MEL200 Group Research Articles

Assessing Outcomes in Patients With Multiple Myeloma Postautologous Stem Cell Transplantation: Contrasting the Effects of Melphalan Dosages at 200 mg/m2 versus 140 mg/m2

BackgroundNo standard criteria for dose reduction exists for high-dose melphalan for autologous stem cell transplantation (ASCT) for multiple myeloma (MM) due to limited and conflicting evidence. ObjectiveTo evaluate efficacy and safety of standard dose (200 mg/m2 = Mel200) versus reduced dose 140 mg/m2 = Mel140) of melphalan in patients with MM undergoing ASCT. DesignA single-center retrospective review of adults with MM for their first ASCT between January 1, 2010, and November 1, 2022, who received Mel200 or Mel140 as conditioning. Primary endpoint was progression-free survival (PFS). Secondary safety and efficacy endpoints included overall survival (OS), incidence of febrile neutropenia and acute kidney injury, and time to engraftment. Subgroup analyses were performed based on patient age and renal function. ResultsA total of 322 patients were included in the study, 240 in the Mel200 group and 82 in the Mel140 group. Baseline demographics were similar except patients receiving Mel140 were on average older and had worse kidney function. PFS at 2 years was not different between groups (P = .2335). No difference existed in 2 year PFS or OS for patients < 65 years of age versus ≥ 65 years of age or for patients with CrCl 30-59 mL/min versus CrCl ≥ 60 mL/min within either Mel200 group or Mel140 group (all P > .05). No differences existed between groups across all secondary outcomes. ConclusionReduced doses melphalan showed no differences in safety or efficacy outcomes versus standard dose even when analyzed based on age and renal function. Larger randomized controlled trials need to be performed to validate these findings.

Increased Exceptional Response and Overall Survival Advantage for Patients with Multiple Myeloma Receiving Melphalan 200mg/m 2 Vs 140 Mg/m 2 Conditioning for Autologous Hematopoietic Stem Cell Transplantation

The standard conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic stem cell transplant (HSCT) is intravenous melphalan dosed at 200mg/m 2 (mel200). Prior retrospective studies indicated that dose reduction to melphalan 140 mg/m 2 (mel140) confers similar progression-free (PFS) and overall survival (OS), leading to increased use of mel140 in patients with comorbidities or advanced age. A recent single-center retrospective study (Sharma et al, Leukemia Lymphoma 2023) identified an OS advantage yet similar PFS for mel200 vs mel140, suggesting that certain patient cohorts may benefit from mel200. These findings require confirmation and better understanding of the risks and benefits to different dosing strategies. We performed a single-center retrospective study of mel dosing and transplant outcomes at the University of Nebraska Medical Center between 2008-2018. Three hundred and sixty-two patients underwent a first autologous HSCT with mel conditioning; 95 received mel140 while 267 received mel200. Nearly all patients received maintenance therapy (n= 357, 99%). Patient demographic and disease factors were largely comparable between mel140 and mel200 cohorts including sex, response prior to HSCT (both 73% for very good partial response or better), and presence of high-risk cytogenetics (t(4;14), t(14;16), t(14;20), del17p; 15% vs 14%). The mel140 group was older (65.1 years vs 59.7 years), had higher hematopoietic cell transplantation-specific comorbidity index (HCT-CI) scores (64% vs 40% at ³3), and International Staging System (ISS) stages (40% vs 22% at stage III) than the mel200 group. Average creatinine clearance at transplant was 71 vs 91 mL/min/m 2 in the mel140 vs mel200 cohorts, respectively. OS favored mel200 with a median survival time of 94.4 vs 69.1 months (mel200 vs mel140, Figure 1, p = 0.002). There was no statistical difference in PFS between mel200 vs mel140 (median PFS 73.0 vs 60.5 months, p = 0.43, respectively). With Cox proportional hazards regression, we performed a multivariate analysis of risk factors on PFS and OS. For OS, age ( p = 0.02) retained statistical significance within the model. Mel dosing and high-risk cytogenetics (both p = 0.09) did not retain significance. HCT-CI may have an effect ( p = 0.04), but due to missing data on n= 125/362 subjects this could not be well evaluated. Response prior to HSCT, creatine clearance at transplant, and ISS stage were not statistically significant. Given the multiple variables assessed and missing data for HCT-CI we separately analyzed mel dosing together with the most significant variable in the model, age. In this subset OS model, mel200 was associated with an improved OS (hazard ratio (HR) 0.64, p = 0.03) while age was associated with an adverse effect (HR 1.11 per 5-year increase, p = 0.06). For the multivariate PFS model, only high-risk cytogenetics (HR 1.82 yes vs no, p = 0.004) retained statistical significance. Median engraftment was faster in mel200 cohort (67% vs 92% engraftment starting at ³D+12, p &amp;lt;0.001). We next examined the impact of mel dosing on the rate of exceptional response (Paquin et al, Blood Cancer Journal 2020), defined as alive and progression-free for 8 or more years. Twenty-nine of 362 patients (8%) met the requirements for exceptional response. Two (7%) received mel140 while 27 (93%) received mel200. Exceptional responders were younger and split evenly between male and female. The majority had at least a very good partial response prior to HSCT (79%). Only 2 exhibited high-risk cytogenetics; one received bortezomib and lenalidomide maintenance, the other only bortezomib. On multivariate analysis, only two factors contributed to exceptional response: mel dose (mel200 odds ratio (OR) 5.22, Table 1, p = 0.01) and HCT-CI (OR 0.66 for increasing score, Table 1, p = 0.02. High-risk cytogenetics was not associated with exceptional responders (OR 0.43 yes vs no, p = 0.38) which may be due to low sample size. We conclude that mel dosing impacts OS but not PFS in our cohort, though this effect is confounded by increasing age and potentially comorbidity. We report for the first time that mel200 dosing increases the rate of exceptional response compared to mel140. Overall, these data support recent conclusions by Sharma et al and challenge the previous reports of similar OS outcomes between mel200 and mel140 dosing.

Modified High Dose Versus High Dose Melphalan Conditioning in Older Patients Undergoing Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis

