SCT In Multiple Myeloma Research Articles

MM-518 Outcome of Non-Cryopreserved DMSOFree Peripheral Blood Stem Cells in Autologous SCT in Multiple Myeloma: An Attempt to Overcome Financial Toxicity of Cryopreservation

MM-518 Outcome of Non-Cryopreserved DMSOFree Peripheral Blood Stem Cells in Autologous SCT in Multiple Myeloma: An Attempt to Overcome Financial Toxicity of Cryopreservation

Outcome of Non-Cryopreserved DMSO-Free Peripheral Blood Stem Cells in Autologous SCT in Multiple Myeloma: An Attempt to Overcome Financial Toxicity of Cryopreservation

Outcome of Non-Cryopreserved DMSO-Free Peripheral Blood Stem Cells in Autologous SCT in Multiple Myeloma: An Attempt to Overcome Financial Toxicity of Cryopreservation

Allogeneic SCT in Multiple Myeloma: Limited Predictive Value of Chimerism Analysis for Heralding Relapse/Progression Due to Extramedullary Disease

Background Allogeneic stem cell transplantion (allo SCT) for multiple myeloma (MM) takes advantage of a tumor cell-free graft along with potential immunosurveillance of residual malignant plasma cells. However, multiple factors such as treatment-related mortality (TRM) and morbidity and post-allo disease progression question the more widespread use of allo SCT. The induction of an early complete donor chimerism (DC) is thought to be associated with a low incidence of relapse and improved survival. Interestingly, data on chimerism analysis are relatively scarce for allo SCT in MM. Therefore, we retrospectively evaluated longitudinal DC results by short tandem repeat (STR)-based techniques from a single lab. Data were correlated with a set of baseline and outcome variables. In addition, disease- and treatment related factors like extramedullary disease (EMD), acute and chronic graft-versus-host disease (GvHD) and post-transplant consolidation were analyzed for impact on outcome.Patients and methods We identified 118 MM patients (pts) receiving non-myeloablative allo SCT at two German centers between 01/2006 and 12/2014. 90% of pts underwent allo SCT at relapse. Median follow-up was 42 months (mos), median overall survival (OS) 25 mos (range, 1-106) and TRM was 15%. Two-thirds of pts had received treosulfan/fludarabine as conditioning regimen. Median interval between MM diagnosis and allo SCT was 40.5 mos (range, 7-175) and median number of prior treatment lines was 3 (range, 1-10). 24 pts received allografts from matched related donors, 61 from matched-unrelated donors, and 33 pts from mismatched donors. Chimerism analysis was performed by STR-PCR on whole blood and T cell subsets using a validated multiplex STR-assay with a documented sensitivity of 1%. Response assessment was performed according the international myeloma working group guidelines.Results 1398chimerism samples (mean: 12/patient, 119 marrow, 1279 blood)) were analyzed. Median interval from allo SCT to first assessment was 15 (range, 3-62) days. Median duration of chimerism sampling was 24 mos. No graft rejections occurred. Full DC (> 99%) was achieved in 117/118 pts. Pts who lost full DC had a significantly shorter progression free survival (PFS) than those with sustained DC (HR 0.2; p<.0001). OS, however, was not different. In patients who developed disease progression, loss of DC versus sustained DC was not predictive for outcome. In spite of relapse, a full DC was found in peripheral blood in 82% and in 45% in bone marrow samples of pts, respectively. With respect to clinical predictors of outcome, the occurrence of acute GvHD had no impact on PFS nor OS. In contrast, induction of chronic GvHD was associated with prolonged PFS (HR 0.50; p=.0088) and OS (HR 0.39; p<.001). Despite the induction of full DC in the blood, 13/118 (11%) of pts not in complete response received preemptive donor lymphocyte infusions (DLI). DLI without any concomitant signs of graft rejection or disease progression was associated with favourable OS (HR 0.43; p=.0067). When analysing relapse patterns after allo SCT, a 35% rate of EMD was observed. Interestingly, OS was not different when compared to intramedullary relapses. However, when allo SCT was performed as part of a consolidation therapy for prior EMD or plasma cell leukemia, OS was significantly shorter than compared to patients without EMD history (median OS 6 vs. 41 mos, p=.0035) Nevertheless, 25% of these EMD patients showed long-lasting remissions beyond 4 years. High risk cytogenetics (del17p, t(4;14) and +1q21), CMV reactivation or use of ATG had no impact on outcome.Conclusions To the best of our knowledge, this is the largest study of serial DC analysis in a cohort of clinically well characterized MM pts. The robust engraftment in almost all patients as well as the lack of graft rejections indicate the severe immunosuppression in MM due to pre-treatment and underlying disease. On the other hand, the most important predictors for PFS and OS was the occurrence of cGvHD. Preemptive DLI may further improve tumour control. The frequent spread of myeloma to extramedullary sites can be interpreted as an escape to more immuno-privileged regions as compared to the bone marrow. This pattern clearly limits the potential of prolonged serial DC analysis as the only tool for relapse detection. Our observations underscore the need to prospectively evaluate complementary strategies in this setting. DisclosuresEinsele:Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Knop:Celgene Corporation: Consultancy.

