Ruby Delgado

High-dose gemcitabine, busulfan, and melphalan for autologous stem-cell transplant in patients with relapsed or refractory myeloma: a phase 2 trial and matched-pair comparison with melphalan

BACKGROUND High-dose melphalan is of little benefit as a regimen for patients with relapsed or refractory myeloma undergoing an autologous stem-cell transplant (ASCT). The poor performance of single-agent melphalan in this setting prompted us to study a new high-dose combination of infused gemcitabine, busulfan, and melphalan. METHODS We did a phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). We enrolled patients with primary refractory or relapsed myeloma who had received treatment with bortezomib, an immunomodulatory drug, or both, or who were receiving a salvage ASCT. Gemcitabine was infused at 1875 mg/m2 for 3 h for 2 days, followed by busulfan (target area under the curve 4000 μmol/L per min per day for 4 days) and melphalan (60 mg/m2 per day for 2 days). The primary endpoint of this trial was to establish the proportion of patients with measurable disease at ASCT receiving gemcitabine, busulfan, and melphalan who achieved stringent complete remission in accordance with the International Myeloma Working Group criteria. We then retrospectively compared the patients in this study with all other concurrent patients at the MD Anderson Cancer Center who were eligible for this trial but declined to participate or had no financial coverage for ASCT in a clinical trial and instead received melphalan at 200 mg/m2 intravenously over 30 min on 1 day, followed by ASCT (control group). To compare survival outcomes, we used a statistical algorithm to select a subset of patients from this control cohort who were matched in a 1-2:1 ratio with the patients in the gemcitabine, busulfan, and melphalan group by sex, age, disease status, refractory to both proteasome inhibitors and immunomodulatory imide drugs, time from diagnosis to ASCT, and cytogenetic risk. All analyses were per protocol. This is the final analysis of the clinical trial, which is registered at ClinicalTrials.gov, number NCT01237951. FINDINGS Between Nov 30, 2010, and Dec 11, 2013, we enrolled 74 patients into the gemcitabine, busulfan, and melphalan trial. In these patients, median age was 58 years (IQR 51-62), median number of previous lines of therapy was two (2-5), 38 patients had high-risk cytogenetics, 17 were unresponsive to all previous treatments, and 32 were receiving a salvage ASCT. We identified 184 patients for the concurrent control cohort. The study patients and the concurrent controls received similar post-ASCT maintenance. Among patients with measurable disease at ASCT, 16 of 65 patients (24·6%, 95% CI 14·2-35·0) in the gemcitabine, busulfan, and melphalan group had stringent complete remission compared with 22 of 174 patients (12·6%, 10·1-15·1) in the concurrent control group (p=0·040). Median follow-up time was 36 months (IQR 30-46) in the patients receiving gemcitabine, busulfan, and melphalan and 34 months (25-53) in the matched control subset (n=111). With respect to the secondary survival endpoints, the gemcitabine, busulfan, and melphalan cohort had significantly longer median progression-free survival than the matched control cohort (15·1 months [95% CI 8·7-22·1] vs 9·3 months [8·0-10·7]) with a significantly reduced risk of progression or death (HR 0·55, 95% CI 0·38-0·81, log-rank p=0·030), as well as significantly longer median overall survival (37·5 months [26-not reached] vs 23·0 months [16·6-30·5]) and a lower risk of death (HR 0·60, 0·34-0·84, log-rank p=0·0092). For only the patients treated with gemcitabine, busulfan, and melphalan, grade 3 or worse adverse events included grade 3 mucositis (12 patients), grade 3 dermatitis (five patients), grade 3 aminotransferase elevation (seven patients), grade 3 diarrhoea (two patients), and three treatment-related deaths. One death was cardiac sudden death and two were due to sepsis. INTERPRETATION Gemcitabine, busulfan, and melphalan is a comparatively safe and active regimen for ASCT in patients with refractory or relapsed myeloma. Better outcomes were achieved in patients who received this regimen than in a concurrent matched cohort receiving melphalan, although this will need to be confirmed in a prospective, randomised trial. FUNDING Otsuka Pharmaceutical Development & Commercialization and US National Cancer Institute.BACKGROUND High-dose melphalan is of limited benefit as autologous stem-cell transplantation (ASCT) regimen for relapsed/refractory myeloma. Its poor results in this setting prompted us to study a new high-dose combination of infusional gemcitabine/busulfan/melphalan (Gem/Bu/Mel). METHODS We conducted a phase 2 trial of Gem/Bu/Mel in patients with primary refractory or relapsed disease after bortezomib and/or an immunomodulatory drug (IMiD), or receiving a salvage ASCT. Gemcitabine (1,875 mg/m2 over 3 hours × 2 days) was followed by busulfan (target AUC 4,000/day × 4 days) and melphalan (60 mg/m2/day × 2 days). The primary endpoint of this trial was to determine the stringent complete remission (sCR) rate of Gem/Bu/Mel in this population. We then retrospectively compared the study patients with all other concurrent patients eligible for this trial who, instead, received melphalan at 200 mg/m2 IV at our center. For survival outcomes, we used a statistical algorithm to select a subset from the control cohort that matched with the Gem/Bu/Mel patients by gender, age, disease status, double refractoriness to proteasome inhibitors/IMIDs, duration from diagnosis to transplant and cytogenetic risk, in a 1–2:1 ratio. All analyses are per protocol. This is the final analysis of the clinical trial. Trial registered at NCI.gov (NCT01237951). FINDINGS We enrolled 74 patients on the Gem/Bu/Mel trial, median age 58 (interquartile range [IQR], 11), median 2 prior therapy lines (IQR, 3), 38 high-risk cytogenetics, 17 unresponsive to all prior treatments, and 33 receiving a salvage ASCT. Toxicities of Gem/Bu/Mel included grade 3 mucositis (N=12), grade 3 dermatitis (N=5), grade 3 transaminase elevation (N=7), grade 3 diarrhea (N=2), grade 5 sudden death (N=1) and grade 5 sepsis (N=2). The study patients and the 184 concurrent controls received similar post-ASCT maintenance. Gem/Bu/Mel resulted in more sCR (24.6% v 12.6%, P=0.040), similar overall responses (73.8% v 74.1%, P=0.77) and similar transplant-related mortality (4.0% v 3.8%, P=0.90). The median follow-up times for the Gem/Bu/Mel patients and the matched subset (N=111) were 36 months (IQR, 15.2) and 34 months (IQR, 27), respectively. Gem/Bu/Mel resulted in improved progression-free survival (median 15.1 v 9.3 months, P=0.0030; hazard ratio=0.60; P=0.021) and overall survival (median 37.5 v 23 months, P=0.0092; hazard ratio=0.65, P=0.0087). INTERPRETATION Gem/Bu/Mel is a safe and active ASCT regimen for refractory/relapsed myeloma, with better outcomes than a concurrent matched cohort receiving melphalan. Funding Supported by a grant from Otsuka Pharmaceutical Development & Commercialization Inc. and NCI Grant P30 CA016672.