Introduction: High dose melphalan and autologous stem cell transplantation (HDM/SCT) results in deep and durable responses and prolonged survival in highly selected patients with systemic immunoglobulin light chain (AL) amyloidosis. HDM/SCT is offered to select patients &amp;gt;65 years but melphalan dose is often reduced due to concerns for tolerability and toxicities in older patients. However, older adults are a diverse population and chronological age alone does not accurately predict chemotherapy tolerance. While both melphalan 140 mg/m2 (MEL-140) and 200 mg/m2 (MEL-200) are commonly used in clinical practice, there are very few studies comparing these two doses in older patients. Available studies suggest that MEL-140 may be associated with worse event-free survival and progression-free survival, but it is unclear whether this is confounding for increased co-morbidities and frailty in this group. We report transplant-related toxicities and outcomes in patients &amp;gt;65 years undergoing first HDM/SCT with MEL-140 versus MEL-200 within 12 months of diagnosis of AL amyloidosis. Methods: We analyzed transplant-related toxicities and outcomes of patients &amp;gt;65 years who received first HDM/SCT within 12 months of diagnosis between January 2011 and June 2020. We excluded patients receiving additional conditioning agents and those undergoing tandem or second transplantation. Patients were stratified based on melphalan dose. All statistical analyses were performed using GraphPad Prism version 8©. Independent (unpaired) t tests with unequal variance and a 95% confidence interval were used to calculate the two-tailed p values for continuous variables. Chi-squared tests were used to compare categorical variables. Hazard ratios (HR) and odds ratios (OR) with 95% confidence intervals (CI) and p values are reported. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) and log-rank tests were used to compare the survival measurements of each group. In this cohort, PFS was defined as the time from SCT to hematologic progression, next line of therapy and/ or death, whichever came first. Transplant-related mortality was defined as death occurring within 100 days of SCT. Results: Forty patients were included in the final analysis with a median follow up of 55.0 months (range 7 - 109, n = 18) for surviving patients in both groups. Table 1 displays patient and disease characteristics, transplant-related toxicities, 2-year PFS and median OS. Patients receiving MEL-140 were older (69 versus 66 years, p &amp;lt;0.0001) and more likely to be male (82.6% versus 47.1%, p 0.0383). Karnofsky performance status (KPS) was similar in both groups. Median number of organs involved was 2 with 91.3% and 82.4% of patients having renal involvement in the MEL-140 and MEL-200 groups, respectively. For patients who underwent induction therapy with anti-plasma cell agents, 22.2% treated with MEL-140 and 50.0% treated with MEL-200 were in &amp;gt;VGPR prior to HDM/ SCT (p 0.3348). There was no transplant-related mortality observed in either group. Severe transplant-related toxicities (grade &amp;gt;3) were reported in 88.2% of the MEL-200 group versus 72.7% of the MEL-140 group (p 0.4260) but the frequency of various toxicities were different. Patients who underwent conditioning with MEL-200 were significantly more likely to experience febrile neutropenia, sepsis and infections (88.2%, n = 15 versus 50.0%, n = 11; OR 0.13, 95% CI 0.03 - 0.73, p 0.0173 [Table 2]). Notably, the 2-year PFS was almost twice as long in the MEL-200 group (82.5% versus 42.6%, p 0.0534 [Figure 1]). The median PFS was 12.1 months in the MEL-140 group but was not reached in the MEL-200 group. There was no difference in median OS among the two groups (not reached, p 0.1454). Conclusion: Our study results suggest that highly selected patients ≥65 years with good performance status can safely undergo melphalan at a dose of 200 mg/m2 prior to stem cell transplantation in AL amyloidosis although there may be an increased risk of febrile neutropenia, sepsis and infections. Additionally, the melphalan conditioning dose 140 mg/m2 is potentially associated with a significantly shorter progression-free survival than 200 mg/m2 in older patients undergoing HDM/SCT for AL amyloidosis. Disclosures Sanchorawala: Takeda: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents &amp; Royalties; Prothena: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

Busulfan, Melphalan, and Bortezomib Compared to Single Agent High-Dose Melphalan As a Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma: Long Term Follow up of a Novel Conditioning Regimen

Introduction: Multiple myeloma (MM) remains incurable when treated with novel myeloma therapies in combination with high dose chemotherapy and autologous stem cell transplantation (ASCT). In contrast to the accelerated development of effective new drugs for induction, maintenance, and relapse, single-agent melphalan remains the standard for conditioning before ASCT. Is this phase II trial, we prospectively evaluated a conditioning regimen consisting of high-dose intravenous busulfan and melphalan followed by bortezomib (BUMELVEL), an agent shown to be potentially synergistic in combination with alkylating agents. We report our 7 year long term follow up with direct comparison to a contemporaneous CIBMTR cohort with the primary aim of both long term progression-free (PFS) and overall survival (OS). Methods: This phase I/II study was conducted between July 2009 and May 2012 at Loyola University Medical Center. MM patients with any disease response following induction were enrolled at time of stem cell transplantation. 43 patients received BUMELVEL conditioning followed by ASCT on the phase II portion of this study. Busfulan was administered intravenously (i.v.) daily for 4 days with the first 2 days (days −6 and −5) at fixed dose of 130 mg/m2 over 3 hours and the subsequent 2 doses (days −4 and −3) adjusted to achieve a target AUC total of 20,000 μM·min determined by pharmacokinetic (PK) analysis. Melphalan at 140 mg/m2 and bortezomib at 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively. Maintenance therapy was not planned. Patients received prophylaxis for oral mucositis with palifermin. Data from this phase II clinical trial were compared against a matched control cohort of contemporaneous North American MM patients from the CIBMTR database (n = 162) receiving conditioning with single agent iv melphalan at a dose of 200mg/m2. The primary objectives of this study were median PFS and toxicities. Results: Baseline patient characteristics are described in Table 1. More patients in the BUMELVEL arm received greater than one line of therapy prior to transplant (53 v 33%). There were more standard risk patients per Mayo Stratification (Kumar et al, Mayo Clin Proc 2009) in the MEL200 group (78%) v the BUMELVEL group (40%). There was no difference in response rates at day 100 (p=0.48) but a trend toward improved response at 1 year in the BUMELVEL arm with 77% achieving a VGPR or better versus 60% in the MEL200 group (p-0.09). No patients in the BUMELVEL group received planned maintenance therapy post-transplant whereas 112 (69.6%) in the MEL200 control arm received planned post-transplant maintenance. Non-relapse mortality was 2% (range 0-9%) in the BUMELVEL group and 10 (6%, range 3-11) in the MEL200 but this was not statistically significant in both univariate and multivariate modeling (p=0.25). There were no episodes of sinusoidal obstructive syndrome in the BUMELVEL group and 37% of patients experienced grade 3 mucositis with no grade 4 mucositis. After a median of more than seven years of follow up, the five year PFS was 47% (95% CI; 32-62) in the BUMELVEL group versus 30% (95% CI; 23-37) in the MEL200 group (p=0.05) (Figure 1). Notably the 7-year PFS in the BUMELVEL group was 32% (range 18-48). In multivariate analysis for PFS, BUMELVEL conditioning (HR 0.65; 95% CI 0.44-0.97)(p=0.036), time from diagnosis to transplant of greater than versus less than 12 months (HR 1.64; 95% CI 1.18 - 2.27), and disease status at transplant CR versus other (p=0.006) were all predictive of PFS (table 2). OS was not different between the two groups with a 7 year survival of 64% (95% CI; 48-79) in the BUMELVEL group versus 55% (95% CI; 46-64%) in the MEL200 group (Figure 1) which was confirmed on multivariate analysis (p=0.33). Discussion: Similar to recent reports in the literature comparing busulfan and melphalan to melphalan alone (Bashir et al, Lancet Hem 2019), we show that although depth of response was similar between the BUMELVEL group and the historical MEL200 comparator, the BUMELVEL group experienced an improved PFS. Importantly, we report no cases of SOS and a low non-relapse mortality of only 2% (v 6% in the historical control) reinforcing that the preparatory regimen in myeloma can be intensified safely with improved duration of unmaintained PFS. These long term results confirm a sustained benefit of novel combination conditioning in MM and the need for novel transplant preparative regimens. Disclosures D'Souza: EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Stiff:Unum: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Amgen: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding.

