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Daratumumab has shown promising first results in systemic amyloid light-chain (AL) amyloidosis. We analyzed a consecutive series of 168 patients with advanced AL receiving either daratumumab/dexamethasone (DD, n = 106) or daratumumab/bortezomib/dexamethasone (DVD, n = 62). DD achieved a remission rate (RR) of 64% and a very good hematologic remission (VGHR) rate of 48% after 3 months. Median hematologic event-free survival (hemEFS) was 11.8 months and median overall survival (OS) was 25.6 months. DVD achieved a 66% RR and a 55% VGHR rate. Median hemEFS was 19.1 months and median OS had not been reached. Cardiac organ responses were noted in 22% with DD and 26% with DVD after 6 months. Infectious complications were common (Common Terminology Criteria [CTC] grade 3/4: DD 16%, DVD 18%) and likely related to a high rate of lymphocytopenia (CTC grade 3/4: DD 20%, DVD 17%). On univariable analysis, hyperdiploidy and gain 1q21 conferred an adverse factor for OS and hemEFS with DD, whereas translocation t(11;14) was associated with a better hemEFS. N-terminal prohormone of brain natriuretic peptide >8500 ng/L could not be overcome for survival with each regimen. Multivariable Cox regression analysis revealed plasma cell dyscrasia (difference between serum free light chains [dFLC]) >180 mg/L as an overall strong negative prognostic factor. Additionally, nephrotic-range albuminuria with an albumin-to-creatinine-ratio (ACR) >220 mg/mmol was a significantly adverse factor for hemEFS (hazard ratio, 2.1 and 3.1) with DD and DVD. Daratumumab salvage therapy produced good results and remission rates challenging any therapy in advanced AL. Outcome is adversely influenced by the activity of the underlying plasma cell dyscrasia (dFLC) and nephrotic-range albuminuria (ACR).

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

Amyloidosen sind Erkrankungen, bei denen fehlgefaltete Proteine als unlosliche Fibrillen im Korper abgelagert werden und die betroffenen Organe schadigen. Lesen Sie im Folgenden, uber Pathogenese, Diagnostik und Unterscheidung verschiedener Amyloidoseformen. Dabei liegt der Fokus auf den haufigeren Amyloidoseformen Leichtketten(AL)-Amyloidose und Transthyretin(Wildtyp-ATTR)-Amyloidose.

Trotz gewisser Fortschritte in der Therapie der AL-Amyloidose ist die Prognose in vielen Fallen immer noch ungunstig. Grund dafur ist, dass die Diagnose haufig erst dann gestellt wird, wenn schon ausgedehnte Organschaden bestehen, die meist irreversibel sind. Dies soll sich zukunftig jedoch andern.

We analyzed 44 patients with newly diagnosed systemic light-chain amyloidosis (AL) and del 17p, a rare finding in AL. Predictors of overall and progression-free survival were cardiac involvement at diagnosis and hematologic response to therapy, respectively. Median survivals of patients with > 50% and ≤ 50% del 17p plasma cells were 28 and 52 months (P = .08). Introduction: Deletion 17p (del 17p) portends a poor prognosis in myeloma, but its significance in light-chain amyloidosis is unknown. Patients and Methods: We identified patients with light-chain amyloidosis and del 17p at diagnosis, and analyzed presenting characteristics, treatments, and clinical outcomes. All had baseline biopsy results showing amyloid and serologic and marrow studies, including standard fluorescence in-situ hybridization determinations of del 17p using commercial probes. Consensus criteria for hematologic and organ involvement, progression, and response were used. Kaplan-Meier (log rank) analyses and Cox regression analysis of baseline variables were used to identify predictors of overall and progression-free survival (PFS). Six-month landmark analyses were performed to assess the impact of treatment-related variables. Results: We identified 44 patients from 7 countries with median marrow and del 17p plasma cells of 22% (range, 3%–100%) and 30% (2%–93%). Ninety-five percent had cardiac involvement, including 44% stage III. Two-thirds of the patients initially received bortezomib-based therapy. Forty-nine percent of patients experienced complete response or very good partial response, with median time to best response of 4 months (range, 1–28 months). Median overall survival and PFS were 49 and 32 months. Cardiac stage and hematologic response were the key predictors of outcomes. Patients with > 50% and ≤ 50% del 17p in clonal plasma cells had median survivals of 28 and 52 months, respectively (P = .08). In landmark analyses, only hematologic response predicted both overall survival and PFS. Conclusion: Cardiac stage, hematologic response, and del 17p percentage impact outcomes in these cases. Emphasis should be placed on optimizing supportive care and achieving a deep hematologic response.

