Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) displays microcirculation and permeability by application of contrast-media and diffusion-weighted imaging (DWI) is a tool for ...quantification of cellularity in the investigated area. Recently published examples cover breast cancer, CNS tumors, head and neck cancer, gastrointestinal cancer, prostate cancer as well as hematologic malignancies.
To investigated the influence of age, sex, and localization of the investigated region on findings of DCE-MRI and DWI.
DCE-MRI-parameters amplitude A and exchange rate constant kep as well as the DWI-parameter ADC of the bone marrow of the lumbar vertebral column of 30 healthy individuals covering the typical range of age of tumor patients were evaluated. ADC was calculated using b=0 and a maximal b value of either 400 or 750 s/mm(2).
Amplitude A of DCE-MRI decreased with age (P = 0.01) and amplitude A, exchange rate constant kep as well as ADC based on b = 400 s/mm(2) and b = 750 s/mm(2,) respectively, decreased significantly from the first to the fifth lumbar vertebra with P = 0.02, P = 0.05, P = 0.003, and P = 0.002, respectively.
Quantitative parameters of functional imaging techniques in bone marrow are influenced by the age of the examined individual and the anatomical location of the investigated region.
Abstract 3086▪▪This icon denotes a clinically relevant abstract
Therapeutic options for patients with relapsed multiple myeloma (MM) after autologous stem cell transplantation (ASCT) include novel ...agents, conventional chemotherapy or salvage ASCT, with no standard of care.
We retrospectively reviewed all myeloma patients who relapsed after upfront ASCT and received an autologous re-transplantation as salvage therapy at our center over a period of 15 years (n=200). The aim of our study was to evaluate the role of salvage ASCT in terms of efficacy and to define patients who may benefit most from this treatment approach.
The median follow up after salvage ASCT was 57.1 months. Median progression-free survival (PFS) and overall survival (OS) after salvage ASCT were 15.2 and 42.3 months, respectively. Overall response rate (≥partial response) was 80.4% at day 100, excluding 6 patients who died before assessment. Factors associated with improved PFS and OS after salvage ASCT included remission duration of >18 months after upfront ASCT, bortezomib- or lenalidomide containing therapies for reinduction, response to reinduction, ISS stage I prior to salvage ASCT and year of salvage ASCT 2005 or thereafter. The remission duration after upfront ASCT and the ISS prior to salvage ASCT were combined to create a risk-stratification model with three distinct prognostic groups.
Salvage ASCT causes low morbidity and is capable of achieving sustained disease control in patients with myeloma. The use of lenalidomide and bortezomib for reinduction has improved the results after salvage ASCT, suggesting that novel agents and salvage ASCT are complementary rather than alternative treatment approaches. Stratification by duration of remission after upfront ASCT and ISS allows prediction of survival after salvage ASCT. To circumvent the problem of stem cell harvest in intensively pretreated patients, we recommend collecting and cryopreserving sufficient stem cells for both upfront and salvage ASCT early in the course of myeloma treatment. Display omitted
No relevant conflicts of interest to declare.
Abstract 1933
Bendamustine is a bifunctional alkylating agent with low toxicity that produces both single- and double-strand breaks in DNA, and shows only partial cross resistance with other ...alkylating drugs. Treatment of patients with newly diagnosed multiple myeloma using Bendamustine and Prednisone in comparison to Melphalan and Prednisone results in superior complete response rate and prolonged time to treatment failure (Poenisch et al, Res Clin Oncol 132: 205–212;2006). So far, however, reliable information on stem cell toxicity and mobilization of stem cells for autologous stem cell transplantation (SCT) after Bendamustine therapy is missing.