Outcomes in patients with multiple myeloma with TP53 deletion after autologous hematopoietic stem cell transplant.

TP53 gene deletion is associated with poor outcomes in multiple myeloma (MM). We report the outcomes of patients with MM with and without TP53 deletion who underwent immunomodulatory drug (IMiD) and/or proteasome inhibitor (PI) induction followed by autologous hematopoietic stem cell transplant (auto‐HCT). We identified 34 patients with MM and TP53 deletion who underwent IMiD and/or PI induction followed by auto‐HCT at our institution during 2008–2014. We compared their outcomes with those of control patients (n = 111) with MM without TP53 deletion. Median age at auto‐HCT was 59 years in the TP53‐deletion group and 58 years in the control group (P = 0.4). Twenty‐one patients (62%) with TP53 deletion and 69 controls (62%) achieved at least partial remission before auto‐HCT (P = 0.97). Twenty‐three patients (68%) with TP53 deletion and 47 controls (42%) had relapsed disease at auto‐HCT (P = 0.01). Median progression‐free survival was 8 months for patients with TP53 deletion and 28 months for controls (P < 0.001). Median overall survival was 21 months for patients with TP53 deletion and 56 months for controls (P < 0.001). On multivariate analysis of both groups, TP53 deletion (hazard ratio 3.4, 95% confidence interval 1.9–5.8, P < 0.001) and relapsed disease at auto‐HCT (hazard ratio 2.0, 95% confidence interval 1.2–3.4, P = 0.008) were associated with a higher risk of earlier progression. In MM patients treated with PI and/or IMiD drugs, and auto‐HCT, TP53 deletion and relapsed disease at the time of auto‐HCT are independent predictors of progression. Novel approaches should be evaluated in this high‐risk population. Am. J. Hematol. 91:E442–E447, 2016.

Outcome of Patients with Multiple Myeloma and CKS1B Gene Amplification after Autologous Hematopoietic Stem Cell Transplantation