Long-Term Survivors after Stem Cell Transplantation in Multiple Myeloma: Bone Marrow Minimal Residual Disease, PET/CT and Immunological Status

Abstract Introduction: Multiple myeloma (MM) is considered an incurable disease. Best results are obtained with autologous stem cell transplantation (ASCT). The achievement of complete remission (CR) is the crucial step for a prolonged survival. Unfortunately, even with the use of new regimens, the vast majority of patients will ultimately relapse. In fact, with conventional chemotherapy, ASCT or allogeneic stem-cell transplantation (alloSCT), only 1‰, 10% and 15%, respectively are alive and in continued CR beyond 10 years in the best circumstances. The aim of the present research was to evaluate the proportion of patients in long-term CR after stem-cell transplantation, describing the different aspects related to minimal residual disease (MRD) and immunological correlative studies. Methods: We analyzed the medical records of 160 patients who underwent single melphalan-based ASCT from March 31th 1994 to December 31th 2010, allowing at least 5 years of follow up from diagnosis (median follow-up of 8 years), as well as 58 patients who had received an alloSCT over a 28-year period. Bone marrow (BM) samples from the alive CR patients beyond 5 years were analyzed to assess MRD using multiparameter flow cytometry (MFC) with Euroflow 8-color consensus panel. Serum free-light chains (FLC) and immunoglobulin heavy/light chains (HLC) (The Binding Site) were assayed by immunonephelometry. A whole-body PET/CT (Siemens) was also performed to evaluate extramedullary and bone disease. Furthermore, a detailed panel of surface cell markers by MFC was also developed to evaluate B, T and NK cell compartments, among other immune cell subpopulations in BM and/or peripheral blood. Results: Twenty patients (20/160; 12.5%) were alive and in continuous CR after ASCT beyond 5 years; nine (5.7%) remained in CR for more than 10 years. In the alloSCT group, 6 out 58 patients (10.3%) were in CR beyond 5 years (3 of them for more than 10 years). Remarkably, two patients were in CR after 20 and 28 years after ASCT and alloSCT, respectively. Fourteen long survivors after ASCT (70%) had received maintenance therapy. These regimens were mainly interferon (8 patients), followed by thalidomide (3) or thalidomide plus bortezomib (3). None patient showed increased uptake of FDG by PET/CT suspicious of MM activity, neither in bone lesions nor previous plasmacytomas. However, in the vast majority of patients (16/22; 72.7%) there were stable lytic lesions, usually with sclerotic borders. Unspecific findings, particularly lymph nodes with unspecific FDG uptake, were described in 28.6%. Fourteen out of 20 patients after ASCT (70%) and 2 after alloSCT (33.3%) showed oligoclonal bands (OB) in serum and/or urine, differents from the original monoclonal paraprotein by immunofixation. Among the 22 evaluated patients, all but 2 were negative by MFC for MRD in BM. These two patients were in stable CR, with evidence of OB in serum, considering the clone found unrelated to the original one. The aberrant plasma cell population (CD38+/++, CD56+, CD27-, CD19-, CD45-, CD81-, CD117+) was found to a frequency of 0.09% and 0.004% BM cells. Other 4 patients showed a population of plasma cells with some aberrant markers expression; two of them also showed OB. All patients showed normal serum FLC ratio except one patient after alloSCT. Levels of IgG and IgA HLC were also normal, except in one patient each. Six patients had higher IgM HLC ratio than normal, all of them showing OB. We also investigated whether T cell clonal expansion could be also involved. Indeed, patients with OB showed a higher diversity of TCR Vb over-represented, preferentially 13.1 and 17, suggesting a potential oligoclonal expansion of the T cell response. Characterization of TCR repertoire of the long survivors also indicated a higher involvement of the CD8+ compared to CD4+ T cells. In BM, the expression of the co-inhibitory receptor PD-1 on CD8+ T cells was elevated in active MM compared to MGUS and long survivors suggesting that exhausted PD1+CD8+ T cells increase in active MM and recover to normal levels in long survivors. Conclusions: There are a small proportion of long-term survivors after SCT in MM. MRD studies are negatives, but some false positives could be observed by MFC when OB are present. PET invariably showed metabolic CR with stable bone lesions. Our results support that oligoclonal humoral and cellular responses may play an important role in the disease control over the years. Disclosures No relevant conflicts of interest to declare.