Introduction Currently there are no sufficient epidemiology data on systemic amyloidosis in Germany. Our aim was to collect epidemiological data on amyloidosis diseases to determine incidence and distribution of amyloidosis types in Germany. In addition, data on diagnosic pathways, demographic, clinical and biological factors, quality of life (Qol) and overall survival (OS) have been collected. Methods: The actual registry population consists of the first n=1000 reported cases of newly diagnosed amyloidosis patients between 4.1.18 - 21.11.19. Data cutoff of the analysis was June 30, 2021. Patients were included in the registry by two main ways: personal presentation at the amyloidosis outpatient clinic or phone contact of the attending physician to the Amyloidosis Center. Inclusion criteria were either a Congo Red positive tissue sample or unequivocal findings in bone scintigraphy (ATTR amyloidosis). Patients were contacted every 6 months to obtain QoL data using EORTC QLQ-C30, EQ-5D-5L and SF36-v2 questionnaires. This registry was financially supported by Prothena. Results: During this time period 963 of the first 1000 reported newly diagnosed patients (37 pts. did not fulfil inclusion criteria and were excluded) were evaluated mainly through the amyloidosis outpatient clinic (n=581, 60.3%). Seventy-three percent of cases were male (n=706). The median age at diagnosis was 71 years and differed between the AL pts.(65,5 years) and ATTRwt (78 years) patients. The subgroup distribution was as follows: 438 (45,5%) AL pts., 318 (33%) ATTRwt pts., 35 (3,6%) ATTRv pts, 60 (6,2%) ATTR of unknwon subtype, 66 (6,8%) local amyloidosis, 30 (3,1%) AA amyloidosis, 12 (1,2%) others and 4 (0,4%) not typed. Diagnosis was confirmed by biopsy in 88% and in 12% by bone scintigraphy. The most commonly involved organs were heart (n=733, 76,1%) and kidney (n=305, 31,7%). Cardiac staging systems were used for systemic AL (Kumar et al., 2014) with heart involvement and ATTR amyloidosis (Gillmore et al., 2018). Data on survival were available in all cases (median follow-up 27 months). During the observation time 249 patients died (60 ATTRwt and 153 AL pts., 36 other, figure). The most frequent cause of death was amyloidosis itself (n=191, 76,7%). Seven (2,8%) patients died due to therapeutic complications. Compared to ATTRwt patients with cardiac AL amyloidosis had a higher hazard to die, 1 year survival was 78.96% (95% CI 75.23% - 82.88%) compared to 94.30% (95% CI 91.80% - 96.90%), respectively. In multivariate analysis (including age, cardiac staging systems and time from symptoms to diagnosis) factors associated with worse OS were increasing age for AL pts. (HR 1.04, p Conclusion: The first 2 years of the German clinical amyloidosis registry have been successful to generate valuable clinial data for all types of amyloidosis from newly diagnosed patients. Subtyping the amyloid precursor protein was successful in nearly all patients. The most common form is AL followed by ATTRwt amyloidosis. Heart involvment was very common and pts. were mostly in advanced cardiac stage. Main cause of death was amyloidosis related. In 2020 we have started an extended registry (financially supported by Janssen) including anonymized biopsy reports from reference pathologists. With this approach we will probably obtain more precise data on incidence in Germany. Figure 1 Figure 1. Disclosures Hegenbart: Alnylam: Honoraria; Akcea: Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Prothena: Research Funding. Carpinteiro: Janssen: Honoraria; BMS: Honoraria; GSK: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Müller-Tidow: Pfizer: Research Funding; Bioline: Research Funding; Janssen: Consultancy, Research Funding. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Prothena: Honoraria, Other: Travel grants; Pfizer: Honoraria; Takeda: Honoraria, Other: Travel grants; Sanofi: Research Funding.

Rationale: CD38 is a target for the therapy of multiple myeloma (MM) with monoclonal antibodies such as daratumumab and isatuximab. Since MM patients exhibit a high rate of relapse, the development of new biologics targeting alternative CD38 epitopes is desirable. The discovery of single-domain antibodies (nanobodies) has opened the way for a new generation of antitumor therapeutics. We report the generation of nanobody-based humanized IgG1 heavy chain antibodies (hcAbs) with a high specificity and affinity that recognize three different and non-overlapping epitopes of CD38 and compare their cytotoxicity against CD38-expressing hematological cancer cells in vitro, ex vivo and in vivo. Methods: We generated three humanized hcAbs (WF211-hcAb, MU1067-hcAb, JK36-hcAb) that recognize three different non-overlapping epitopes (E1, E2, E3) of CD38 by fusion of llama-derived nanobodies to the hinge- and Fc-domains of human IgG1. WF211-hcAb shares the binding epitope E1 with daratumumab. We compared the capacity of these CD38-specific hcAbs and daratumumab to induce CDC and ADCC in CD38-expressing tumor cell lines in vitro and in patient MM cells ex vivo as well as effects on xenograft tumor growth and survival in vivo. Results: CD38-specific heavy chain antibodies (WF211-hcAb, MU1067-hcAb, JK36-hcAb) potently induced antibody-dependent cellular cytotoxicity (ADCC) in CD38-expressing tumor cell lines and in primary patient MM cells, but only little if any complement-dependent cytotoxicity (CDC). In vivo, CD38-specific heavy chain antibodies significantly reduced the growth of systemic lymphomas and prolonged survival of tumor bearing SCID mice. Conclusions: CD38-specific nanobody-based humanized IgG1 heavy chain antibodies mediate cytotoxicity against CD38-expressing hematological cancer cells in vitro, ex vivo and in vivo. These promising results of our study indicate that CD38-specific hcAbs warrant further clinical development as therapeutics for multiple myeloma and other hematological malignancies.

