Autologous Stem Cell Transplantation For Myeloma Research Articles

OAB-038: Physiotherapist-led exercise prehabilitation embedded within the multiple myeloma autologous stem cell transplantation pathway: a feasibility randomised controlled trial

OAB-038: Physiotherapist-led exercise prehabilitation embedded within the multiple myeloma autologous stem cell transplantation pathway: a feasibility randomised controlled trial

Antimicrobial stewardship in high-risk febrile neutropenia patients

BackgroundThe 2011 4th European Conference on Infections in Leukemia (ECIL4) guidelines recommend antibiotics de-escalation/discontinuation in selected febrile neutropenia (FN) patients. We aimed to assess the impact of an antimicrobial stewardship (AMS) program based on these guidelines on antibiotics use and clinical outcomes in high-risk FN patients.MethodsWe conducted an observational study in the hematology department of Cochin University Hospital in Paris, France. An ECIL4-based antibiotics de-escalation and discontinuation strategy was implemented jointly by the hematologists and the AMS team. The pre-intervention (January–October 2018) and post-intervention (January-October 2019) periods were compared. We retrospectively collected clinical and microbiological data. We compiled antibiotics consumptions via hospital pharmacy data and standardized them by calculating defined daily doses per 1000 patient-days. We analyzed the two-monthly antibiotic consumption using an interrupted time series method and built a composite endpoint for clinical outcomes based on transfer to the intensive care unit (ICU) and/or hospital death.ResultsOverall, 273 hospital stays (164 patients) in the pre-intervention and 217 (148 patients) in the post-intervention periods were analyzed. Patients were mainly hospitalized for intensive chemotherapy for acute leukemia or autologous stem-cell transplant for myeloma. Patients were slightly younger in the pre-intervention compared to the post-intervention period (median age 60.4 vs 65.2 years, p = 0.049), but otherwise comparable. After implementation of the AMS program, glycopeptide and carbapenem use decreased by 85% (p = 0.03) and 72% (p = 0.04), respectively. After adjustment on confounders, the risk of transfer to the ICU/death decreased significantly after implementation of the AMS program (post-intervention period: odds-ratio = 0.29, 95% Confidence Interval: 0.15–0.53, p < 0.001).ConclusionImplementation of a multidisciplinary AMS program for high-risk neutropenic patients was associated with lower carbapenem and glycopeptide use and improved clinical outcomes.

The Impact of Maintenance Therapy in the Treatment of Multiple Myeloma with a Subset Analysis on Patients Who Achieve a Complete Response (CR) or Better: A Retrospective Analysis