Material and Methods: A retrospective analysis of peripheral blood stem cell mobilization and autologous SCT was performed in 63 patients with multiple myeloma who had received Bendamustine pretreatment at the university Hospitals Leipzig and Heidelberg over a period of sixteen years. Patients had a median age of 59 (range, 31–72) years. The cumulative dosis of Bendamustine per patient ranged between 120 and 2400mg/qm and was administered during a median of three (range 1–10) cycles. The mobilization regimen consisted of Cyclophosphamide 4g/qm (n=41) or 7g/qm (n=4) and G-CSF (2×5ug/kg). Alternative regimens such as CAD, CED, TCED and others were also used in the remaining patients. Apheresis was started as soon as peripheral blood CD34+ counts exceeded 10×106/l with a harvest target of 4×106 CD34+/kg using 4 times the blood volume. The minimal accepted target was 2×106 CD34+/kg.
Stem cell mobilization and harvest was successful in 60 of the 63 patients (95 %). In 19 of 60 patients (32 %) a single apharesis was sufficient to reach the target. The median number of aphareses was two (range 1–7) and the median CD34+ cell-count/kg was 5.9 (range 1.7–20.4) x106. Information on autologous SCT is available from all 60 patients with successful harvest. Engraftment was successful in 59 of 60 patients. The median time to leucocytes count > l ×109/l was reached after 12 days and the time to untransfused platelet count of >50×109/l was 14 days. 54 patients (90%) responded after the autologous SCT with 6 CR, 4 nCR, 12 VGPR, and 32 PR. The event free survival at 36 months was 31 % and overall survival was 68 %.
In conclusion, the stem cell mobilization and autologous SCT is feasible in multiple myeloma patients who have received Bendamustine pretreatment.
Pönisch:Mundipharma: Honoraria, Research Funding. Niederwieser:Mundipharma: Research Funding.
Abstract 3568
High dose chemotherapy with melphalan followed by autologous peripheral blood stem cell transplantation (PBSCT) is a standard treatment regimen for young patients with multiple myeloma. ...However, there are few studies, mainly with low patient counts, testing the benefit of the reapplication of high dose chemo therapy in relapsed or refractory myeloma.
Here we retrospectively analyzed 178 patients (56% male, 44% female, median age 60 years) with relapsed or refractory myeloma who were treated by reapplying high dose chemotherapy with melphalan followed by autologous PBSCT in our institution over the last 18 years. The median follow up of this study was 54 months.
Median progression free survival (PFS) and overall survival (OS) after relapse autologous transplantation were 16 and 35 months, respectively. 66% of the patients received newer antimyeloma agents for reinduction therapy (39% thalidomide, 6% bortezomib, 21% lenalidomide). In univariate analysis, time between first transplantation and progression of disease had a significant impact on PFS and OS (p=0.001 and p<0.001). Estimated hazard ratio (HR) for prolongation of time to progression (TTP) after first transplantation of one year for PFS and OS are 0.85 and 0.73, respectively. The effect of TTP after first PBSCT on PFS and OS with respect to different clinically relevant cutoff values is illustrated in Table 1.
Table 1:Impact of time to progression (TTP) after first autologous transplantation (TPL) on PFS and OSPFSOSTTP after first TPLHazard ratiop-valueHazard ratiop-value<6 months: >6 months1.290.582.600.04<12 months: >12 months1.720.043.52<0.001<18 months: >18 months1.680.0042.28<0.001
Reapplication of high dose chemotherapy can be an effective treatment option for relapsed or refractory myeloma, in particular in patients with a time to progression after first autologous transplantation of more than one year.
Display omitted
No relevant conflicts of interest to declare.
Abstract 4439
The alkylating agent bendamustine has structural similarities to both alkylating agents and purine analogs, and is effective in the treatment of patients with multiple myeloma. So far, ...no data are available on stem cell toxicity or on stem cell mobilization. Since autologous stem cell transplantation is an established treatment for multiple myeloma after primary treatment, we were interested in analysing the experience of stem cell mobilization after bendamustine treatment.