Melphalan Dose Intensity for Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma

Background High-dose melphalan 200 mg/m2 (Mel200) is the standard preparative regimen for multiple myeloma (MM). Reduced-dose melphalan 140 mg/m2 (Mel140) is frequently used as an alternative for older patients (pts), or those at higher risk of toxicity. There is conflicting data regarding the efficacy of Mel140 compared to Mel200. A recent report by EBMT suggested no survival advantage for Mel200 vs Mel140 except for a subset of pts with pretransplant suboptimal response to induction therapy. Objectives To assess treatment outcomes for MM pts who underwent ASCT by Mel200 vs Mel140. Methods Patients with newly diagnosed MM who underwent frontline ASCT using single agent melphalan conditioning regimen were included. To correct for potential bias in the melphalan dose comparisons, propensity score analysis was used for matching (by age, ISS, cytogenetic risk status, serum creatinine, induction and maintenance therapy), within response to induction at ASCT (PR or less vs VGPR or better). Primary endpoints were PFS and OS. Secondary endpoints included cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM). Results A total of 1628 consecutive pts were identified during study period; 1525 (94%) received Mel200 and 103 (6%) received Mel140. Propensity score matching resulted in 3:1 matches for a total of 312 pts (234 in the Mel200 group and 78 in the Mel140 group). The majority of pts were older with a median age of 69.6 (range: 43.3 – 80.6) years. For all matched pts, there was a statistically significant OS advantage for Mel200 with a HR of 0.46 (95% CI: 0.26, 0.80; P=0.006), but no significant differences in PFS (HR 0.87; 95% CI: 0.58, 1.31; P=0.51), CIR (HR 0.96; 95% CI: 0.66, 1.39; P=0.83) or NRM (HR 0.57; 95% CI: 0.22, 1.49; P=0.25). In pts with VGPR or better, PFS, OS, CIR, and NRM were not significantly different between the Mel200 (n=111) and Mel140 (n=37) groups. However, for pts with PR or less, there was significantly better OS for Mel200 (n=123) compared to Mel140 (n=41) (HR 0.39; 95% CI: 0.19, 0.82; P=0.013), but no significant differences in PFS, CIR, or NRM. The adjusted 3-year PFS with Mel200 and Mel140 for the matched pts were 13% and 14% (P=0.25), respectively, and adjusted 3-year OS were 67% and 46% (P=0.007). Additionally, multivariable regression models were fit using all the data adjusting the models with the same measures that were used in the matching. The results and conclusions between the two methods were consistent. Conclusion Mel200 remains standard of care with superior survival in patients with PR or worse, however Mel140 is a suitable alternative for patients in VGPR or better. Depth of response prior to transplantation is a strong predictor for selecting melphalan dose intensity and treatment outcomes. Our findings highlight the importance of improving remission status prior to transplant. Prospective randomized trials are needed to define the optimal melphalan dose.

Full Dose or Reduced Dose Melphalan (MEL) for Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM): A Single Center Analysis on 187 Consecutive Patients

IntroductionMEL at the dose of 200 mg/m2 (MEL200) is considered the standard conditioning regimen before ASCT in MM patients (pts). Lower doses of 140 mg/m2 (MEL140) or 100 mg/m2 (MEL100) are used when toxicity is a concern. Whether these lower doses are equally effective is still a matter of debate and available data are conflicting.Aims and MethodsTo compare full dose with reduced dose MEL, we performed a retrospective analysis on MM pts in all disease stages treated at Jena University Hospital between 2003 and 2017. Statistical analysis included descriptive statistics and Cox regression. Progression free survival (PFS) and overall survival (OS) were calculated from the time of ASCT. Here, preliminary data on 187 pts are presented. For pts receiving more than one ASCT (n=69), only data on the first ASCT were included in the analysis. Pts treated with MEL140 and MEL100 were pooled (MELRed group).ResultsOf 187 ASCTs, 163 were performed as first-line and 24 as salvage therapies. Median follow up of the entire population was 77 months (range 3-172). Induction treatment included at least 1 novel agent (immunomodulatory drugs, IMiDs or proteasome inhibitors, PI) in 119 pts, whilst 68 pts received conventional chemotherapy. Median number of induction cycles before ASCT was 3 (range 1-10). Prior to ASCT 31 pts (17%) had achieved at least a very good partial remission (VGPR). MEL200 was used in 112 (60%) and MELRed in 75 pts (40%, 72 MEL140 and 3 MEL100). There was no difference in the two groups in the number of transplant performed as first line or as salvage therapy (p=0.54), as well as in the rate of pts achieving at least a VGPR before ASCT (17% vs. 16%, for MEL200 and MELRed respectively, p=0.84). More pts treated with MEL200 received induction treatment containing novel agents (70% vs. 55% for MEL200 and MELRed respectively, p=0.037). High quality responses (≥VGPR) after ASCT were higher in the MEL200 group: 89% of pts treated with MEL200 vs. 73% of those receiving MELRed, p=0.005. The main reasons for MEL dose reduction were older age (40%) and renal insufficiency (29%). Median age (range) and creatinine values (range) were 55 (35-68) vs. 63 (47-70) years (p<0.001) and 73 (51-186) vs. 90.5 (51-1022) μmol/l (p<0.001) for MEL200 and MELRed, respectively. More pts in the MELRed group had a Charlson Comorbidity Index (CCI) >2 (83% vs. 99% for MEL200 and MELRed respectively, p=0.001). Toxicities and duration of hospitalization of the two groups are depicted in Table 1. The higher response rate seen in pts treated with MEL200 translated in a longer median PFS (43 vs. 27 months for MEL200 and MELRed respectively, p=0.023) and OS (66% vs. 51% at 5 years for MEL200 and MELRed respectively, p=0.046). Multivariate analysis included CCI >2, response before and after ASCT ≥VGPR, disease stage at ASCT, age >65 years, treatment with new drugs, glomerular filtration rate ≥60 ml/min at the time of ASCT and treatment with MEL200. Disease stage (HR 0.57, 95% CI 0.331-0.978, p=0.041) and MEL200 (HR 0.49, 95% CI 0.295-0.802, p=0.005) were associated with an improved PFS, whilst none of the above mentioned variables had an impact on OS.ConclusionIn comparison with MELRed, MEL200 provides favorable responses and improves PFS and OS with only moderate increase of toxicity in this retrospective pts cohort. At least in pts treated with standard-induction therapy, MEL200 should be considered the standard conditioning regimen for ASCT eligible MM pts. DisclosuresBrioli:Janssen: Honoraria; Celgene: Honoraria, Other: Travel support, Research Funding. Mügge:Amgen: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria, Research Funding. Scholl:Abbivie: Other: Travel support; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Alexion: Other: Travel support; MDS: Other: Travel support; Carreras Foundation: Research Funding. Hilgendorf:Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Sayer:RIEMSER Pharma GmbH: Honoraria. Ernst:Novartis: Research Funding. Hochhaus:Incyte: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding. von Lilienfeld-Toal:Takeda: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding; Janssen: Honoraria, Other: Travel support, Research Funding.

Maintenance Therapy With Lenalidomide Significantly Improved Survival Of Yong Newly Diagnosed Multiple Myeloma Patients

