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Reduced intensity conditioning has decreased mortality in HCT and has increased the age of eligible patients (pts), but has increased risk of post-transplant relapse. One strategy to decrease the risk of relapse in MDS pts with IPSS > Int-1 who benefit from immediate HCT is pre-transplant treatment with 5-azacitidine. We analyzed outcomes of 22 pts who received a median of 3 (1–7) cycles of 5-azacitidine (AZA) and 13 pts who received supportive care alone (NO-AZA) prior to allogeneic HCT. Pts who received other chemotherapy for treatment of MDS were excluded. Pts received targeted busulfan (3500–6000 AUC) and fludarabine conditioning followed by peripheral blood HCT from an HLA sibling or unrelated donors between July 2004 and April 2007. Pts received GVHD prophylaxis consisting of tacrolimus plus either methotrexate or mycophenolate mofetil. AZA pts were significantly older [median age 56 (range 40–69) yr] than the NO-AZA pts [median age 49 (range 34–63) yr] (p=0.03). At referral to HCT and before starting 5-azacytidine, 20 AZA pts had MDS at Int-1 (8), Int-2 (9), or High (3) IPSS risk category; and 1 pt each had CMML-1 and CMML-2. The 12 NO-AZA pts had MDS Low (1), Int-1 (3), and Int-2 (5); 2 pts did not have karyotype information available, and one had CMML-1. Prior to HCT, AZA pts had MDS Low (4), Int-1 (6), Int-2 (7) or High (3), and 1 pt each had CMML-1 and CMML-2; NO-AZA pts had MDS Low (1), Int-1 (4), Int-2 (5) and High (1), and one had CMML-2 (p=0.8). Cytogenetics were not available in 1 pt. Donors for AZA pts were HLA-identical siblings (6), HLA-A, B, C, DRB1 matched unrelated (13), or single locus mismatched unrelated (3). Donors for NO-AZA pts, were HLA-identical siblings (8), matched unrelated (4), or a single locus mismatched unrelated (1) (p=0.06). Post-transplant follow-up for surviving pts is a median of 13.6 (range 3.8–31.2) vs 25.6 (range 3.8–34.7) months, respectively for AZA vs. NO-AZA pts (p=0.12). All evaluable AZA pts achieved complete remission posttransplant. In the NO-AZA pts, 1 pt had persistent MDS at the time of his death on day 62; the remainder achieved complete remission. At 100 days, the cumulative incidence of grade 2–4 GVHD was 92% vs 68% and grade 3–4 GVHD 36% vs. 8% in AZA vs NO-AZA, respectively, but the apparent differences can be at least in part explained by the higher prevalence of unrelated donors used for AZA pts and their higher age. Using a Cox proportional hazards regression model including age and donor, the use of 5-azacitidine was not a significant predictor for GVHD. At 2 years after HCT, the cumulative incidence of relapse was 45% vs 37%, in AZA vs NO-AZA (p=ns), and overall survival was 43% vs. 59%, in AZA vs NO-AZA (p=ns). Causes of non-relapse death in AZA include relapse of pre-existing NHL (1), GVHD (2), infection (1 viral, 1 fungal), interstitial pneumonitis (1), sudden cardiac death (1), and unknown (1) and in NO-AZA pts include GVHD (1), and multiorgan failure (1). From these observations it appears that pretransplant treatment with 5-azacitidine may not be associated with a lower risk of relapse posttransplant. However, 5-azacitidine may be of value in stabilizing disease thereby allowing time for pts who may otherwise experience progressive disease to reach transplant. Further appropriately designed studies will be needed to address the safety of this strategy.