BackgroundMultiple myeloma (MM) is an incurable hematologic malignancy, which is now managed as a chronic disease. The general upfront treatment paradigm is induction therapy, followed by autologous stem cell transplant (ASCT) for those who are candidates, then maintenance for two years or until progression. The development of multiple novel drugs has extended median survival to over seven years. Patients who achieve a complete response (CR) or better following ASCT have improved outcomes. Likewise, minimal residual disease (MRD) negativity is associated with increased progression-free survival (PFS) and overall survival (OS), but its implications on practice patterns remain unclear. This raises the question of whether patients who achieve undetectable disease will benefit from maintenance therapy. Time off treatment may improve quality of life and decrease healthcare expenditure.MethodsA retrospective chart review was performed on all adult patients who underwent ASCT for MM at the University of Virginia between January 2012 and December 2016. Tandem or salvage transplants were excluded from the analysis. Data were collected on patient characteristics (age, sex), disease characteristics (immunoglobulin and light chain restriction, ISS stage, cytogenetic abnormalities), lines of systemic treatment prior to ASCT, depth of response achieved pre- and post-ASCT, and post-ASCT maintenance therapy. For patients who achieved CR or better post- ASCT, time to relapse, time to death, and duration of follow-up were collected. Patients with t(4;14), t(14;16), deletion 17p (or p53 deletion) were categorized as poor risk.Cox proportional hazard models were used to assess the relationship between the outcomes of interest and the different covariates of interest. In the univariate models, if the p -value was less than 0.1, then the covariate was considered in the final model. In the final model, covariates were removed if their p -values were greater than 0.1. For the final model, hazard ratios (HR) with confidence intervals (CI) are provided.ResultsSeventy-six patients were included in the analysis. Patient demographics and pre- and post-ASCT disease characteristics are described in Table 1. Median age at ASCT was 62 years. Sixty-three percent were male and 37% were female. Eighty-five percent of patients had poor-risk cytogenetics. Most patients proceeded to transplant after one (72%) or two (20%) lines of induction therapy. Thirteen percent achieved CR or better pre-ASCT versus 28% post-ASCT. Maintenance therapy was the only variable associated with time to relapse post-ASCT (p=0.005), as shown in Figure 1. Patients who did not receive post-ASCT maintenance were three times more likely to relapse (HR 3.0, 1.4-6.4 95% CI).Twenty-one patients (28%) achieved CR or better post-ASCT. Median follow-up was 27.5 months. Median time to relapse and death for these patients was 19.3 and 25.6 months, respectively. Thirteen patients received maintenance with bortezomib or lenalidomide, while seven were observed off maintenance. Data were unavailable for one patient. Four of the 13 patients on maintenance relapsed, while six of seven patients off maintenance relapsed. There was no significant difference in time to relapse between those who received maintenance and those who did not (p=0.91; HR 1.1, 0.3-4.1 95% CI).DiscussionMultiple myeloma is a chronic disease. New drug development and optimizing treatment combinations continue to extend time to next therapy and OS. Our findings of improved PFS with post-ASCT maintenance are consistent with prior large studies. The proportion of our patients who achieved CR or better post-ASCT is comparable to those in other prospective trials. Interestingly, maintenance did not seem to impact outcomes for our patients who achieved CR or better post-ASCT. Considering these findings, we question the additional benefit of maintenance therapy for patients with undetectable disease. It is possible these patients may remain off therapy for years and realize higher quality of life while sparing healthcare resources and expenditure. Our findings and conclusions are limited by the small population size and retrospective analysis. Larger, prospective studies are warranted. [Display omitted] DisclosuresFoster:Bristol Meyers-Squibb: Other: Clinical trial investigator.

Autologous Stem-Cell Transplantation for Myeloma: Here to Stay?

Autologous Stem-Cell Transplantation for Myeloma: Here to Stay?

Association between CMV and Invasive Fungal Infections After Autologous Stem Cell Transplant in Lymphoproliferative Malignancies: Opportunistic Partnership or Cause-Effect Relationship?

Unlike allogeneic transplant, autologous stem cell transplantation (ASCT) represents a procedure with a low-risk of cytomegalovirus (CMV) symptomatic reactivation-infection/end-organ disease (CMV complications) and invasive fungal disease (IFD). However, novel drugs for the treatment of lymphoproliferative malignancies could cause an increase of such opportunistic infections, even after ASCT. To the best of our knowledge, there are no published data demonstrating an association between CMV and IFD in the autologous setting, while this association has been widely reported in allogeneic transplantation. We have reviewed our series of 347 ASCT in myeloma and lymphoma patients performed over a period of 14 years with the aim of investigating the descriptive and analytical epidemiology of bacterial, CMV and IFD complications, focusing on the association between CMV and IFD. Patients with myeloma have significantly fewer bacterial infections and IFD than patients with lymphoma, but a similar rate of CMV complications. Descriptive epidemiological data are consistent with the literature, indicating an overall incidence of 36%, 3.5% and 15.5% for bacterial infections, IFD and CMV complications, with a case mortality rate of 4%, 16.7% and 3.7%, respectively. A strong correlation between CMV and IFD exists, with 8 cases of IFD out of a total of 12 presenting a CMV complication. At multivariate analysis, a diagnosis of lymphoma, ≥3 previous treatment lines and age ≥60 years were found to be independent risk factors for IFD. Duration of neutropenia (ANC < 500/mm3) ≥7 days represents an independent risk factor for CMV complications, where neutropenia most likely represents a crude surrogate biomarker indicating a deeper and longer state of overall immunosuppression. From our data we conclude that (1) myeloma patients are at lower risk of bacterial infections and IFD as compared with lymphoma patients but are at equal risk of CMV complications, most likely as a consequence of a selective impact of bortezomib on Herpes Viruses infection control; (2) a significant association exists between CMV and IFD, although a possible cause-effect relationship remains to be determined; (3) IFD is a rare complication after ASCT but burdened by a mortality rate of about 17%, with peak rates in older lymphoma patients who underwent more intensive therapeutic regimens.