▪ BackgroundHigh-dose chemotherapy (HDT) with autologous stem cell transplant improves outcome of multiple myeloma (MM) patients in comparison to conventional chemotherapy. The incorporation of new drugs into induction, consolidation and maintenance therapy is changing the treatment paradigm and is questioning the role of HDT in newly diagnosed MM (NDMM) patients <65 years. Previous finding have been presented (Boccadoro, ASCO 2013) and this analysis provides a longer follow-up. AimsTo compare in a prospective randomized trial melphalan-prednisone-lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) both followed by maintenance with lenalidomide or no maintenance in NDMM patients. MethodsA 2x2 factorial randomized trial was designed. The induction treatment consisted of four 28-day cycles of lenalidomide (25 mg d 1-21) and low-dose dexamethasone (40 mg d 1,8,15,22) (Rd). As consolidation, patients were randomized to MPR (N=202) [six 28-day cycles of melphalan (0.18 mg/k g d 1-4), prednisone (2 mg/kg d 1-4) and lenalidomide (10 mg d 1-21)] or MEL200 (N=200)[tandem melphalan 200 mg/m2 with stem-cell support]. Patients were further randomized, within each group, to receive lenalidomide maintenance (10 mg, days 1-21, N=198) or no maintenance (N=204). Primary study endpoint was progression free survival (PFS). The secondary study endpoints included response rates, safety and overall survival (OS). Data were analyzed in the intent-to-treat (ITT) population. ResultsFrom November 2007 to July 2009, 402 patients with NDMM <65 years of age were enrolled. All patients were stratified according to International Staging System (ISS) and age. Patient characteristics were well balanced in all groups. In the MPR group, the Very Good Partial Response (VGPR) rate was 50% with 13% of Complete Response (CR) while the VGPR rate was 52% including 19% of CR in the MEL200 group. In the MPR group the CR rate improved from 13% after consolidation to 17% after maintenance. In the MEL200 group the CR rate improved from 19% after consolidation to 25% after maintenance.After a median follow-up of 48 months, the median PFS was 24.2 months in MPR group and 38.6 months in MEL200 group ( P< 0.0001).A multivariate analysis confirms the PFS benefit associated with MEL200 across all subgroups of patients defined by stratification factors and baseline characteristics.The 5-year OS rate was similar between MPR (62%) and MEL200 (71%; P= 0.27). In a landmark analysis, lenalidomide maintenance significantly extended PFS from the start of maintenance (median 42,7 months) compared with no maintenance (median 17.5 months; P<.0001). The 4-year OS rate from the start of maintenance was higher in patients who received lenalidomide maintenance (80%) compared with patients who did not (62%; P= 0,01). No significant interaction was detected between MPR/MEL200 (P=0.704) and maintenance/observation (P=0.984) effects.During consolidation, the incidence of grade 3-4 adverse events (AEs) between MPR and MEL200 were as follow: neutropenia (50% vs. 90%), thrombocytopenia (8% vs. 89%), infections (1% vs. 15%) and gastrointestinal (0% vs. 18%), with complications being higher with MEL200.During the maintenance phase, grade 3-4 hematologic AEs were reported in 17% of patients receiving lenalidomide (16% neutropenia). For individual group comparisons during maintenance, grade 3-4 hematologic AEs were observed in 20% of patients receiving MPR plus lenalidomide maintenance compared with 15% receiving MEL200 plus lenalidomide maintenance. Second primary malignancies were observed in 11 patients (3%), and were mainly solid tumors. Four solid tumors were observed in the MEL200 group and one in the MPR group in the maintenance arm, while three solid tumors were observed in the MEL200 group and three in the MPR group in no maintenance arm. ConclusionThe administration of MPR was significantly inferior to MEL200 in terms of PFS. Toxicities were significantly higher in MEL200 group, but manageable. OS is similar between MPR and MEL200. Lenalidomide maintenance significantly reduced the risk of progression and of death independently from the previous treatment. Disclosures:Gay:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Caravita:Celgene: Honoraria, Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Randomized Comparison of Melphalan 200 Mg/m2 v. 280 Mg/m2 As a Preparative Regimen for Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation

Abstract 2009 IntroductionMelphalan 200 mg/m2 has remained the standard of care as a preparative regimen for patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). Higher doses of melphalan are associated with unacceptable gastrointestinal toxicity. Preliminary studies suggested that administration of the cytoprotective agent amifostine could protect patients with MM undergoing ASCT from excessive toxicity from doses of melphalan as high as 280 mg/m2. We conducted a prospective, multicenter, randomized trial comparing melphalan 200 mg/m2 (mel200) v. 280 mg/m2 (mel280) using amifostine pretreatment in patients with MM undergoing ASCT. MethodsThe primary endpoints of the trial were grades 3–4 toxicity and near complete response (nCR) or better 60–120 days after ASCT. Eligibility included age ≤70, no prior ASCT, acceptable organ function, measurable monoclonal protein in serum or urine by protein electrophoresis and adequate stem cells for ASCT. Patients were stratified by ß2 microglobulin >5 at study entry, del 13 by FISH and response (<≥PR) to the last cytoreductive regimen prior to ASCT. Amifostine 710 mg/m2, with appropriate hydration and pre-medications, was given by intravenous push the day prior to and again 15 minutes prior to mel200 or mel280 given as a single infusion over 30 minutes. ResultsOf 134 patients consented, consent was withdrawn for 4 patients, 1 patient who had abnormal renal function, one after a hypotensive episode following the first amifostine infusion, and 2 for other reasons. Manageable toxicities associated with amifostine infusion were hypotension (18), hypertension (3), dizziness (4), and nausea (33). Of 130 patients, 64 randomized to 200 mg/m2 and 66 280 mg/m2; 26 had del 13, and 55 had <PR to their last therapy; no patient had a ß2 microglobulin >5. Their median age was 60 years (range 42–70), they had received a median of 2 regimens (range 1–8) prior to stem cell collection, and 28 (22%) had received local radiation prior to ASCT. A total of 21 patients had grade 3–4 toxicity, 11% who received mel200 and 21% who received mel280 (p=0.11). Four of the seven in the mel200 group had a single grade 3–4 toxicity, while 3 had 2 grade 3–4 toxicities. Eight of the 14 in the mel280 group had a single toxicity, and 6 patients had two toxicities. By organ systems respectively, for mel200 v. mel 280, they were cardiac 1 v. 0, gastrointestinal 6 v. 11, mucositis 3 v. 7, CNS 0 v. 1 and pulmonary 0 v. 1. Hospitalization occurred in 94 patients 106 times; among the group receiving mel200 40 (62%) patients were hospitalized compared to 54 (82%) in the mel280 group, p=0.01. The mean total days of hospitalization were 7.3 and 10.2 days for mel200 and mel280, respectively (p=0.06); 3 patients in the mel200 group required 2 hospitalizations, 2 were admitted 3 times, while 5 patients in the mel280 group were admitted twice. The primary reasons for hospitalization for patients in receiving mel200 v mel280, respectively were, conditioning and transplant 9 v. 12, mucositis 2 v. 12, nausea and vomiting 8 v. 12, fever and infection 21 v. 18 and other 6 v. 6. No treatment related deaths occurred in this study. Responses following ASCT by EBMT criteria were for mel200 v. mel 280, respectively, ≥nCR 22% v. 39%, p=0.04, ≥PR 56% v. 70%, p= 0.09. The estimated progression-free survival at 1 and 3 years was 86% and 48%, respectively, for mel200 and 77% and 53%, respectively, for mel280. The risk of failure (death or progression) was similar (hazard ratio (mel280 vs. mel200) 1.12; 95% CI 0.64–1.95, p=0.69). The median follow-up among patients alive without progression was 524 and 555 days for mel200 and mel280, respectively. The estimated overall survival at 1 and 3 years was 96% and 83%, respectively, for mel200 and 89% and 73% for mel280, respectively. The risk of death was similar in the mel280 group relative to mel200 (HR=0.86; 95% CI 0.40–1.84; p=0.70). ConclusionsIn summary the combination of amifostine and mel280 was generally well tolerated although there were more grade 3–4 regimen-related toxicities, primarily mucositis and gastrointestinal. This resulted in slightly more frequent and longer hospitalizations (by 3 days) compared to amifostine + mel200. Mel280 resulted in a higher major response rate (CR + nCR) and warrants further study. Disclosures:Off Label Use: amifostine.

