka: Research Funding; Millennium: Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Vesole:Millennium: Speakers Bureau.

2-Hour Cryotherapy Effectively Reduces Severe Mucositis Associated with High-Dose Melphalan Followed By Stem Cell Rescue: Results from a Randomized Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3960-3960 ◽  
Author(s):  
Douglas W. Sborov ◽  
Misty Lamprecht ◽  
Don Benson ◽  
Karen Tackett ◽  
Yvonne A Efebera ◽  
...  
Keyword(s):  
Stem Cell ◽  
Creatinine Clearance ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Advisory Committees ◽  
Stem Cell Rescue ◽  
Grade 3 ◽  
High Dose Melphalan ◽  
Severe Mucositis

Abstract Introduction: Severe mucositis in the autologous transplant setting has been correlated with adverse outcomes; longer febrile neutropenia duration, doubling of infectious risk, 2.7 additional days of total parenteral nutrition, 2.6 additional days of IV narcotics, increased length of stay (LOS), 3.9-fold increase in 100-day mortality, and US$25,405 increase in hospital charges (Sonis, JCO, 2001 19(8)). In a 40 patient randomized trial investigating cryotherapy (6 hours versus none) following high dose melphalan, grade 3/4 mucositis occurred in only 14% of patients using cryotherapy compared to 74% of patients using saline rinses (Lilleby, BMT, 2006 37). Prolonged cryotherapy is a significant hardship for patients and has resulted in nausea, vomiting, headache, toothache, and chills. We performed a randomized study investigating 2 versus 6 hours of cryotherapy in multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT) with melphalan conditioning. Hypothesis: We hypothesized that a 2-hour cryotherapy regimen would be non-inferior to 6-hours in severity of mucositis, LOS, and incidence of bacteremia. Methods: We conducted a non-inferiority investigation of 146 sequential MM patients undergoing high dose melphalan with autologous stem cell rescue. Patients were consented and randomized to either 2 (n = 73) or 6 hours (n = 73) of cryotherapy via block randomization based on hemoglobin (less or greater than 11 g/dL), fat free mass (30-50, 50-70, >70 kg), or measured 24hr creatinine clearance (<30, 30-60, >60 mL/min). The cryotherapy process consisted of patients’ melting shaved ice inside their mouth for the designated period of time; flavoring with snow cone syrup was permitted. Inpatient nurse practitioners graded mucositis via WHO criteria. Patients received antifungal (fluconazole) and antiviral (acyclovir or valacyclovir) prophylaxis. Subset analyses investigated the incidence of bacteremia in all patients. Results: Median age was 59 years (range 35 - 72) and 60 (range 38 – 71), and the median measured creatinine clearance was 90.6 mL/min (range 0.2 – 168.7) and 85.4 mL/min (range 21.5 – 196.5) for the 2 hour and 6 hour groups respectively. Length of hospitalization (mean of 15 days) did not differ significantly between the 2 cohorts (p = 0.54). Mucositis was graded daily after melphalan infusion. In the 2-hour cohort, 59% of the patients had mucositis (31 patients with grade 1, 10 with grade 2, and 2 patients with grade 3). In the 6-hour cohort, 64% had mucositis (35 patients with grade 1, 9 with grade 2, and 3 patients with grade 3). These results suggest that 2-hour cryotherapy was not inferior to 6-hour therapy in decreasing mucositis grade. In the entire 146 patient group, approximately 30% developed a positive blood culture after transplant, including 25 (34%) and 20 (27%) in the 6-hour and 2-hour groups respectively. The three most common infectious organisms included gram negatives (n = 12 patients), polymicrobial (n = 7), and non-group A streptococcus (n = 7). In the cohort treated with 2-hour cryotherapy, positive blood cultures did not correlate with grade of mucositis (r = 0.05, p = 0.65). Conclusions: In MM patients undergoing ASCT, 2-hour cryotherapy did not increase mucositis compared to 6-hours. The incidence of blood stream infection was not different between groups. In addition, having an infection did not correlate with grade of mucositis.These results suggest that a 2-hour cryotherapy regimen is not inferior to a 6-hour regimen, and may be considered a standard supportive care measure in patients receiving high dose melphalan. Disclosures Hofmeister: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Honoraria, Research Funding; ARNO Therapeutics: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees.