Allogeneic hematopoietic SCT in multiple myeloma: long-term results from a single institution.

The role of allogeneic hematopoietic SCT (allo-HCT) in multiple myeloma (MM) remains controversial. A total of 58 patients received an allo-HCT (25 of them with myeloablative conditioning-allo-MAC-and 33 with reduced-intensity conditioning-allo-RIC) at our institution over a 28-year period. The CR rate for allo-MAC was 36%. The incidence of grade III-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) was 28% and 39%, respectively The TRM at any time was 60% and the main causes of death were aGVHD or infectious complications not directly related to GVHD. The estimated PFS and OS at 15 years were 8% and 15%, respectively. The CR rate with allo-RIC was 45%. The incidence of grade III-IV aGVHD and cGVHD were 24% and 41%, respectively. The TRM at any time was 33% and was mainly related to aGVHD. The estimated PFS and OS at 5 years were 22% and 38%, respectively. Despite its high TRM, a proportion of patients with high-risk myeloma (early relapse and newly diagnosed ultrahigh risk) may obtain long-term disease control with allo-HCT. New approaches aimed at decreasing the incidence of aGVHD, and consequently to decrease the TRM, are needed.

Pattern of relapse and progression after autologous SCT as upfront treatment for multiple myeloma

The achievement of CR is the crucial step for a prolonged PFS and OS after an autologous SCT in multiple myeloma (MM). Unfortunately, even with the use of new regimens and the current high CR rates, most, if not all, patients will ultimately relapse or progress. We analyzed the type of relapse or progression (asymptomatic vs symptomatic), clinical features including the presence of extramedullary involvement and time to next treatment in 211 patients who underwent melphalan-based autologous SCT over an 18-year period at our institution. After autologous SCT, serological or asymptomatic relapse/progression was observed in about one half of the patients. The treatment-free interval was significantly longer in patients relapsing from CR than in those progressing from PR (P=0.017). Patients with serological relapse/progression had a significantly longer OS than those relapsing from symptomatic disease (P=0.002). The relapse pattern was similar to the initial clinical presentation. Survival after relapse/progression was shorter in those patients with a 24-h urine M-protein excretion of at least 200 mg (P=0.048). Extramedullary involvement was frequent (24%), being the highest risk in patients with extramedullary involvement at diagnosis (P=0.001).

Donor KIR-Haplotype B Improved Relapse-Free Survival After Allogeneic Stem Cell Transplantation for Multiple Myeloma

AbstractAbstract 2373NK-cell alloreactivity determined by donor killer-cell immunoglobulin-like receptors (KIRs) has been shown to be predictive for relapse-free survival in myeloid leukemia after allogeneic stem cell transplantation. The role role of NK-cell allo reactivity in patients with multiple myeloma is unclear. Although the ligands for activating KIRs remain elusive, inhibitory KIRs on donor derived NK-cells and HLA class I molecules on the recipient cell determine NK cell alloreactivity. KIR genes on chromosome 19 segregate independently from HLA genes KIR haplotypes can be distinguished in two groups: group A has a fixed number of inhibitory receptors and only one activating receptor (KIR2DS4), while group B haplotype includes more activating receptor genes. Therefore individuals can be categorised as having A-KIR haplotype (A/A), or B-KIR haplotype which contains either A/B heterocygotes or B/B homocygotes KIRs. To analyse the effect of donor KIR-haplotype on outcome in multiple myeloma, we analysed 118 patients with a median age of 51 years (r: 29 – 68) who underwent allogeneic stem cell transplantation. Gender of the study population was predominantly male (n = 75, female: n = 33). Stem cell source was mainly peripheral blood stem cells (n = 105) and derived from unrelated donors (n = 81) or HLA-identical sibling (n = 37). 46 patients received graft from HLA-mismatched donor. The majority of the patients received a melphalan (100 – 140 mg/m2)/fludarabine-based reduced conditioning regimen (N = 106), either as part of an auto-allo-tandem protocol or as an allogeneic salvage protocol after relapse to an autograft. 46 patients had experienced relapse to an autograft prior to allogeneic stem cell transplantation. 79 patients were transplanted from KIR haplotype Bx and 39 from KIR haplotype A. Both groups were well balanced regarding age, HLA match, stem cell source, CMV seropositivity, remission status prior to transplantation, del 13q14, and relapse to prior autograft.After a median follow-up of 5 years the 5-year estimated disease-free and overall survival was better for KIR haplotype B donors in comparison to KIR haplotype A donors (30 % vs. 14 %, p = 0.008, and 49 % vs. 36 %, p = 0.07). The disease-free survival benefit for KIR haplotype B was mainly seen in HLA-matched patients (4y DFS: 39 % vs. 18 %, p = 0.005), while in HLA mismatch transplantation no difference according to KIR haplotype could be detected (26 % vs. 18 %, p = 0.5).The difference in survival in the HLA-matched group was due to higher risk of relapse for KIR haplotype A in the HLA-matched group (cumulative incidence at 1 year 46 % vs. 17 %, p = 0.005).In a multivariate Cox model KIR haplotype A remained a significant factor for worse disease-free (HR: 1.82, p = 0.008) and overall survival (HR: 1.69, p = 0.042). Other significant factors in the multivariate analysis were female donor sex (HR: 1.67, p = 0.04) and chemo-refractory disease at transplantation (HR: 1.76, p = 0.03) for OS and factors for DFS were unrelated donor (HR: 1.83, p = 0.02) and patient's age as continous variable (HR: 1.03, p =0.008) and donor female sex (HR: 1.62, p = 0.03).We conclude that female donor sex and KIR haplotype A are important risk factors for outcome of allogeneic SCT in multiple myeloma and should be considered for donor selection. Disclosures:No relevant conflicts of interest to declare.