Background: Despite major advances in therapy, multiple myeloma is still an incurable malignancy in the majority of patients. To increase survival, deeper remissions (i.e. CR) translating into longer PFS need to be achieved. Incorporation of new drugs (i.e. bortezomib and lenalidomide) as induction and maintenance treatment in an intensified treatment concept, including high dose melphalan (200 mg/m2), has resulted in increased CR rates, and is considered the standard of care for younger patients. Elotuzumab in combination with lenalidomide and dexamethasone has given better results as lenalidomide and dexamethasone alone in a phase III trial. The GMMG-HD6 trial will be the first phase III trial investigating the role of elotuzumab in combination with bortezomib, lenalidomide and dexamethasone (VRD) induction/consolidation and lenalidomide maintenance within a high dose concept. Methods: GMMG-HD6 is a randomized, open, multicenter phase III trial. The planned recruitment number is 564 NDMM patients. All patients will receive 4 VRD cycles as induction and undergo peripheral blood stem cell mobilization and harvesting. Thereafter they will be treated with high dose melphalan therapy plus autologous stem cell transplantation followed by 2 cycles of VRD consolidation and lenalidomide maintenance. Patients in arm B1 + B2 will additionally receive elotuzumab in the induction phase, whereas patients in A2 + B2 will be treated with elotuzumab added to consolidation and maintenance. The primary endpoint of the trial is PFS. Secondary objectives and endpoints are OS, CR rates after induction therapy comparing the two arms VRD (A1 + A2) vs VRD + elotuzumab (B1 + B2), CR rates after consolidation treatment, best response to treatment during the study, time to progression (TTP), duration of response (DOR), toxicity and quality of life. Results: Since this is the publication of a study protocol of an ongoing study, no results can be presented. Discussion: This phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab. Trial registration: NCT02495922 on June 24th, 2015.

Within a prospective protocol, the incidence and impact of achievement of molecular remission (mCR) and high-risk cytogenetics was investigated in 73 patients with multiple myeloma (MM) after autologous (auto)–allogeneic (allo) tandem stem cell transplantation (SCT). After induction chemotherapy, patients received melphalan 200 mg/m2 before undergoing auto-SCT, followed 3 months later by melphalan 140 mg/m2 and fludarabine 180 mg/m2 before allo-SCT. Sixteen patients had high-risk cytogenetic features, defined by positive FISH for del(17p13) and/or t(4;14). Overall, 66% of the patients achieved CR or near-CR, and 41% achieved mCR, which was sustained negative (at least 4 consecutive samples negative) in 15 patients (21%), with no significant difference in incidence between the patients with high-risk cytogenetics and others (P = .70). After a median follow-up of 6 years, overall 5-year progression-free survival was 29%, with no significant difference between del 17p13/t(4;14)-harboring patients and others (24% versus 30%; P = .70). The 5-year progression-free survival differed substantially according to the achieved remission: 17% for partial remission, 41% for CR, 57% for mCR, and 85% for sustained mCR. These results suggest that auto–allo tandem SCT may overcome the negative prognostic effect of del(17p13) and/or t(4;14) and that achievement of molecular remission resulted in long-term freedom from disease.

We subjected 90 patients covering a biological spectrum of plasma cell dyscrasias (monoclonal gammopathy of undetermined significance (MGUS), amyloid light-chain (AL) amyloidosis and multiple myeloma) to next-generation sequencing (NGS) gene panel analysis on unsorted bone marrow. A total of 64 different mutations in 8 genes were identified in this cohort. NRAS (28.1%), KRAS (21.3%), TP53 (19.5%), BRAF (19.1%) and CCND1 (8.9%) were the most commonly mutated genes in all patients. Patients with non-myeloma plasma cell dyscrasias showed a significantly lower mutational load than myeloma patients (0.91±0.30 vs 2.07±0.29 mutations per case, P=0.008). KRAS and NRAS exon 3 mutations were significantly associated with the myeloma cohort compared with non-myeloma plasma cell dyscrasias (odds ratio (OR) 9.87, 95% confidence interval (CI) 1.07–90.72, P=0.043 and OR 7.03, 95% CI 1.49–33.26, P=0.014). NRAS exon 3 and TP53 exon 6 mutations were significantly associated with del17p cytogenetics (OR 0.12, 95% CI 0.02–0.87, P=0.036 and OR 0.05, 95% CI 0.01–0.54, P=0.013). Our data show that the mutational landscape reflects the biological continuum of plasma cell dyscrasias from a low-complexity mutational pattern in MGUS and AL amyloidosis to a high-complexity pattern in multiple myeloma. Our targeted NGS approach allows resource-efficient, sensitive and scalable mutation analysis for prognostic, predictive or therapeutic purposes.