MM is the most common indication for high-dose chemotherapy (HDC) and autologous stem cell rescue. Among 13,431 pts receiving HDC for MM, the 3-year probability of survival is 67% ± 1% with autotransplantation (IBMTR data). Pre-clinical data from our lab demonstrate a synergistic cytotoxic interaction from sequential M and topoisomerase I inhibitors in human MM cell lines. Thus, we conducted a trial where poor prognosis chemosensitive, relapsed, and primary refractory pts were primed for stem cell collection with cyclophosphamide (50 mg/kg/d X 2d) and GCSF. Pts were then treated with fixed doses of M (50 mg/m2/d X 3d; total dose = 150 mg/m2) followed immediately by dose-escalated T (6.7–56.7 mg/m2/d X 3d; total dose = 20–170 mg/m2) in separate cohorts of younger (≤ 60) and elderly (> 60) patients with MM. The standard dose of M was decreased to allow for dose-escalation of T. One hundred nineteen patients are evaluable for toxicity, response and survival (54 elderly and 65 younger). The maximum tolerated dose (MTD) in the elderly cohort is 30 mg/m2 total dose T (dose level 2); dose-limiting toxicity (DLT) at 40 mg/m2 was grade 3 musculoskeletal toxicity. The median age of the elderly pts was 65 yrs (range 61–77). The MTD in younger patients was a total T dose of 127.3 mg/m2 (dose level 7); DLT at 170 mg/m2 was grade 4 transaminitis. The median age of the younger pts was 53 yrs (range 33–60). The response rate (CR + PR) in elderly subjects (includes 38 pts enrolled at the MTD) was 65%, and 77% in those ≤ 60 (7 pts enrolled at the MTD thus far). Grade 3–4 mucositis was common at all dose levels of T and increased in incidence with T dose-escalation. Median days to ANC ≥ 500/ml X 3d for all patients was d+11, and for platelets ≥ 20K X 7d was d+16. No correlation between time of engraftment and dose level was observed. The 100 day non-relapse mortality was 1.7% (one patient died from sepsis and one from ARDS). At a median follow up of 25.3 and 35.3 months for the elderly and young cohorts, respectively, the 3-year overall survival is 70% for both groups. At a median follow up of 15.3 months for the elderly and 14 months for the young cohort, the 3-year event-free survival is 32% and 40%, respectively. The pharmacokinetics of high-dose M and T have been determined in all patients on this trial, and the AUC and CMAX of T appear to be linear with dose. Pts with stable disease after transplant were found to have an increased clearance of melphalan and a lower AUC of T lactone and T total drug. SNP analyses of 71 pts using the Nanogen DrugMet SNP genotyping assay showed that CYP3A5*3 carriers appear to have increased T metabolism that is associated with a poorer response to MT. The relative risk a CYP3A5*3 allele carrier would have a PR or SD was 1.77 with a 95% CI of 1.37–2.28. The remaining goals of this trial are to enroll 43 pts at the MTD for both the young and elderly cohorts, to determine topoisomerase I levels and distribution in CD138-selected plasma cells, and to define the levels and function of the ABCG2/BCRP pump in plasma cells (for which T is the best substrate). This trial was supported in part by NCI grant CA082533 and GlaxoSmithKline.

Background: Approximately 25% of patients with newly diagnosed (MM) fail to respond and progress while receiving conventional induction. As a result, these patients have primary refractory disease. Even though these patients still benefit from HD chemotherapy, their PFS ranges from 4–8 months, while OS is approximately 12 months. PCL accounts for approx. 2% of newly diagnosed MM patients and represents the most aggressive form of disase. These patients often do not respond to standard systemic cytotoxic therapies and their median survival is less than 12 months. Therefore, novel treatment approaches are paramount for patients with primary refractory MM and PCL. The proteasome inhibitor BTZ has been shown to sensitize myeloma cells to melphalan both in vitroand in vivo, but the mechanism is not well understood. In this study we examine the effects of BTZ, followed by BTZ and HDMel as conditioning regimen for TanPSCT in this poor-risk group.