Phase II trial of high-dose topotecan, melphalan and CY with autologous stem cell support for multiple myeloma

In spite of high-dose chemotherapy followed by autologous hematopoietic SCT multiple myeloma (MM) eventually recurs, highlighting the need for more effective treatment approaches. Patients received topotecan 3.5 mg/m(2) intravenously on days -6 to -2, melphalan 70 mg/m(2) intravenously on days -3 and -2 and CY 1 g/m(2) intravenously on days -6, -5 and -4. Overall response rate (ORR) consisting of complete response and partial response (CR+PR, PFS, OS and toxicity are reported. Between August 2002 to March 2004, 60 patients (34 men and 26 women) with a median age of 61 years (range 45-72) were enrolled. Forty-one patients were treated for consolidation of first remission, while 19 patients had relapsed/refractory disease. ORR was 85% (CR 12%, very good PR 43% and PR 30%). Median time to neutrophil (ANC>0.5 × 10(9)/L) and plt engraftment (>20 × 10(9)/L) was 10 (range 7-12 days) and 9 days (range 6-79 days), respectively. A majority of the common adverse events were grade 1-3 mucositis/stomatitis (65%), grade 1 or 2 nausea (59%) and grade 1 or 2 diarrhea (41%). Median PFS was 18.5 months and median OS has yet not been reached. In conclusion, topotecan, melphalan and CY is a safe and active conditioning regimen for auto hematopoietic SCT in MM. The ORR and PFS were comparable to high-dose melphalan.

Long–Term Survival of Allogeneic Transplantation(Allo SCT) In Selected Patients with Multiple Myeloma (MM): Disease Free Survival at Two Years May Indicate Long Term Survival

Introduction: Allo SCT offers long term control and in some cases cure in patients with MM. In this study we reviewed our experience at H. Lee Moffitt Cancer Center, of Allo SCT for MM and examined indicators of long term survival.

High-Dose Topotecan, Melphalan and Cyclophosphamide (TMC) with Autologous Stem Cell Support for Multiple Myeloma