Syngeneic stem cell transplantation generates antigen-specific T cells that maintain myeloma-immune equilibrium

Abstract Multiple myeloma (MM) is a largely incurable hematological malignancy characterized by clonal expansion of plasma cells in bone marrow (BM). Autologous stem cell transplantation (ASCT) remains a standard treatment for MM, allows intensive cytoreduction and induces inflammation in the context of lymphodepletion. We hypothesized that SCT may overcome myeloma-induced immune defects to restore immune-equilibrium. To address this, we developed a model of ASCT for MM using Vk*MYC myeloma. Surprisingly, we demonstrate the induction of T cell-dependent MM control after SCT as recipients of syngeneic BM grafts containing T cells had prolonged survival and reduced tumor burden compared to BM alone. This anti-myeloma activity was independent of γδ T, natural killer (NK) and NK T cells and was dependent on CD4+and CD8+ T cells. MM-primed T cells, harvested from SCT recipients with controlled MM, protected against relapse in secondary recipients and were Vk*MYC clone-specific. Recipients of MM-primed T cells had increased central memory CD8+ T cells and transfer of MM-primed CD8+ T cells was sufficient to prevent relapse. Furthermore, TCR sequencing of CD8+ T cells from mice with controlled MM revealed a higher clonotype overlap relative to MM-free SCT recipients, consistent with MM-specific T cells. Donor IFNγ secretion and signaling was critical to protective immunity and CD8+ T cells from mice with relapsed MM had impaired IFNγ production compared to those with controlled disease. Importantly, IFNγ production was profoundly augmented by CD137 agonist treatment such that majority of mice controlled disease. These data provide new insights into the mechanisms of action of SCT in myeloma and suggest the use of CD137 agonists to prevent relapse.

Improved survival with salvage autologous stem-cell transplantation in myeloma

Improved survival with salvage autologous stem-cell transplantation in myeloma

High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation.

High dose melphalan (HDM) and autologous stem cell transplantation (ASCT) retains a central role in the treatment of myeloma. The aim of this study was to determine whether HDM exposure (area under the concentration vs. time curve, AUC), is significantly associated with transplant outcomes. Melphalan concentrations were measured in six to 11 plasma samples collected after HDM (median 192mgm(-) (2) ) to determine melphalan AUC for a total of 114 patients. Binary logistic regression was used to assess whether melphalan AUC was associated with severe (≥ grade 3) oral mucositis. Multivariate Cox regression was used to assess whether melphalan AUC was significantly associated with time to progression, progression-free survival and overall survival (OS). Melphalan AUC ranged from 4.9 to 24.6mgl(-1) h, median 12.84mgl(-1) h. Melphalan AUC above the median was a risk factor for severe mucositis (HR 1.21, 95% CI 1.06, 1.38, P=0.004) but was also associated with significantly improved overall survival (OS) (HR 0.40, 95% CI 0.20, 0.81, P=0.001), with an estimated median survival of 8.50years vs. 5.38years for high vs. low AUC groups. Multivariate analysis did not identify melphalan AUC as being significantly associated with time to progression or progression-free survival. This large scale pharmacodynamic analysis of HDM demonstrates that high melphalan exposure is associated with improved survival, with an acceptable increase in transplant toxicity. These results suggest studies targeting a higher AUC are warranted in patients undergoing HDM and ASCT for myeloma.

Propylene glycol-free melphalan as conditioning regimen for autologous transplantation in myeloma.

High-dose melphalan has been the drug of choice for preparative regimens for autologous stem cell transplantation in multiple myeloma. Propylene-free melphalan (Evomela™) is a newer formulation of melphalan, which incorporates Captisol® to produce a stable product upon reconstitution. In addition to avoiding propylene glycol with its' potential side effects, this approach improves the overall stability of reconstituted melphalan and can ensure intended dose delivery. In this paper, we review the published literature regarding this formulation. We focus on its' chemistry, pharmacokinetics and clinically available data for its use in myeloma autologous stem cell transplantation setting.

Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

These Clinical Practice Guidelines are endorsed by the Japanese Society of Medical Oncology (JSMO) incidence and epidemiology Multiple myeloma (MM) accounts for 1% of all cancers and ∼10% of all haematological malignancies. The incidence in Europe is 4.5–6.0/100 000/year with a median age at diagnosis of between 65 and 70 years; the mortality is 4.1/100 000/year. Almost all patients with MM evolve from an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to MM at a rate of 1% per year. In some patients, an intermediate asymptomatic but more advanced pre-malignant stage termed smouldering (or indolent) multiple myeloma (SMM) can be recognised. SMM progresses to myeloma at a rate of 10% per year over the first 5 years following diagnosis, 3% per year over the following 5 years and 1.5% per year thereafter [1]. diagnosis Diagnosis of MM should be based on the following tests: [1] -Detection and evaluation of the monoclonal (M-) component by serum and/or urine protein electrophoresis (concentrate of 24 h urine collection); nephelometric quantification of IgG, IgA and IgM immunoglobulins; characterisation of the heavy and light chains by immunofixation; and serum-free light-chain (FLC) measurement; -Evaluation of bone marrow (BM) plasma cell infiltration: BM aspiration and/or biopsies are the standard options to evaluate the number and characteristics. Moreover, the BM sample should be used for cytogenetic/fluorescence in situ hybridization (FISH) studies and also has the potential for immunophenotypic and molecular investigations; -Evaluation of lytic bone lesions: a radiological skeletal bone survey, including spine, pelvis, skull, humeri and femurs is necessary. A magnetic resonance imaging (MRI) or computed tomography (CT) scan may be needed to evaluate symptomatic bony sites, even if the skeletal survey is negative and the patient has symptoms suggesting bone lesions. Moreover, MRI provides greater detail and is recommended whenever spinal cord compression is suspected. Fluorodeoxyglucose positron emission tomography is currently under evaluation but should not be systematically used; -Complete blood cell count, with differential serum creatinine and calcium level.

Role of autologous bone marrow transplant in multiple myeloma

The treatment of newly diagnosed multiple myeloma has evolved rapidly over the recent years. In younger patients, autologous stem cell transplantation (ASCT) is still considered the standard of care, but the availability of new effective drugs with novel mechanisms of action in the last decade has resulted in a new scenario that has caused the role of transplantation itself to be currently undergoing scrutiny. Maintaining the response of first-line therapy is an important objective in multiple myeloma, where despite intensive therapy followed by ASCT the majority of patients will relapse. In this field, the recent results of different consolidation and maintenance therapies after transplant are very encouraging. These strategies have come to stay and will play an essential role in the next future to improve the prognosis of young patients with newly diagnosed multiple myeloma. Finally, new conditioning regimens will also be tested in the forthcoming years in an attempt to further improve posttransplant responses. Multiple myeloma ASCT must be integrated within a more global therapeutic approach including new and more effective induction, consolidation, and maintenance approaches. Efforts aimed in the development of more effective and less toxic preparative regimens to further augment disease control are also warranted.

1086P - Aggregated Analysis of Reported Efficacy for Salvage Autologous Stem-Cell Transplantation for Myeloma

ABSTRACT The rate of complete response (CR) achieved soon after autologous stem cell transplantation (ASCT) is often used as a measure of relative success when comparing interventions in similar or randomized identical settings. New therapies are often tried in salvage and rescue settings early on in development and some of these therapies may electively or necessarily be combined with ASCT also in the rescue/salvage setting. Response rates in such settings are anecdotally low however few studies exist and many variables confound their understanding not least of which is the small numbers of patients involved. Methods A pubmed/medline/googlescholar search strategy along with hand-searching key haematology and oncology journal archives and key paper bibliographies was adopted. 13 published cohorts were identified that reported CR as an outcome from second/salvage ASCT across a total of 1064 patients ( table 1 ). Reported data that included patients who did not have measurable disease (i.e. already in CR) going into the second transplant were excluded as the intent was to observe salvage ASCT effects in measurable disease. Complete response rate (CR), Event free survival/Progression free survival (EFS ∼ PFS were considered heuristically similar) and overall survival (OS) were aggregated. Weighted mean estimates (WME) of efficacy were derived for each setting adjusted according to the number of patients associated with each CR rate. Table: 1086P . CR rate % Number of patients PFS/EFS Months OS Months Krishnan 2011 35 295 Olin 2007 5 41 8.5 20.7 N Shah 2011 11 44 12.3 31.7 Simpson 2007 33 45 12.5 30.6 Jiminez 2011 7 81 Mehta 1998 33 42 12.5 32 Qazilbash 2006 21.4 14 6.8 29 Elice 2006 3.8 26 14.8 38.1 Giaccone 2011 17.4 46 Cavo 2007 19.4 103 Sirohi 2002 31.3 94 10.5 15 Rosinol 2012 11 85 Cook 2011 26 148 Sum 1064 Weighted Average 23.8 11.3 20.8 Results The WME CR rate after a second ASCT was calculated to be ∼24%. Aggregated WME of EFS was 11.2 months and OS 20.8 months. Conclusions Complete responses can be expected in approximately 1 in 4 patients who are selected for clinical trials and given a second transplant for relapsed or non-responding disease. Variability in reported rates is considerable.CR rate Percent Number of Patients PFS/EFS months OS months Disclosure D.P. Smethurst: Full time employee of Immunocore Ltd. and Consultant to Adaptimmmune Ltd. Share options in Immunocore Ltd. and Adaptimmune Ltd.