Melphalan/Prednisone/Lenalidomide (MPR) Versus High-Dose Melphalan and Autologous Transplantation (MEL200) in Newly Diagnosed Multiple Myeloma (MM) Patients

Abstract 3069▪FN2▪This icon denotes a clinically relevant abstract Background:High-dose chemotherapy with haemopoietic stem-cell improves outcome in multiple myeloma (MM). The introduction of novel agents questions the role of autologous stem-cell transplantation (ASCT) in MM patients. Aims:In this prospective randomized study, we compared conventional melphalan-prednisone-lenalidomide (MPR) with tandem high-dose melphalan (MEL200) in newly diagnosed MM patients younger than 65 years. Methods:All patients (N=402) received four 28-day cycles of lenalidomide (25 mg, d1-21) and low-dose dexamethasone (40 mg, d1, 8, 15, 22) (Rd) as induction. As consolidation, patients were randomized to MPR (N=202) consisting of six 28-day cycles of melphalan (0.18 mg/kg d1-4), prednisone (2 mg/kg d1-4) and lenalidomide (10 mg d1-21); or tandem melphalan 200 mg/m2 MEL200 (N=200) with stem-cell support. All patients enrolled were stratified according to International Staging System (stages 1 and 2 vs. stage 3) and age (<60 vs. ≥60 years). Progression-free survival (PFS) was the primary end point. Data were analyzed in intention-to-treat. Results:Response rates were similar: at least very good partial response (≥VGPR) rate was 60% with MPR vs. 58% with MEL200 (p=.24); the complete response (CR) rate was 20% with MPR vs. 25% with MEL200 (p=.49). After a median follow-up of 26 months, the 2-year PFS was 54% in MPR and 73% in MEL200 (HR=0.51, p<.001). The 2-year overall survival (OS) was similar in the two groups: 87% with MPR and 90% with MEL200 (HR 0.68, p=.19). In a subgroup analysis, MEL200 significantly prolonged PFS in both standard-risk patients without t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 46% in the MPR group vs. 78% in the MEL200 group, HR=0.57, p=.007) and high-risk patients with t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 27% for MPR vs. 71% for MEL200, HR=0.32, p=.004). In patients who achieved CR, the 2-year PFS was 66% for MPR vs. 87% for MEL200 (HR 0.26; p<.001); in those who achieved a partial response (PR), the 2-year PFS was 56% for MPR vs. 77% for MEL200 (HR 0.45; p<.001). In the MPR and MEL200 groups, G3-4 neutropenia was 55% vs. 89% (p<.001); G3-4 infections were 0% vs. 17% (p<.001); G3-4 gastrointestinal toxicity was 0% vs. 21% (p<.001); the incidence of second tumors was 0.5% in MPR patients and 1.5% in MEL200 patients (p=.12). Deep vein thrombosis rate was 2.44% with MPR vs. 1.13% with MEL200 (p=.43). Conclusions:PFS was significantly prolonged in the MEL200 group compared to MPR. This benefit was maintained in the subgroup of patients with standard- or high-risk cytogenetic features. Toxicities were significantly higher in the MEL200 group. This is the first report showing a PFS advantage for ASCT in comparison with conventional therapies including novel agents. These data will be updated at the meeting.TableClinical outcome after MPR or MEL200 consolidationMPRMEL200P valueAll patientsCR20%25%.49≥VGPR60%58%.242-year PFS54%73%<.0012-year OS87%90%.19Standard-risk patients2-year PFS46%78%.007High-risk patients2-year PFS27%71%.004Patients who achieved CR2-year PFS66%87%<.001Patients who achieved PR2-year PFS56%77%<.001 Disclosures:Palumbo:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria; Janssen-Cilag: Honoraria. Cavo:celgene: Honoraria. Ria:celgene: Consultancy. Caravita Di Toritto:Celgene: Honoraria, Research Funding. Di Raimondo:celgene: Honoraria. Boccadoro:celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) in newly diagnosed multiple myeloma (MM) patients: A phase III trial.

8020 Background: The introduction of novel agents questions the role of autologous stem-cell transplantation (ASCT). This is the first prospective randomized study comparing conventional chemotherapy plus novel agents (MPR) with tandem high-dose melphalan (MEL200) and ASCT in newly diagnosed MM patients (Pts). Methods: All pts (N=402) received four 28-day cycles of lenalidomide (25 mg, d1-21) and low-dose dexamethasone (40 mg, d1,8,15,22) (Rd) as induction. Pts (N=202) were then randomized to MPR [six 28-day cycles of melphalan (0.18 mg/kg d1-4), prednisone (2 mg/kg d1-4) and lenalidomide (10 mg d1-21); pts (N=200)] or MEL200 (tandem melphalan 200 mg/m2 with stem-cell support). Primary end point was PFS. Results: Response rates were similar in the two groups (MPR vs MEL200): ≥ VGPR (60% vs. 58%, p=0.24) and CR (20% vs. 25% p=0.49). After a median follow-up of 20 months, the 18-months PFS was 68% in MPR and 78% in MEL200 (HR=0.58, p=0.006). CR prolonged the 18-months PFS in the MPR (90% vs 66%) and in the MEL200 group (87% vs 76%). The 18-months OS was similar (91% vs 95%; p=0.073). In the MPR and MEL200 groups, G3-4 neutropenia was 55% vs 89% (p <.001); G3-4 infections were 0% vs 17% (p <.001); G3-4 gastrointestinal toxicity was 0% vs. 21% (p<.001); DVT was 2.44% vs 1.13% (p=0.43); second tumors were 0.005% in both arms. Conclusions: MEL200 was superior to MPR for PFS, although toxicities were significantly higher. This is the first report showing a PFS advantage for ASCT in comparison with combinations including novel agents. At present OS is not significantly different in the two groups.

A Phase III Study of Enoxaparin Vs Aspirin as Thromboprophylaxis for Newly Diagnosed Myeloma Patients Treated with Lenalidomide-Based Regimen.

AbstractAbstract 1092 Background:Newly diagnosed myeloma (MM) patients who receive thalidomide-based regimens have a high risk of thromboembolic events. Preliminary studies on MM patients receiving a combination of lenalidomide (R) and dexamethasone have shown an increased incidence of thrombosis as well, with a calculated odds ratio of about 3.5 of developing thrombosis. Aims:In a prospective, multicenter phase III trial (RV-MM-PI-209) newly diagnosed patients were treated with lenalidomide and low-dose dexamethasone (Rd) induction and subsequently randomized to receive consolidation with lenalidomide + melphalan + prednisone (MPR) or high dose melphalan (MEL200). In this sub-study we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) as anticoagulant prophylaxis during Rd induction and MPR consolidation. End-points were incidence of venous thromboembolism (VTE), acute cardiovascular events, sudden death, major and minor bleeding. Methods:402 newly diagnosed MM patients were enrolled in the randomized trial RV-MM-PI-209. Treatment schedule included four 28 day cycles of lenalidomide (25 mg days 1–21) and low-dose dexamethasone (40 mg days 1,8,15,22) (Rd) as induction. As consolidation, patients were randomized to receive six 28-day cycles of melphalan (0.18 mg/kg days 1–4), prednisone (2 mg/kg days 1–4) and lenalidomide (10 mg days 1–21) (MPR, N=202) or tandem melphalan 200 mg/m2 with stem-cell support (MEL200, N=200). All eligible patients were randomly assigned to receive LMWH (Enoxaparin 40 mg/d, N=166) or ASA (Aspirin 100 mg/d, N=176) for the duration of the induction therapy and for consolidation therapy in the MPR group; 60 patients were excluded from this sub-study because of indication for anticoagulant/antiplatelet therapy or high-risk of bleeding. Results:Patient characteristics and distribution of major risk factors were similar in the two groups. At the time of the present analysis 381 and 130 patients are evaluable during Rd induction and consolidation respectively. During the induction phase, the overall incidence of any grade 3–4 thrombotic events was 1% in the LMWH group, 2,4% in the ASA group (p=.45). VTE, mostly of the lower limbs were equally distributed in the two groups (1%; p not significant), while pulmonary embolism was observed only in the ASA group (2%; p not significant). Median time to onset of thrombotic events for patients who received LMWH or ASA were 2.1 and 1 months, respectively. No acute cardiovascular events were observed and only minor bleeding was detected in the LMWH group (1%). During consolidation no thrombotic events were observed in the MPR group, only one central venous catheter thrombosis was observed in the MEL200 group. Conclusion:The overall incidence of thrombotic events was less than 5% in all groups and confirmed the safety of low dose dexamethasone in association with Lenalidomide. No significant benefit was seen with LMWH over ASA in this patient population. LMWH and ASA are likely to be effective thromboprophylactic regimens in lenalidomide treated patients with newly diagnosed multiple myeloma. The analysis will be updated for the meeting.Table 1Incidence of thrombotic events, acute cardiovascular events, sudden death and bleeding events.EventsLMWH (N =166)ASA (N =176)Grade 3–4 thrombotic events, (%)12Acute cardiovascular events, (%)00Sudden deaths, (%)00Major and minor bleeding, (%)10Total events, (%)22 Disclosures:Cavallo:CELGENE: Honoraria. Guglielmelli:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Boccadoro:CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; JANSSEN-CILAG: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; JANSSEN-CILAG: Honoraria, Membership on an entity's Board of Directors or advisory committees.