A retrospective analysis over a period of fifteen years was carried out in 56 (34 male and 22 female) patients with multiple myeloma after bendamustine pretreatment at the university hospitals Leipzig and Heidelberg. Patients had a median age of 58 (range 31–72) years. The median number of cycles was 3 (range 1–10) and the cumulative bendamustine dose ranged from 120 to 2400 mg/qm. The mobilization regimen in 37 cases was either cyclophosphamide 4 g/qm (n=33) or 7 g/qm (n=4) followed by G-CSF (2×5 ug/kg s.c.). Alternative regimens such as CAD, CED, TCED and others were used for mobilization in the remaining 19 patients. Apheresis was started as soon as peripheral blood CD34+ counts exceeded 10×106/l with a harvest target of 4×106 CD34+/kg using 4 times the blood volume. The minimal accepted target was 2×106 CD34+/kg.
Stem cell harvest was successful in 54 of the 56 patients. In one patient the peripheral blood CD34+ cell count failed to reach 10 × 106/l and no apheresis was performed. In one further patient a rapid decrease in peripheral blood CD34+ counts resulted in insufficient recovery of stem cells in the apheresis product. In 18 out of 54 patients (33%) the target was reached with a single apharesis. The median number of aphareses in the 54 patients was 2 (range 1–7) and the median CD34+ cell-count obtained was 5.5 (range 1.7–20.4) × 106/kg. Engraftment was successful in 52/53 patients receiving a stem cell transplant. One patient was successfully harvested and did not receive the transplant yet.
From this retrospective analysis we conclude that mobilization of PBSC is possible after intensive bendamustine pretreatment.
Niederwieser:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Research Funding; Celgene: Research Funding; Chugai Pharma: Research Funding; Amgen: Research Funding.
Abstract 2950
Smoldering MM (sMM) is a plasma cell disorder defined by the presence of ≥10% plasma cells in bone marrow and/or a monoclonal protein level of ≥3 g/dl in serum without organ damage. The ...aim of this retrospective study was to analyze whether genomic abnormalities confer prognostic information in patients with sMM who are at high risk of progression into symptomatic MM. By using fluorescent in situ hybridization (FISH), we analyzed the prognostic value of 14 chromosomal abnormalities and hyper-/non-hyperdiploidy (HD and NHD, respectively) in a series of sMM-patients (n=200). In addition, the most frequent chromosomal aberration was used to determine the percentage of clonal plasma cells (cPC) in the bone marrow.
Interphase-FISH-analysis on CD138-enriched plasma cells detected gains of chromosomes 1q21 (31%), 5p15/5q35 (35%), 9q34 (45%), 11q23 (41%), 15q22 (40%), and 19q13 (41%), as well as deletions of chromosomes 8p21 (9%), 13q14 (37%) and 17p13 (7%). Furthermore, the IgH-translocations t(14;16), t(4;14), t(11;14) and IgH-translocations with unknown translocation partner were observed in a frequency of 5%, 10%, 24% and 22%, respectively. The median percentage of cPC was 85.5 (IQR: 62 – 95).
For the entire group, the median follow-up time was 27.2 months (range, 18.2 – 33.5). We analyzed the prognostic impact of each chromosomal aberration on time to progression (TTP). Of all chromosomal abnormalities analyzed, only del(8p21) and the percentage of cPC showed a significant impact on TTP. The TTP at 3 years for patients with del(8p21) was 53% versus 73% for those without (p=0.01). An incremental increase of cPC in the bone marrow by 10% was associated with an elevated relative risk to develop a symptomatic MM of 33% (p<0.001). After adjustment of p-values for multiple testing, only the percentage of cPC showed a statistically significant impact on TTP (p=0.02).
Our results show that FISH-analysis on CD138-enriched plasma cells is a useful technique in the study of sMM, because it allows myelomatous plasma cells to be discriminated from their normal counterparts. In addition, our findings suggest that the proportion of cPC (analyzed by FISH) rather than single chromosomal abnormalities predict progression from sMM to symptomatic MM. FISH-based information can be obtained easily at the time of diagnosis, which would help to establish an individually adapted follow-up strategy.