The gain/amplification of the CKS1B gene on chromosome 1q21 region is associated with a poor outcome in patients with multiple myeloma (MM). However, there are limited data on the outcome of patients with CKS1B amplification after a single high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). We retrospectively evaluated the outcome of patients with CKS1B amplification who received an auto-HCT between June 2012 and July 2014 at our institution. We identified 58 patients with MM and CKS1B gene amplification detected by fluorescent in situ hybridization (FISH). We compared their outcomes with a propensity score-matched control group of 58 patients without CKS1B amplification who were treated at approximately the same time. The primary objective was to compare the progression-free (PFS) and overall survival (OS) between the CKS1B and the control groups. Stratified log-rank test with the matched pairs as strata and double robust estimation under the Cox model were used to assess the effect of CKS1B gene amplification on PFS or OS in the matched cohort. Patients in the CKS1B and control groups were well matched for age, gender, disease status, year of auto-HCT, response to pretransplantation therapy, and baseline hemoglobin level. In both groups, 57% patients were in first remission and 43% had relapsed disease at auto-HCT. Twenty-seven (47%) patients with CKS1B amplification had concurrent monosomy 13 or 13q deletion; 6 (10%) by conventional cytogenetics only, 16 (28%) by FISH only, and 5 (9%) by both. Median follow-up after auto-HCT was 25.4 months. The median PFS of the CKS1B and the control groups were 15.0 months and 33.0 months (P = .002), respectively. The median OS have not been reached yet. The 2-year OS rates in the CKS1B and the control groups were 62% and 91% (P = .02), respectively. In conclusion, Patients with CKS1B amplification are more likely to have additional high-risk cytogenetic abnormalities and a shorter PFS and OS after an auto-HCT.

Outcome of autologous hematopoietic stem cell transplantation in refractory multiple myeloma

Despite the introduction of effective, novel agents, the outcome of patients with refractory multiple myeloma remains poor, particularly those who are refractory to both proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs). Limited data are available on the role of autologous hematopoietic stem cell transplantation in this population.

A case control study of syngeneic transplantation versus autologous transplantation for multiple myeloma: two decades of experiences from a single center

High dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) are the standard of care for eligible patients with newly diagnosed myeloma [1]. Unfortunately, relapse rate...

High-risk myeloma and minimal residual disease postautologous-HSCT predict worse outcomes

Abstract The aim of our study was to determine the impact of high-risk disease (HRD) and MRD on outcomes in myeloma patients receiving bortezomib-based induction followed by autologous hematopoietic stem cell transplant (auto-HSCT). HRD included t(4:14), t(14;16), del 17p, del 1p and/or amplification 1q by cytogenetics/FISH; all others were standard-risk disease (SRD). A subset of 165 newly diagnosed myeloma patients in a 2:1 ratio of HRD:SRD was generated using propensity score based nearest neighbor matching. Multiparametric flow cytometry (MFC) was used to detect MRD after auto-HSCT in select patients. MRD+ status at 3 months post auto-HSCT (hazard ratio (HR = 4.23, p = .028) and HRD (HR = 1.72, p = .026) were associated with a shorter PFS. Similarly, MRD+ 3 months post auto-HSCT (HR = 6.93, p = .08) and HRD (HR = 3.54, p < .001) and were associated with a shorter OS. Despite bortezomib-based induction, upfront auto-HSCT, and use of maintenance therapy, PFS and OS remained worse in MRD+ and HRD patients.

Amifostine reduces gastro-intestinal toxicity after autologous transplantation for multiple myeloma

Abstract High-dose melphalan (HDM) followed by autologous hematopoietic cell transplantation (auto-HCT) remains the standard-of-care therapy for multiple myeloma (MM) even with the availability of proteasome inhibitors and immunomodulatory drugs. Gastrointestinal (GI) toxicity is the main cause of morbidity after HDM. Amifostine, a cytoprotective agent, may reduce HDM-associated GI toxicity. We conducted a case control study comparing HDM + auto-HCT with or without amifostine for MM patients. One hundred and seven patients treated at University Hospitals Cleveland Medical Center who received pre-transplant amifostine were compared to 114 patients treated at MD Anderson Cancer Center without use of this agent. Amifostine 740 mg/m2 was administered as a bolus infusion at 24 h and 15 min before HDM. Patients’ characteristics were similar in both the groups. Amifostine therapy was well tolerated without any significant adverse effects. Grade II or greater oral mucositis (27.1% vs 47.4%; p = .002), nausea (31.8% vs. 86.0%; p = .0001), vomiting (18.7% vs. 52.6%; p = .0001) and diarrhea (56.1% vs. 72.7%; p = .006) occurred less frequently in the amifostine-treated group. There was no discernable effect of amifostine on engraftment, progression-free or overall survival. Our results indicate that amifostine decreases GI toxicity while preserving anti-myeloma efficacy of HDM and auto-HCT.

Melphalan based autologous transplant in octogenarian multiple myeloma patients

the need to account for age when comparing survival between these WHO morphologic categories. The current study also suggests clustering of adverse disease features with SSM, when compared to ISM. Consistent with these differences in phenotype, univariate analysis favored ISM over SSM, in terms of survival. However, the difference in survival was not sustained during age-adjusted multivariable analysis that also included other previously established risk factors. By contrast, a similar analysis confirmed the independent survival effect of ASM, when compared to ISM. These observations suggest that functional consequences rather than mast cell burden dictate prognosis in SM. From a practical standpoint, when confronted with the diagnostic dilemma of distinguishing ISM from SSM, survival prediction appears to depend more on age and the presence or absence of risk factors, rather than the specific morphologic distinction. Finally, we emphasize the need for additional studies with larger number of informative cases, before endorsing the findings in the current study, considering the relatively small sample size.