scholarly journals High-Dose Bendamustine, Etoposide, Cytarabine and Melphalan (BeEAM) Conditioning Prior to Autologous Transplantation for Patients with Multiple Myeloma: Results of a Prospective Phase II Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1831-1831
Author(s):  
Scott R. Solomon ◽  
Melhem Solh ◽  
Stacey Brown ◽  
Nancy Shegda ◽  
Katelin C Jackson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Genetic Risk ◽  
Research Funding ◽  
Phase Iii ◽  
High Dose ◽  
Post Transplant ◽  
Grade 3 ◽  
One Year ◽  
High Dose Melphalan

Abstract Single-agent high-dose melphalan followed by autologous stem cell transplantation (ASCT) remains a standard of care in eligible patients with multiple myeloma (MM). Efforts to improve transplant outcomes by intensifying transplant conditioning have mostly failed, with the exception of a sole phase III study showing improved progression-free survival (PFS) with the addition of busulfan to melphalan (Lancet Haematology 2019, 6:266-75). Bendamustine is a synthetic agent that combines the alkylating properties of a mustard-group with the antimetabolic activity of a purine analog. It can induce responses in MM resistant to other alkylators and is therefore a promising agent to test synergy in conditioning regimens. The high-dose chemotherapy combination of bendamustine, etoposide, cytarabine and melphalan (BeEAM) has been shown to be a safe and effective transplant regimen for lymphoma patients (Blood 2011, 118:3419-25). We performed a phase II study to test the safety and efficacy of BeEAM in MM patients, 18-70 years of age, with adequate organ function (EF≥40% predicted, CrCl ≥40ml/min) and within 9 months of starting induction therapy. Results were compared to a contemporaneously treated control group receiving a single high-dose melphalan 200mg/m2 transplant (Mel200) but otherwise meeting study eligibility criteria. Study patients (n=65) had a median (range) age of 59 (40, 69) years and were transplanted from 2015-2020. Other characteristics included KPS&lt;80%, HCT-CI≥3, ISS III, and high-risk FISH in 35%, 46%, 26% and 44% respectively. Pre-BMT status was (s)CR1, VGPR1, PR1 and &lt;PR1 in 26%, 43%, 26% and 5% respectively. ASCT following BeEAM was well tolerated with no non-relapse deaths through one-year post-transplant. Although at least one non-hematologic grade 3 toxicity was reported in 32 (49%) patients, there were no grade ≥3 renal or hepatic toxicity and no grade ≥4 non-hematologic toxicity. With a median f/u of 44 (13, 70) months, three-year OS and PFS was 92% and 57% respectively. When BeEAM patients were compared to contemporaneously treated Mel200 patients, there were no significant differences in baseline characteristics, induction regimen or use of post-transplant maintenance therapy. Neutrophil and platelet engraftment was faster following BeEAM (11 vs. 12 days, 17 vs 18 days, p&lt;0.001 and p=0.007 respectively), when compared to Mel200 patients. One-year non-relapse mortality was 0% with both BeEAM and Mel200. No significant differences were seen in quality of response, PFS or OS between BeEAM and Mel200, when analyzing either the whole cohort (see figure) or by genetic risk stratification. In multivariate analysis, controlled for genetic risk and year of transplantation, the use of BeEAM conditioning offered no benefit to Mel200 in terms of OS, PFS or risk of relapse/progression. In summary, BeEAM was shown to be a safe and effective conditioning regimen prior to up-front autologous transplant for MM. However, BeEAM conditioning appears to offer no significant advantage when compared to conventional Mel200 conditioning. Figure 1 Figure 1. Disclosures Solh: Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; Partner Therapeutics: Research Funding; ADCT Therapeutics: Consultancy, Research Funding. OffLabel Disclosure: Bendamustine for Multiple Myeloma

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