Aberration yes vs. noNIncidence3-yr TTP (present vs. absent)Hazard ratioWald test p-value adjusteddel(8p21)1909%53% vs. 73%2.590.1del(13q14)20037%61% vs. 79%1.770.8del(17p13)1987%56% vs. 72%1.951t (4;14)19810%52% vs. 73%1.681t (11;14)19824%77% vs. 69%0.511t (14;16)1975%57% vs. 71%1.591+1q2119731%60% vs. 75%1.711HD vs. NHD19740%65% vs. 74%1.67110% increase of cPC200––1.330.02cPC >95 vs. ≤95%20023% vs. 77%46% vs. 80%3.84<0.001
No relevant conflicts of interest to declare.
Abstract 2978
Bone marrow infiltration of monoclonal plasma cells can be displayed by magnetic resonance imaging (MRI). While focal lesions - which have been shown to be of prognostic significance in ...multiple myeloma - can be measured and counted, until now diffuse infiltration could only be estimated qualitatively mainly by subjective comparison of the appearance of the respective vertebra with the intervertebral discs. Diffusion weighted imaging (DWI) which does not require application of contrast medium is established in neuro-radiology as method for early ischemia detection. DWI provides a so called apparent diffusion coefficient (ADC) which hypothetically correlates inversely with cellular density. The measured ADC is dependent of preset b-values with lower values being more influenced by perfusion and higher b-values by diffusion. In our study, we used b-values of 0, 400 and 750 s/mm2 to assess tissue cellularity. In 56 patients with monoclonal plasma cell disease ranging from monoclonal gammopathy of undetermined significance (MGUS) to symptomatic multiple myeloma (MM), correlation of the findings of immuno-histology of a trephine of the iliac crest, cytological smear and apparent diffusion coefficient of DWI of the iliac crest and the lumbar spine were analyzed. Furthermore the DWI-parameters of 30 healthy controls were evaluated for comparison. For histological correlation 25 patients were evaluable. A trend test for comparison of ADC and histological parameters revealed a significantly increasing trend of both plasma cell infiltration level and vessel density compared to ADC (p<0.001 for both histological parameters and both b-values). A significant positive correlation of ADC at b = 400 s/mm2 and b = 750 s/mm2 with bone marrow cellularity (p=0.04 for both b-values) and a moderate positive correlation with the degree of plasma cell infiltration (Spearman's correlation coefficient of 0.32 95%-CI: 0.07, 0.57, p=0.04 and 0.37 95%-CI: 0.11, 0.63, p=0.01) could be demonstrated. Of 26 patients with symptomatic MM, 15 were examined before and after therapy. ADC at b = 400 s/mm2 and 750 s/mm2 respectively decreased significantly after therapy (p<0.001 for both b-values). We conclude that DWI is a valuable non-invasive tool not only for assessment of initial tumor mass but also for monitoring of treatment in patients with monoclonal plasma cell disease. The finding that ADC increased with bone marrow cellularity in our opinion is caused by the also increasing perfusion which overlays the diffusion effect as confirmed by the positive correlation of ADC and vessel density in histology. Further development should aim at differentiating the diffusion and perfusion effects. First investigations on this subject are currently under way.
No relevant conflicts of interest to declare.
Abstract 4868
In magnetic resonance imaging (MRI) multiple myeloma (MM) presents with circumscribed focal lesions or diffuse infiltration of bone marrow. To identify genetic mechanisms influencing ...the growth pattern, whole-body MRI of 99 patients with asymptomatic and 114 patients with symptomatic MM were evaluated retrospectively by two experienced radiologists. The pattern was analyzed in the spine and focal lesions were counted in the whole body differentiating intra-osseous and soft tissue lesions as well as osseus tumors affecting cortical bone. Cytogenetic analysis was performed using interphase fluorescence in-situ hybridization (iFISH) on CD138-purified monoclonal plasma cells acquired by unilateral bone marrow aspiration for the following aberrations: t(4;14), t(11;14), t(14;16), deletions 13q14 and 17p13, as well as gain of 1q21. Statistical analysis was performed to address the following questions: i) Is there a significant correlation of chromosomal abnormalities with the presentation of MM in MRI ii) Is there an association of the occurrence of affection of cortical bone with cytogenetic aberrations. As a number of more than 7 focal lesions in the axial skeleton has been shown to be an adverse prognostic factor for patients with symptomatic MM, we performed a search for an optimal cut-off point in number of focal lesions in whole body MRI with respect to progression free survival and overall survival. As event for progression free survival initiation of treatment for asymptomatic MM and progression after the first line of treatment for symptomatic MM was defined.