Current Trends in Autologous Stem-Cell Transplantation for Myeloma in the Era of Novel Therapies

Since the mid 1990s, high-dose therapy followed by autologous stem-cell transplantation (ASCT) has been considered the standard of care for frontline therapy in younger patients with multiple myeloma (MM). During the past 10 years, thalidomide, bortezomib, and lenalidomide have been widely incorporated to the therapeutic armamentarium for the treatment of this disease. These agents show promise for improving the rate of complete remission both before and after ASCT without increasing toxicity. However, it is not clear whether such therapies are superior if they are used as an alternative to transplantation or whether they may reduce the need for and use of transplantation in patients in whom treatment is indicated. Therefore, the role of ASCT itself is a matter of debate: Should it be used upfront or as salvage treatment at the time of progression in patients initially treated with novel agents? This review presents current trends in ASCT for MM in the era of novel therapies.

The Introduction of Novel Agents Improves Outcomes of Young Patients with Myeloma (MM) Treated with Autologous Stem Cell Transplant (ASCT)

AbstractAbstract 1348 Background:There has been an improvement in the population based survival of patients with MM in the UK (Office of National Statistics), however, because of the way the data is collected it is uncertain what has happened to the outcome of younger patients. High dose melphalan with ASCT has formed an integral part of the treatment of younger patients with myeloma for more than 20 years. During this time the context within which this treatment has been delivered has changed. Peripheral blood stem cell harvesting has replaced bone marrow harvesting, and importantly, novel agents have become available at induction and at relapse. It is not known how these changes have affected patient outcome. We analysed the survival of patients undergoing ASCT for MM in a single referral centre over an 18 year period to assess the impact of these changes. Patients:1291 patients with myeloma were registered on the Royal Marsden Hospital Database in the period between 1981–2009, of which 875 patients underwent autologous transplantation. Bone marrow transplant (BMT) was performed in 191 patient, while 684 patients had peripheral blood stem cell transplant (SCT). Prognostic Factors:The following factors were found to be associated with improved overall survival (OS) in univariate analysis: Salmon Durie Stage A vs Stage B (p<0.004), ISS Stage I vs II vs III (p<0.001), response to chemotherapy CR vs PR vs Other (p<0.007), Platelets >130 vs <130 × 109/L (p<0.001), Hb >10 vs <10 g/dl (p<0.001), Calcium <10 vs >10mg/dl, Albumin >35 vs <35g/L (p<0.034), B-2M >3.5 vs <3.5 mg/l (p<0.001), IgG vs IgA vs BJ (p<0.038). Variables significant in multivariate testing were: Response to chemotherapy CR vs <CR (HR 1.4; 95% CI 1.0–2.0), Platelets >130 (HR 0.52; 95% CI 0.3–0.9), Calcium (HR1.7; 95% CI 1.2–2.5) and B2M (HR2.1; 95% CI 1.5–2.9). These variables were significantly associated with OS in the overall dataset, and in the subgroup of younger patients under the age of 60. Response and Survival:The overall response (OR) rate following induction chemotherapy was 84%, including 22% complete responses (CR). Following autologous SCT, CR rates improved to 42%, with an OR of 91%. Analysis of actuarial survival for the whole group of patients who had SCT showed that young patients had significantly longer survival (Median survival: <60yrs vs. >60yrs; 8.7yrs vs 6.2yrs, p<0.009). In order to assess the impact of the introduction of new therapeutic agents in, we defined groups of patients treated in five year periods: 1991–1996, 1997–2003, 2004–2009. 5 year OS was unchanged when comparing the first two cohorts. However, the cohort of patients treated from 2004–2009 were associated with significant improvement in 5 year survival rates, from 61% for the earlier quinquennia to 82% for those treated in 2004-9 (p<0.001). We also assessed the impact of the introduction of SCT compared to BMT. SCT entered routine use at this centre in 2002, and patient outcomes did not improve from 2002–2004. The improved survival after 2004 is therefore unlikely to be due to the introduction of SCT. Summary:We found that patient survival following ASCT did not change significantly during the period 1991–2004. However, since 2004 survival rates have improved significantly, and the group that benefitted most were patients under the age of 60. This time period corresponds to the incorporation of novel agents such as thalidomide, bortezomib and lenalidomide into induction and relapse regimens, and suggests that novel agents have significantly improved the outcome of younger patients with myeloma in the context of treatment with ASCT. Disclosures:Boyd:celgene: Honoraria. Davies:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Presence of the Killer Immunoglobulin-Like Gene KIR3DS1 Is Associated with Poor Progression Free and Overall Survival Following Autologous Stem Cell Transplantation in Patients with Myeloma.