Introduction High dose chemotherapy and autologous stem cell transplantation (auto SCT) was associated with prolonged event-free (EFS) and overall survival (OS) in selected patients with multiple myeloma (MM) in at least two randomized controlled trials. High-dose melphalan at 200 mg/m2 is considered the standard regimen, but the complete remission (CR) rate at best is 30–40% and the EFS approximately 2 years. Novel preparative regimens are being evaluated to improve the efficacy without increasing the toxicity. We evaluated the safety and efficacy of a new regimen, Topotecan, Melphalan and Cyclophosphamide (TMC) in patients undergoing auto SCT for MM.Methods The primary objectives were to determine the safety and to evaluate if TMC could increase the CR rate in MM patients undergoing auto SCT. Patients received cyclophosphamide at the dose of 1 g/m2 intravenously over 2 h on days -6, -5, -4; melphalan at the dose of 70 mg/m2 intravenously over 30 min on days -3 and -2 and topotecan at a dose of 3.5 mg/m2 over 30 min for 5 total doses on days -6 to -2.Results 44 patients (26 males, 18 females) with primary refractory disease or in first remission received the TMC regimen followed by auto SCT between August 2002 and March 2004. The median age of patients at auto SCT was 55 years (range 40–67) and the median interval between the diagnosis and auto SCT was 6.3 month (range 2.2– 42 months). Twelve patients (27%) had chromosomal abnormalities on conventional cytogenetic studies. Median follow-up in surviving patients was 47.8 months. Median time to neutrophil engraftment (ANC > 500/dl) and platelet engraftment (>20,000/dl) were 10 (range 7–11 days) and 9 days (range 6–9 days), respectively. Thirty seven patients (84%) were transplanted for consolidation of first remission and 7 for primary refractory disease (16%). Most common adverse events were: grade 1& 2 nausea (59%), grade 1 & 2 diarrhea (41%) and dysphagia (34%). Non-hematologic grade 3 & 4 toxicities were seen in 9 patients (20%) and included infectious complications (2 patients), congestive heart failure exacerbation (2 patients), electrolyte abnormalities including hypocalcemia and hypokalemia (1 patient each), GI complications like dysphagia and vomiting (1 patient each) and cardiac arrhythmia (1 patient). Febrile neutropenia occurred in 8 patients (18%). Thirty-three patients (75%) had a complete or partial response, 9 patients (21 %) had a minimal response or stable disease, while 2 patients had progressed within 3 months of auto SCT. At the time of this analysis, 31 patients are alive, 13 of whom in remission. Four-year EFS was 23.5%, and 4-year OS was 63%. Patients with chromosomal abnormalities had a shorter time to progression (13.9 vs. 19.7 months, p=0.18) that was not statistically significant. These results were similar to those reported by our group in 89 patients who received high-dose mephalan (200 mg/m2) only: complete + partial response rate of 66%; 4-year Kaplan-Meier estimates of EFS and OS 20% and 57%, respectively. (Anagnostoupoulos et al. Cancer 2004).Conclusion TMC is a safe preparative regimen for auto SCT for MM. There is no major advantage over high-dose melphalan alone in terms of CR rate or EFS in patients in first remission or primary refractory disease.

Impact of additional cytoreduction following autologous SCT in multiple myeloma

Reported results of high-dose therapy (HDT) reflect the combined effect of initial therapy and HDT. The incremental contribution of HDT is often difficult to analyze with varying degrees of response pre-HDT. Here we analyze results of HDT in patients with measurable disease at transplant, defined as a serum or 24 h urine M protein of >1.0 g per 100 ml and >200 mg per day, respectively. Paraprotein responses were calculated using measurements prior to HDT and the lowest subsequent measurement. A total of 431 patients were studied; 264 (61.3%) transplanted within 1-year of diagnosis. An additional reduction in paraprotein by 50% following HDT was seen in 86% patients; with 129 patients (30%) obtaining a 90% reduction. Patients with at least a 90% reduction had longer time to progression with no overall survival advantage and this was independent of other prognostic factors for decreased risk of progression. This study provides an estimate of the degree of tumor reduction provided by HDT, in addition to that provided by the initial therapy. In this group of patients with measurable disease after initial therapy, HDT therapy leads to complete responses in nearly a quarter of the patients and a 90% reduction in another 7%, an outcome associated with better progression-free survival.

Multiple myeloma patients receiving pre-emptive donor lymphocyte infusion after partial T-cell-depleted allogeneic stem cell transplantation show a long progression-free survival

The purpose of this study was to determine the role of pre-emptive donor lymphocyte infusion (pDLI) after partial T-cell-depleted allogeneic SCT in patients with multiple myeloma (MM). A cohort of 24 MM patients was treated with partial T-cell-depleted myeloablative SCT between December 1997 and April 2002. These patients were intended to receive pDLI after SCT. The overall response rate after SCT was 83% (20 of 24 patients) with 10 patients (42%) in complete remission (CR). Transplant-related mortality within 1 year after SCT was 29%. Thirteen patients (54%) received pDLI and four patients in partial remission reached CR. GVHD>grade I after pDLI developed in 4 out of 13 patients (30%). Four patients received therapeutic DLI, without preceding pDLI. Eleven patients (46%) are alive, with a median follow-up of 67 months (range, 48-100 months). Seven of these patients (29%) are in continuous CR (CCR), which was confirmed by a negative patient-specific IgH PCR in four patients. All seven patients in CCR received pDLI. Although myeloablative SCT in MM induces high toxicity, we show that the concept of T-cell depletion followed by pDLI is promising and needs to be investigated in a reduced-intensity conditioning setting.