A Phase III Study to Compare Melphalan, Prednisone, Lenalidomide (MPR) Versus Melphalan 200 Mg/m2 and Autologous Transplantation (MEL200) In Newly Diagnosed Multiple Myeloma Patients

AbstractAbstract 3573 Background:In this randomized study we question the role of HDT, when new drugs are incorporated in the conventional treatment or in the autologous transplant setting in newly diagnosed multiple myeloma (MM) patients. Aims:To compare melphalan, prednisone and lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) in MM patients younger than 65 years. Methods:The induction treatment consisted of four 28-day cycles of lenalidomide (25 mg d 1–21) and low-dose dexamethasone (40 mg d 1,8,15,22) (Rd). Cyclophosphamide plus G-CSF was used to mobilize stem cells. As consolidation, patients were randomized to MPR (N=202) [six 28-day cycles of melphalan (0.18 mg/k g d 1–4), prednisone (2 mg/kg d 1–4) and lenalidomide (10 mg d 1–21))] or MEL200 (N=200)[tandem melphalan 200 mg/m2 with stem-cell support]. All patients were also randomized to receive either aspirin or low-molecular weight heparin (enoxaparin) as thromboprophylaxis during Rd and MPR. Primary study endpoint was progression free survival (PFS). Data were analyzed in intention-to-treat. Results:From november 2007 to july 2009, 402 patients with newly diagnosed symptomatic MM younger than 65 years of age were recruited and randomized. All patients enrolled were stratified according to International Staging System (ISS) (stages 1 and 2 vs stage 3) and age (<60 vs ≥60 years). Results:On an intention to treat basis, best responses after Rd induction, were: partial response (PR) rate was 87%, very good partial response (VGPR) rate was 52%, including 13% complete responses (CR). The median yields of stem cells harvested was 8.7 ×106 CD34+ cells/Kg; 91% of patients collected the minimum dose of 4×106/kg CD34+ cells. As of August 10th, 257 patients are evaluable for response after at least 3 cycles of MPR (124) and after the first MEL200 (133); best responses to consolidation: in the MPR group, the VGPR rate was 60% including 20% CR; in the MEL200 group the VGPR rate was 58% including 25% CRs. No differences in responses were reported according to chromosomal abnormalities, such as del13, t(4;14), t(14;16) or del17p. After a median follow-up of 14 months, the projected 2-year PFS and OS were similar in the two groups (table). The achievement of at least VGPR after consolidation was a predictive factor of longer PFS in both groups: in the MEL200 group, the 2-year PFS was 92% for patients with at least VGPR vs 70% for those with PR (p<.0001); in the MPR group 86% vs 61% respectively (p<.0001). MPR and MEL200 were equally effective in patients with chromosomal abnormalities (2-year PFS was 71% vs 77%; p=.39) or ISS 3 (2-year PFS was 58% vs 66%; p=.48). Induction with Rd was well tolerated: the most frequent grade 3–4 adverse events were neutropenia (8%), anemia (7%), infections (4%) and skin rash (5%). The incidence of thromboembolic events was similar in patients randomized to aspirin (2%) or low molecular weight heparin (1%) as thromboprophylaxis (p=.45). During consolidation, the incidence of grade 3–4 neutropenia (97% vs 32%;p <.001), thrombocytopenia (59% vs 5%; p<.001), infections (10% vs 1%, p<.001) and gastrointestinal (15% vs 1%, p<.001) complications was higher in MEL200 patients.TableClinical outcome after MPR or MEL200 consolidationMPRMEL200P valueCR20%25%0.49≥VGPR60%58%0.242-year PFS73%78%0.482-year OS95%97%0.18 Conclusion:Our study confirms the efficacy and safety of Rd induction. Both MPR and MEL200 improved the quality of response, achieved by Rd induction. At present, PFS and OS are not significantly different in the two groups, but longer follow-up is needed. These data will be updated at the meeting. Disclosures:Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janseen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria. Patriarca:Celgene: Honoraria; Roche: Honoraria; Janssen-Cilag: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees. Caravita:Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janseen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Melphalan 200 mg/m2 versus melphalan 100 mg/m2 in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study

AbstractHigh-dose (200 mg/m2, MEL200) and intermediate-dose melphalan (100 mg/m2, MEL100) showed significant activity in myeloma. In a phase 3 study, 298 patients were randomly assigned to receive 2 autologous transplantations after conditioning with MEL200 or MEL100. Ninety-six of 149 (64%) completed MEL200 and 103 of 149 (69%) MEL100. Best response to MEL200 was: complete remission 22 of 149 (15%); partial remission 95 of 149 (64%), for an overall response rate of 79%. Best response to MEL100 was: complete remission 12 of 149 (8%); partial remission 95 of 149 (64%), for an overall response rate of 72%. Overall survival did not differ (P = .13); median progression-free survival (31.4 vs 26.2 months, P = .01), median time to progression (34.4 vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in the MEL200 and 2.9% in the MEL100 group. Severe neutropenia and infections were marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestinal adverse events, and the overall occurrence of at least 1 nonhematologic grade 3 or 4 adverse event were significantly higher in the MEL200 cohort. We conclude that MEL200 leads to longer remission duration and should be considered the standard conditioning regimen for autologous transplantation. This study was registered at www.clinicaltrials.gov as #NCT00950768.

Melphalan 200 Mg/m2 (Mel200) Versus Melphalan 100 Mg/m2 (Mel100) in Newly Diagnosed Myeloma Patients: A Prospective, Randomized Phase III Study

Background. Several trials have shown the superiority of high-dose melphalan (usually 200 mg/m2, MEL200) versus standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m2, MEL100) was also superior to the standard dose, but MEL100 has not been clinically compared with MEL200 in a randomized study. In this prospective, randomized, phase III trial, we compared the efficacy and toxicity of MEL200 and MEL100.Aims. The primary end points were complete remission (CR) rate, event-free survival (EFS) and incidence of gastrointestinal toxicity, infections and treatment-related mortality (TRM).Methods. Inclusion criteria were previously untreated myeloma, aged ≤ 65 and Durie and Salmon stage II or III. Exclusion criteria were abnormal pulmonar, cardiac, liver and renal function, HBV, HCV, or HIV positivity, concomitant cancer or psychiatric disease. The institutional review board approved the protocol and written informed consent was obtained from all patients. All patients received 2 cycles of 28-day-dexamethasone- doxorubicin-vincristine (doxorubicin 50 mg/m2 day 1, vincristine 1 mg day 1, dexamethasone 40 mg days 1–4) and 2 cycles of cyclophosphamide (4 g/m2, day 1) followed by stem cell harvest. MEL200 patients was conditioned with 2 cycles of melphalan 200 mg/m2 and MEL100 patients with 2 courses of melphalan 100 mg/m2. All MEL courses were followed by stem cell reinfusion.Results. Two-hundred and ninety-eight patients (median age 57) were randomly assigned either to MEL200 (149 patients) or to MEL100 (149 patients). All patients were evaluated for response, EFS and OS in intention-to-treat analysis. Patient characteristics were similar in both groups with the exception of chromosomal 13 deletion, present in 69% of MEL200 and 45% of MEL100 patients (p=0.02). Ninety-six patients completed tandem MEL200; 103 tandem MEL100. The very good partial response rate was higher in MEL200 group (37% versus 21%, p=0.003), but CR was 15% in the MEL200 group and 8% in the MEL100 group (p=0.07). The median follow-up for censored patients was 40.5 months. The 4-years EFS was 44.5% in the MEL200 and 18.3% in the MEL100 group (HR=0.71, 95% CI 0.53–0.95, p=0.02). The 5-years overall survival (OS) was 59.2% in the MEL200 and 44.7% in the MEL100 group (HR=0.78, 95% CI 0.52–1.16, p=0.22). Duration of grade 4 neutropenia and thrombocytopenia was comparable, but a higher proportion of MEL200 patients required platelet transfusions (p=0.002). Grade 3–4 non-hematologic adverse events were reported in 38% of MEL200 patients and in 19% of MEL100 patients (p<0.0001). The incidence of grade 3–4 mucositis was 16% after MEL200 and 3% after MEL100 (p<0.0001). The incidence of severe gastrointestinal toxicity was 19% after MEL200 and 2% after MEL100 (p<0.0001). The incidence of grade 3–4 infections and of TRM was similar in both groups.Conclusions. In conclusion, MEL200 resulted in a significantly higher very good partial response rate. This translated in a superior EFS, but not OS. Mel200 was associated with less gastrointestinal toxicity, including mucositis.