Abstract 2840Poster Board II-816Multiple myeloma (MM) remains incurable with a median survival of 3–4 years. Despite high dose therapy and autologous stem cell transplant (ASCT) most patients relapse with median progression-free survival (PFS) of 2.5–4 years and overall survival (OS) of 4–5 years. Although allogeneic SCT (allo-SCT) is potentially curative due to a graft-versus-myeloma effect, its applicability is significantly limited by high transplant related mortality (TRM). Therefore, the identification of additional independent biological predictors of outcome is required in order to tailor therapy to disease. Natural killer (NK) cells provide first line defence against tumors. NK cells have been shown to recognize and kill myeloma cells both in the allogeneic and autologous settings and donor NK genotype has been shown to influence leukemia free survival following allo-SCT. The aim of this study was to investigate the impact of KIR genotype on event-free (EFS) and OS following ASCT for MM. We performed KIR genotyping on 190 patients with MM receiving a first autologous transplant. KIR genotype and haplotype frequencies were comparable to those published for normal controls. Factors found on univariate analysis to be associated with a shorter EFS included haplotype Bx (containing at least 1 of the KIR B haplotype-defining loci- KIR2DL5, 2DS1, 2DS2, 2DS3, 2DS5, or 3DS1) (median 547 vs 656 days, P = 0.036), ≥3 activating KIR genes (median 547 vs 615 days, P = 0.046), the presence of activating KIR genes KIR2DS1 and KIR3DS1 (median 456 vs 589 days, and 464 vs 619 days, P=0.045 and 0.01 respectively). Disease status at ASCT was the most highly predictive factor for EFS. In patients with good risk disease (CR or PR at ASCT) KIR3DS1 status was highly predictive for EFS 464 days (341–586) vs 731 days (599–862) (P = 0.003) and OS 807days (713-901) vs 967 (925-1009) (P=0.023). KIR3DS1 was not predictive in patients with poor risk disease (P=0.36). Of note KIR3DS1+ve patients were equally represented in good risk (CR and PR) and poor risk (refractory or relapsed) groups at ASCT (around 30% in both groups). Notably the median EFS for KIR3DS1+ good risk patients was not significantly different to poor risk disease patients (P = 0.061). ASCT outcome was then determined according to 3 main groups based on disease status and KIR3DS1 status; A: Good Risk, KIR3DS1-ve; B: Good Risk, KIRDS1+ ve; and C Poor risk (KIR3DS1+ve or -ve). The RR of relapse or death was 1.0, 1.9 (P=0.002, 95% CI 1.3-3.1), and 3.0 (P=0.0001, 95% CI 1.9-4.8) respectively. By multivariate analysis, after adjusting for the presence of adverse cytogenetics and serum albumin and β2m, the KIR3DS1 status and grouping remained highly predictive of poor EFS, RR of 1.0, 2.7 (P= 0.021, 95%CI 1.2-6.2) and 5.3 (P= < 0.0001, 95%CI 2.4-11.7) respectively. The prognostic value of KIR3DS1 however, was greatest in patients in whom the ligand for the corresponding inhibitory KIR3DL1, Bw4 was missing. KIR3DS1+ KIR3DL1+ HLA-Bw4 negative patients had significantly reduced median EFS of 400d (315-495) vs 615 (545-684) for all other patients (P=0.048). Again this was most striking in good risk patients. Patients who had the genotype KIR3DS1+ KIR3DL1+ HLA-Bw4 –ve had a significantly shorter EFS survival of 372 days compared to 509 days in KIR3DS1+KIR3DL1+HLA-Bw4+ patients and 793 days for KIR3DS1 negative individuals (P=0.004). In conclusion: Our data from 190 patients with MM suggests that KIR3DS1, a gene previously linked to an increase risk of progression to invasive cervical carcinoma, independently predicts for poor EFS and OS following ASCT. A significant proportion (30%) of patients who are defined as good risk at ASCT (CR and PR) are KIR3DS1+ve and have an EFS which is not significantly different from patients who have refractory/relapsed disease at ASCT. This effect of KIR3DS1 is more significant in the absence of HLA-Bw4, the ligand for the inhibitory receptor KIR3DL1. The mechanism for this is effect is unclear and we are currently performing functional studies to further understand these findings. Disclosures:Apperley:Novartis: Consultancy, Honoraria. Marin:Novartis: Consultancy, Research Funding.