Background: Approximately 25% of patients with newly diagnosed (MM) fail to respond and progress while receiving conventional induction. As a result, these patients have primary refractory disease. Even though these patients still benefit from HD chemotherapy, their PFS ranges from 4–8 months, while OS is approximately 12 months. PCL accounts for approx. 2% of newly diagnosed MM patients and represents the most aggressive form of disase. These patients often do not respond to standard systemic cytotoxic therapies and their median survival is less than 12 months. Therefore, novel treatment approaches are paramount for patients with primary refractory MM and PCL. The proteasome inhibitor BTZ has been shown to sensitize myeloma cells to melphalan both in vitro and in vivo, but the mechanism is not well understood. In this study we examine the effects of BTZ, followed by BTZ and HDMel as conditioning regimen for TanPSCT in this poor-risk group. Methods: Patients with primary refractory MM or PCL received 2 cycles of BTZ at 1.3 mg/m2. followed by HD Mel (200 mg/m2) and one dose of BTZ at 0.7 mg/m2, 1.0 mg/m2 or 1.3 mg/m2, as a conditioning regimen prior to TanPSCT. The dose of BTZ was given immediately after the last dose of HD Mel. Bone marrow(BM) samples were collected at baseline, on day 4 and after 2 cycles of BTZ, and at 3 months after TanPSCT, for GEP and Fanconi anemia(FA) pathway genes assessment. Results: To date, 17 patients have been enrolled and treated, and 11 patients are evaluable for response. Median age is 59 years (46–70) with the following myeloma distribution: 55% IgA and 45% IgG. FISH analysis showed the following: del 13q (44%), t (4; 14) (11%), t (11; 14) (11%), trisomy 11 (11%), and polyploid (11%); standard karyotype was normal in 88% of patients and complex karyotype in 12%. Median time to WBC engraftment (days) was 13 and 12 after the first and second transplant, respectively. Median time to plt engraftment (days) was 20 and 17, after the first and second transplant, respectively. There were no dose limiting toxicities. Observed grade 3 toxicities were related to the conditioning regimen and similar to those observed with HDMel alone. One patient developed diffuse alveolar hemorrhage after the first cycle of BTZ, which resolved, but was removed from study. After 2 cycles of BTZ, 45% of patients achieved PR, and 55% had stable disease. Overall response rate at 3 months from the second transplant increased to 90%(CR=36%,VGPR=27% andPR=27%). Only 1 patient developed progressive disease after the first transplant. Evaluations of BM samples by GEP and FA pathway gene expression are underway. Conclusions: Single agent BTZ induced responses in 45% and the combination of HD Mel and BTZ as conditioning regimen for TanPSCT was well tolerated and improved response rates to 90%. These early results suggest that this regimen is very active in this poor-risk group. Evaluation of collected BM samples for GEP and FA pathway genes may provide important insight into the mechanisms associated with the observed synergy between BTZ and HD Mel. A Phase II study is underway.

Reduced intensity conditioning has decreased mortality in HCT and has increased the age of eligible patients (pts), but has increased risk of post-transplant relapse. One strategy to decrease the risk of relapse in MDS pts with IPSS > Int-1 who benefit from immediate HCT is pre-transplant treatment with 5-azacitidine. We analyzed outcomes of 22 pts who received a median of 3 (1–7) cycles of 5-azacitidine (AZA) and 13 pts who received supportive care alone (NO-AZA) prior to allogeneic HCT. Pts who received other chemotherapy for treatment of MDS were excluded. Pts received targeted busulfan (3500–6000 AUC) and fludarabine conditioning followed by peripheral blood HCT from an HLA sibling or unrelated donors between July 2004 and April 2007. Pts received GVHD prophylaxis consisting of tacrolimus plus either methotrexate or mycophenolate mofetil. AZA pts were significantly older [median age 56 (range 40–69) yr] than the NO-AZA pts [median age 49 (range 34–63) yr] (p=0.03). At referral to HCT and before starting 5-azacytidine, 20 AZA pts had MDS at Int-1 (8), Int-2 (9), or High (3) IPSS risk category; and 1 pt each had CMML-1 and CMML-2. The 12 NO-AZA pts had MDS Low (1), Int-1 (3), and Int-2 (5); 2 pts did not have karyotype information available, and one had CMML-1. Prior to HCT, AZA pts had MDS Low (4), Int-1 (6), Int-2 (7) or High (3), and 1 pt each had CMML-1 and CMML-2; NO-AZA pts had MDS Low (1), Int-1 (4), Int-2 (5) and High (1), and one had CMML-2 (p=0.8). Cytogenetics were not available in 1 pt. Donors for AZA pts were HLA-identical siblings (6), HLA-A, B, C, DRB1 matched unrelated (13), or single locus mismatched unrelated (3). Donors for NO-AZA pts, were HLA-identical siblings (8), matched unrelated (4), or a single locus mismatched unrelated (1) (p=0.06). Post-transplant follow-up for surviving pts is a median of 13.6 (range 3.8–31.2) vs 25.6 (range 3.8–34.7) months, respectively for AZA vs. NO-AZA pts (p=0.12). All evaluable AZA pts achieved complete remission posttransplant. In the NO-AZA pts, 1 pt had persistent MDS at the time of his death on day 62; the remainder achieved complete remission. At 100 days, the cumulative incidence of grade 2–4 GVHD was 92% vs 68% and grade 3–4 GVHD 36% vs. 8% in AZA vs NO-AZA, respectively, but the apparent differences can be at least in part explained by the higher prevalence of unrelated donors used for AZA pts and their higher age. Using a Cox proportional hazards regression model including age and donor, the use of 5-azacitidine was not a significant predictor for GVHD. At 2 years after HCT, the cumulative incidence of relapse was 45% vs 37%, in AZA vs NO-AZA (p=ns), and overall survival was 43% vs. 59%, in AZA vs NO-AZA (p=ns). Causes of non-relapse death in AZA include relapse of pre-existing NHL (1), GVHD (2), infection (1 viral, 1 fungal), interstitial pneumonitis (1), sudden cardiac death (1), and unknown (1) and in NO-AZA pts include GVHD (1), and multiorgan failure (1). From these observations it appears that pretransplant treatment with 5-azacitidine may not be associated with a lower risk of relapse posttransplant. However, 5-azacitidine may be of value in stabilizing disease thereby allowing time for pts who may otherwise experience progressive disease to reach transplant. Further appropriately designed studies will be needed to address the safety of this strategy.