Veno-Occlusive Disease of the Liver after High-Dose Cytoreductive Therapy with Busulfan and Melphalan for Autologous Blood Stem Cell Transplantation in Multiple Myeloma Patients

Veno-occlusive disease of the liver (VOD) is a potentially severe complication of high-dose cytoreductive therapy (HDT) used for stem cell transplantation (SCT). This complication is uncommon after HDT for autologous SCT (ASCT) in patients with multiple myeloma (MM). The Spanish Myeloma Group/PETHEMA conducted a study (MM2000) for patients with newly diagnosed MM consisting of induction with alternating VBMCP/VBAD chemotherapy followed by intensification with busulfan/melphalan (Bu/MEL) with a second high-dose therapy procedure in patients not achieving at least near-complete remission with the first procedure. After 2 years of the trial, a number of episodes resembling classical VOD but with a late onset were recognized. Consequently, the protocol was modified, and Bu/MEL was replaced by melphalan 200 mg/m 2 (MEL-200). Three years later, after a total of 734 patients had undergone first autologous SCT, the incidence and characteristics of VOD episodes were analyzed in the whole series. Nineteen cases of VOD (8%) were observed among the first 240 patients receiving Bu/MEL, whereas only 2 (0.4%) were observed among the 494 patients treated with MEL-200 ( P < .0001). VOD manifestations in the Bu/MEL group appeared at a median of 29 days (range, 3–57 days) after ASCT. Mortality directly attributable to VOD was 2% in the Bu/MEL group and 0.2% in the MEL-200 group ( P = .026). This high incidence of severe VOD probably had a multifactorial origin (busulfan followed by melphalan and previous use of BCNU). This observation should be kept in mind when designing future trials for the treatment of MM.

A Prospective, Randomized, Phase III Study of Melphalan 200 mg/m2 (Mel200) Versus Melphalan 100 mg/m2 (Mel100) in Newly Diagnosed Myeloma Patients.

Several trials have shown the superior impact of high-dose melphalan (usually 200 mg/m2, MEL200) versus standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m2, MEL100) was also superior to the standard dose, but MEL100 has not been clinically compared with MEL200 in a randomized study. In this prospective, randomized, phase III trial, we compared the efficacy and toxicity of MEL200 and MEL100. The primary end points were complete remission (CR) rate, event-free survival (EFS) and incidence of gastrointestinal toxicity, infections and treatment-related mortality (TRM). Inclusion criteria were previously untreated myeloma, aged ≤ 65 and Durie and Salmon stage II or III. Exclusion criteria were abnormal pulmonar, cardiac, liver and renal function, HBV, HCV, or HIV positivity, concomitant cancer or psychiatric disease. The institutional review board approved the protocol and written informed consent was obtained from all patients. All patients received 2 cycles of 28-day-dexamethasone-doxorubicin-vincristine (doxorubicin 50 mg/m2 day 1, vincristine 1 mg day 1, dexamethasone 40 mg days 1–4) and 2 cycles of cyclophosphamide (4 g/m2, day 1) followed by stem cell harvest. MEL200 patients was conditioned with 2 cycles of melphalan 200 mg/m2 and MEL100 patients with 2 courses of melphalan 100 mg/m2, both followed by stem cell reinfusion. Two-hundred and ninety-eight patients (median age 57) were randomized, 149 to MEL200 and 149 to MEL100. All patients were evaluated for response, EFS and OS. Patient characteristics were similar in both groups. Chromosomal 13 was deleted in 69% of MEL200 and 45% of MEL100 patients (p=0.015). Ninety-six patients completed tandem MEL200; 103 tandem MEL100. In intention-to-treat analysis, the very good partial response rate was higher in MEL200 group (37% versus 21%, p=0.003), but CR was 15% in the MEL200 group and 8% in the MEL100 group (p=0.07). After a median follow-up of 30.5 months, the 3-years EFS was 46% in the MEL200 and 26% in the MEL100 group (HR=0.7, 95% CI 0.51–0.97, p=0.03). The 3-years overall survival (OS) was 81% in the MEL200 and 73% in the MEL100 group (HR=0.69, 95% CI 0.42–1.13, p=0.14). Duration of grade 4 neutropenia and thrombocytopenia was comparable, but a higher proportion of MEL200 patients required platelet transfusions (p=0.002). Grade 3–4 non-hematologic adverse events were more frequent in the MEL200 patients (38% versus 19%, p<0.0001). The incidence of grade 3–4 mucositis was 16% after MEL200 and 3% after MEL100 (p<0.0001). The incidence of severe gastrointestinal toxicity was 19% after MEL200 and 2% after MEL100 (p<0.0001). The incidence of grade 3–4 infections and of TRM was similar in both groups. In conclusion, MEL200 resulted in a significantly higher very good partial response rate. This translated in a superior EFS, but not OS.

A Prospective, Randomized, Phase III Study of Melphalan 200 mg/m2 (MEL200) Versus Melphalan 100 mg/m2 (MEL100) in Newly Diagnosed Myeloma Patients.