Correlation of the presentation of MM in MRI with common chromosomal abnormalities was found neither concerning focal or diffuse infiltration patterns nor an affection of cortical bone, potentially leading to instability.
A search for the optimal cut-off point led to a number of more than one and more than 8 focal lesions in whole body MRI for asymptomatic and symptomatic MM respectively.
The only significant prognostic factors for progression of asymptomatic MM into symptomatic disease were the presence per se and a number of more than one focal lesion or diffuse infiltration in MRI. For symptomatic myeloma a number of more than 8 focal lesions was the only significant prognostic factor for overall survival (HR 4.87; p-value <0.001). In symptomatic disease the factors t(4;14), gain of 1q21 and a diffuse infiltration pattern (for overall survival) and gain of 1q21 (for progression free survival) lost statistical significance after adjustment of p-values because of multiple testing.
In our cohort of 213 patients the most important risk factors for overall survival were focal lesions above a cut-off point of 1 and 8 for asymptomatic and symptomatic MM, respectively. No correlation of the appearance of MM in MRI with the presence of cytogenetic abnormalities in iFISH analysis was found. We therefore conclude that the infiltration pattern in MRI is not associated with cytogenetic abnormalities and that the number of focal lesions in whole body MRI is an important and independent risk factor for patients with multiple myeloma.
No relevant conflicts of interest to declare.
Common genetic variants in immune and inflammatory genes can affect the risk of developing multiple myeloma. The aim of this study was to determine the effect of polymorphic variants in the ...interleukin 10 (IL10), transforming growth factor beta (TGFB1) and tumor necrosis factor alpha (TNFa) genes on the predisposition to multiple myeloma and the effect of these polymorphisms on survival after treatment with chemotherapy. Genotype data of 7 single-nucleotide polymorphisms and clinical follow-up information were available for 239 consecutive patients with multiple myeloma who presented at our outpatient department. All patients were treated with chemotherapy, including high-dose chemotherapy and peripheral blood stem cell transplantation in 191 patients. In particular, there were 155 males and 84 females with a median age of 55 years (range, 30 – 84). The median follow-up period for the entire cohort was 75 months (range, 3 – 190 months). The TGFB1 low producer genotype 10Leu/Leu (n=78) was associated with a 3.5 years older age at start of treatment (57.5 versus 54 years, p=0.005), a higher level of beta2-microglobulin (3.4 versus 2.5 mg/l, p=0.01), a higher frequency of ISS-scores II and III versus I (OR=0.50, p=0.01) and an inferior median survival rate of 71.8 versus 91.6 months (p=0.02) as compared to other genotypes, respectively. In a multivariate analysis, the TGFB1 low producer genotype 10Leu/Leu was identified as an independent factor for survival (p=0.03), indicating that the poor prognosis of these patients is not due to the older age at the start of treatment. All other gene polymorphisms analyzed (IL10–1082A>G, IL10–819C>T, IL10–592C>A, TGFB1 Arg25Pro, TNFa -308G>A, TNFa -238G>A) showed no statistically significant effect on overall survival. Our findings suggest that patients carrying the TGFB1 low producer polymorphism show a later onset of disease and need for chemotherapy treatment as compared to other genotypes. In addition, our findings indicate that TGFB1 genetic variants influence prognosis in patients with multiple myeloma who received chemotherapy and suggest that genetically determined cytokine production affects the clinical course of the disease possibly through regulation of immune surveillance.