Analysis of Beam (Carmustine, Etoposide, Cytosine Arabinoside, Melphalan) Versus High Dose Melphalan (HDM) with Autologous Rescue in Multiple Myeloma(MM).

Autologous stem cell transplantation is an established treatment that leads to prolongation in overall and disease free survival in MM. BEAM and M have been widely used as conditioning regimen for autologous stem cell transplant (ASCT) in patients with MM. At our centre MM patients with low creatinine clearance (Crcl) and a low performance status were offered Melphalan only as conditioning regime for ASCT. We report on our experience of HDM in comparison with standard BEAM. Records of 53 consecutive patients who had ASCT for myeloma at our centre between 2000 and 2003 were examined. Patients were staged as per Salmon and Durie (SD) criteria and EBMT response criteria were used for assessment post transplant .35 patients had BEAM conditioning (SD criteria 31-IIIA, 3-IA, 1-IIA) and 18(SD criteria 14- IIIA, 4-IIIB) had M.).Patients who received BEAM had a median age of 55 (range 38–66), median follow up of 19 months and those who received HDM had a median age of 60 (range 45 –69), follow up of 20.5 months. Stem cell source was peripheral blood (PBSC) in 50 patients, 1 Bone marrow (BM), and 2 BM and PBSC. HDM at a Dosage of 140 –200 mg/m2was administered in all HDM cases except for 1 patient who had 70mg/m2 because of Crcl of 17.4 ml/min. BEAM group had Carmustine 300mg/m2 (−6), Ara- C 800mg/m2 (−5 to −2), Etoposide 800mg/m2 (−5 to −2), M 140mg/m2 (−1). Patients in the M group had significantly lower haemoglobin and higher serum creatinine levels in comparison with the BEAM group. The 100-day treatment related mortality (TRM) was 5.5 % in HDM group, which was comparable to 2.2 % in the BEAM group. 9 out of 18 patients who had HDM relapsed and 9 out of 35 patients who had BEAM relapsed at follow up with Median relapse free survival (RFS) being 575 days in HDM group and has not achieved yet in BEAM group (p= .017). This data confirm that BEAM ASCT lead to significant prolongation of disease free survival with low TRM.Our data also suggest the effectiveness of HDM in patients who because of poor performance status and/or abnormal renal function may not tolerate BEAM ASCT

Outcomes of autologous stem cell transplantation in patients with multiple myeloma who received dexamethasone-based nonmyelosuppressive induction therapy.

High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) improves survival in myeloma (MM). The role of induction therapy on outcomes of ASCT in MM has not been systematically studied. Nonmyelosuppressive (NMS) steroid-based induction can be used in MM, with the potential of reducing neutropenias and other toxic effects prior to ASCT. NMS induction however could be associated with poorer outcomes if disease control or stem cell collection were inadequate. We studied outcomes of 136 MM patients who underwent HDC and ASCT as part of their initial therapy between March 1998 and December 2000. Of these, 46 received HDC and ASCT without any exposure to myelosuppressive agents, 39 received myelosuppressive therapy for disease control and/or stem cell collection, and 51 received alkylating agent-based initial treatment. We compared OS and EFS rates, stem cell collectability, and contamination of the grafts with monoclonal plasma cells. After a median of 33 months, response rates, EFS and OS rates were comparable in the three groups of patients. Adequacy of stem cell collection and plasma cell contamination were similar. Our data support the hypothesis that NMS induction for patients with MM is safe and effective and does not compromise the results of HDC.