Several trials have shown the superior impact of high-dose melphalan (usually 200 mg/m2, MEL200) versus standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m2, MEL100) was also superior to the standard dose, but MEL100 has not been clinically compared with MEL200 in a randomized study. In a case-matched study, response rate and event-free survival of MEL200 were superior to MEL100, but overall survival (OS) was similar. In this prospective, randomized, phase III trial, we compared the efficacy and toxicity of MEL200 and MEL100. Between January 2002 and July 2006, 299 patients were enrolled. Inclusion criteria were previously untreated myeloma, aged < 65 and Durie and Salmon stage II or III. Exclusion criteria were abnormal cardiac function, respiratory disease, abnormal liver function, abnormal renal function, HBV, HCV, or HIV positivity, concomitant cancer or psychiatric disease. The institutional review board approved the protocol and written informed consent was obtained from all patients. All patients received: 2 dexamethasone-doxorubicin-vincristine debulking courses (doxorubicin 50 mg/m2 day 1, vincristine 1 mg day 1, dexamethasone 40 mg days 1, 2, 3, 4, each course repeated every 28 days), 2 cycles of cyclophosphamide (4 g/m2, day 1) plus G-CSF followed by stem cell harvest. The MEL200 group was conditioned with 2 cycles of melphalan 200 mg/m2 followed by stem cell reinfusion; the MEL100 group was conditioned with 2 courses of melphalan 100 mg/m2 followed by stem cell reinfusion. At the present, 246 patients, median age 57 (range 32–65), completed the assigned therapy and were evaluated for response, progression-free survival (PFS) and OS. One-hundred and twenty-four patients were randomized to MEL200 and 122 to MEL100. Patient characteristics were similar in both groups. Abnormal cytogenetics (13q deletion, t(4;14), t(11;14), p53) were 75% in MEL200 patients and 56% in MEL100 patients (p=0.05). Forty-six patients did not complete tandem MEL200; 36 patients did not complete tandem MEL100. The near complete response rate of MEL200 was superior to MEL100 (32% versus 18%, p=0.011), but partial response was 80% versus 71%, respectively (p=0.079). The median follow-up for censored patients was 26.5 months. The 3 years PFS was 51% in the MEL200 arm and 33% in the MEL100 arm (HR=0.81, 95% CI 0.55–1.21, p=0.31). The 3 years OS was 86% in the MEL200 group and 71% in the MEL100 group (HR=0.82, 95 CI 0.45–1.48, p=0.51). Duration of grade 4 neutropenia and thrombocytopenia was comparable in two arms, but MEL200 patients required more platelet transfusions (p=0.03). Grade 3–4 non-hematological adverse events were reported in 49% of the MEL200 patients and in 38% of the MEL100 patients (P=0.07). The most frequent grade 3–4 adverse events were infections (54% of MEL200 patients versus 45% of MEL100 patients, p=0.25), mucositis (31% of MEL200 patients versus 7% of MEL100 patients, p=0.002) and gastrointestinal toxicities (20% of MEL200 patients versus 14% of MEL100 patients, p=0.3). In conclusion, MEL200 resulted in a significantly higher near complete response rate but this did not translate in a superior PFS and OS.

Risk-Adapted Dosing of Melphalan for Systemic AL Amyloidosis (AL) Lowers Treatment-Related Mortality: Early Death but Not Post-3 Month Survival Is Linked to Cardiac Involvement.

Autologous stem cell transplant (SCT) with high-dose melphalan is a standard therapy for selected patients with AL. Treatment-related mortality (TRM), however, remains 10% to 15%. Risk-adapted melphalan (MEL) aims to reduce TRM (Blood 2002; 99). Over the past 6 years we have used risk-adapted MEL at 200, 140 and 100 mg/m2. Dosing was based on age (MEL200 if ≤ 60, MEL140 if 61 to 71, MEL100 if > 71) for patients with no cardiac involvement, involvement of 1 or 2 major organ systems (of kidneys, liver/GI tract and peripheral nervous system) and creatinine clearance (CrCl) ≥ 51ml/min. Similarly, with cardiac involvement and/or CrCl < 51, MEL140 was used for those < 61 and MEL100 for those 61 to 71. Patients < 41 were treated with MEL200 as a rule. Patients with advanced involvement of the heart or ≥3 organ systems, or with cardiac involvement and age ≥ 71, were not SCT candidates. We followed TRM, defined as death during G-CSF mobilization or within 100 days of SCT, and also asked if survival at 3 months post-SCT was affected by achievement of complete hematologic response (CR) or by clonal Ig VL germline gene use. Of the 303 amyloid patients seen in that period, 94 were mobilized with G-CSF for SCT, 50M/44W with a median age of 57 (range, 32–73) at a median of 3 months from diagnosis (1–43). None had prior SCT and 71% (n=67) were untreated for plasma cell disease, including 45 who entered a clinical study employing adjuvant oral therapy after SCT. Fifty percent had dominant renal amyloid, 28% (n=27) cardiac, and 71% (n=67) single organ involvement. Clonal lambda disease was present in 83% (n=78) and serum free light-chain abnormalities in 95% (57/60). Patients were assigned to MEL200 (n=35), MEL140 (n=42) or MEL100 (n=17). There were 8 early deaths, 4 related to treatment (RTT), 1 in mobilization and 3 in SCT, and 4 related to progression of disease before SCT. All were associated with cardiac amyloid. Seven of the 8 were in the MEL100 group (RTT=3) and 1 was MEL140 (RTT=1). Overall TRM was 4.3% (4/94) with 3 in the MEL100 group. With a median follow-up of 22 months (1–77), survival is 81% and median survival has not been reached. From mobilization, non-cardiac patients had significantly better survival [88% (59/67) vs 63% (17/27), p<0.01] but from 3 months post-SCT they survived no better than those with cardiac amyloid (p=0.29). Median survival for the MEL100 group is 47 months (vs MEL 200, p=0.02) while median survivals for the others are not yet reached. At 3 months post-SCT, CR neither differed by dose [MEL200 34% (11/32), MEL140 29% (11/38), MEL100 50% (5/10)] nor significantly affected survival [CR 93% (25/27) versus non-CR 88% (45/53), p=0.22]. Clonal Ig VL germline donors were identified in 81 cases [common: 6a=23, 2a2=15, 3r=9, DPK1=5] but did not affect survival. In sum, risk-adapted dosing of melphalan has a low TRM. Patients with cardiac involvement are at risk of early death but by 3 months post-SCT their survival is not significantly different than non-cardiac patients. These results highlight the need for new approaches to improve survival of AL cardiac patients during SCT with risk-adapted melphalan.

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

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 <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 <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 (<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 CharacteristicsHO <2400 mCiHO ≥ 2400 mCiMelphalan 200p MEL200 vs HON212063Median Age52 (45–61)53 (36–64)55 (35–69)NSIgA Type33%40%14%.03Median B2M @ Dx3.153.153.5NSDurie Salmon III43%55%67%NSNumber with Δ13003NSCR/PR @ SCT5%/57%5%/70%6%/68%NS1ry Refractory38%25%25%NSTransplant OutcomesHO <2400 mCiHO ≥ 2400 mCiMEL200MEL 200 vs HOORR/CR conversion95%/55%90%/48%92%/32%NS/.06NRM5%20%3%.07Median OSNR31 months52 monthsNSMedian EFS30 months23 months19 months.3

Mel-140 and TBI vs Mel-200 Prior to Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma - a Single Institution Experience.

Between 1991–98, twenty-nine patients with myeloma received Mel-140 and TBI (960 cGy) followed by Cytoxan mobilized autologous PBSCT. Between 1998 and April, 2004, 41 patients received Mel-200 alone followed by autologous PBSCT. The two groups were comparable regarding age, gender, stage, number of prior regimens and ß2 microglobulin at diagnosis. However, the Mel-200 group had greater proportion of patients with IgG myeloma (78% vs 38%) and shorter time from diagnosis to transplant (301 days vs 581 days). Results: Neutrophil engraftment was similar in the two groups. However, platelet engraftment, transfusion requirements, length of stay and number of days on antibiotics were worse in the Mel-TBI group. The complete and very good partial responses were high in both groups Mel TBI 58.6% vs Mel-200 56% (p=0.81). Median overall survival (OS) was 3.5 years and 3.8 years for Mel TBI and Mel-200 groups, respectively (p=0.75). Event-free survival (EFS) was 1.9 years and 2.3 years, respectively (p=0.88). Survival after relapse post-PBSCT was short, median 1.1 and 1.8 years, respectively. We present here the results of two groups of myeloma patients treated consecutively in a single institution. The Mel-200 patients had a higher proportion of IgG myeloma and were transplanted earlier in the phase of their disease. As expected, regimen-related toxicities were higher in the Mel-TBI group. The response rates, OS, and EFS were similar. These results are in keeping with published reports of prospective randomized studies. Mel-200 is now the standard conditioning regimen for autologous transplant for myeloma.