MM is the most common indication for high-dose chemotherapy (HDC) and autologous stem cell rescue. Among 13,431 pts receiving HDC for MM, the 3-year probability of survival is 67% ± 1% with autotransplantation (IBMTR data). Pre-clinical data from our lab demonstrate a synergistic cytotoxic interaction from sequential M and topoisomerase I inhibitors in human MM cell lines. Thus, we conducted a trial where poor prognosis chemosensitive, relapsed, and primary refractory pts were primed for stem cell collection with cyclophosphamide (50 mg/kg/d X 2d) and GCSF. Pts were then treated with fixed doses of M (50 mg/m2/d X 3d; total dose = 150 mg/m2) followed immediately by dose-escalated T (6.7–56.7 mg/m2/d X 3d; total dose = 20–170 mg/m2) in separate cohorts of younger (≤ 60) and elderly (> 60) patients with MM. The standard dose of M was decreased to allow for dose-escalation of T. One hundred nineteen patients are evaluable for toxicity, response and survival (54 elderly and 65 younger). The maximum tolerated dose (MTD) in the elderly cohort is 30 mg/m2total dose T (dose level 2); dose-limiting toxicity (DLT) at 40 mg/m2was grade 3 musculoskeletal toxicity. The median age of the elderly pts was 65 yrs (range 61–77). The MTD in younger patients was a total T dose of 127.3 mg/m2(dose level 7); DLT at 170 mg/m2was grade 4 transaminitis. The median age of the younger pts was 53 yrs (range 33–60). The response rate (CR + PR) in elderly subjects (includes 38 pts enrolled at the MTD) was 65%, and 77% in those ≤ 60 (7 pts enrolled at the MTD thus far). Grade 3–4 mucositis was common at all dose levels of T and increased in incidence with T dose-escalation. Median days to ANC ≥ 500/ml X 3d for all patients was d+11, and for platelets ≥ 20K X 7d was d+16. No correlation between time of engraftment and dose level was observed. The 100 day non-relapse mortality was 1.7% (one patient died from sepsis and one from ARDS). At a median follow up of 25.3 and 35.3 months for the elderly and young cohorts, respectively, the 3-year overall survival is 70% for both groups. At a median follow up of 15.3 months for the elderly and 14 months for the young cohort, the 3-year event-free survival is 32% and 40%, respectively. The pharmacokinetics of high-dose M and T have been determined in all patients on this trial, and the AUC and CMAXof T appear to be linear with dose. Pts with stable disease after transplant were found to have an increased clearance of melphalan and a lower AUC of T lactone and T total drug. SNP analyses of 71 pts using the Nanogen DrugMet SNP genotyping assay showed that CYP3A5*3 carriers appear to have increased T metabolism that is associated with a poorer response to MT. The relative risk a CYP3A5*3 allele carrier would have a PR or SD was 1.77 with a 95% CI of 1.37–2.28. The remaining goals of this trial are to enroll 43 pts at the MTD for both the young and elderly cohorts, to determine topoisomerase I levels and distribution in CD138-selected plasma cells, and to define the levels and function of the ABCG2/BCRP pump in plasma cells (for which T is the best substrate). This trial was supported in part by NCI grant CA082533 and GlaxoSmithKline.