Relapse after dose-reduced allograft in advanced myeloma patients remains high. To reduce the risk of relapse, we investigated a myeloablative toxicity-reduced allograft (aSCT) consisting of i.v. BU and CY followed by lenalidomide maintenance therapy in 33 patients with multiple myeloma (MM) who relapsed following an autograft after a median of 12 months. The cumulative incidence of non-relapse mortality at 1 year was 6% (95% confidence interval (CI): 0-14). After a median interval of 168 days following aSCT, 24 patients started with a median dose of 5 mg (r, 5-15) lenalidomide without dexamethasone. During follow-up, 13 patients discontinued lenalidomide owing to progressive disease (n=6), GvHD (n=3), thrombocytopenia (n=2), or fatigue (n=2). Major toxicities of lenalidomide were GvHD II-III (28%), viral reactivation (16%), thrombocytopenia (III-IV°,16%), neutropenia (III/IV°, 8%), peripheral neuropathy (I/II°, 16%), or other infectious complication (8%). Cumulative incidence of relapse at 3 years was 42% (95% CI: 18-66). The 3-year estimated probability of PFS and OS was 52% (95% CI: 28-76) and 79% (95% CI: 63-95), respectively. Toxicity-reduced myeloablative allograft followed by lenalidomide maintenance is feasible and effective in relapsed patients with MM, but the induction of GvHD should be considered.

Fur Patienten mit multiplem Myelom (MM), die nicht fur eine Stammzelltransplantation infrage kommen, ist die Kombination aus Melphalan/Prednison plus Thalidomid oder Bortezomib Standard. Nun wurde Lenalidomid plus Dexamethason in der Ersttherapie des MM untersucht.

Although survival in AL patients is related in part to the number of marrow clonal plasma cells (PC) (1, 2), staging for AL patients is based on end-organ damage without a clear role for cytogenetic aberrations in clonal PC. Recently several groups have described potential roles for gain 1q and t(11;14) as prognostic markers in AL, and possibly as predictive of response to therapy (3-5). In multiple myeloma, del 17p is a cytogenetic aberration present in about 10% at diagnosis and its prognostic impact depends on the percentage of clonal PC with del 17p (6). The relevance of del 17p in AL is undefined. We report our initial analysis of the outcomes and survival of the first multinational retrospective study of AL patients with del 17p as a feature of their clonal plasma cell disease and include preliminary findings from an age-based case-control analysis. AL patients with del 17p were identified and their clinical characteristics and outcomes summarized. Methods for determining the presence of del 17p were reviewed. We compared the overall survival (OS) of patients in whom del 17p was identified in < or ≥ 50% of clonal cells, and evaluated the impact of bortezomib-based therapy and cardiac stage on OS in newly diagnosed and relapsed patients. These cases were then matched for age (± 5 years) with a control cohort from the Amyloidosis Treatment and Research Center in Pavia, IT, representing a subset of patients reported previously (7). Differences between cases and controls for OS were evaluated by Kaplan-Meier with statistical significance by the log-rank test. P < 0.05 was the threshold for significance. Thirty-four AL patients with del 17p in clonal cells were identified, 30 at diagnosis and 4 at relapse. Thirty-one cases had del 17p assessed on CD138-selected marrow cells and 3 on marrow mononuclear cells; for the latter, the percentage of marrow PC was used to estimate the del 17p fraction. Commercially available methods were used at all centers. Median age was 66 years and males constituted 53% of cases. Cardiac involvement was present in 72% of cases, 41% of whom had stage III involvement. Ninety-four percent had free light-chain (FLC) clones of lambda isotype with a median difference between involved and uninvolved FLC (dFLC) of 249mg/L and a median percentage of marrow PC of 18%. In all 34 cases the median percentage of clonal PC with del 17p by FISH was 42% (range 2-93%) while in newly diagnosed AL patients it was 37%. Eighty-three percent of cases had del 17p in combination with other cytogenetic abnormalities including t(11;14) in 36% and gain 1q in 18%. Among the newly diagnosed cases, 32% had ≥ 50% of clonal cells with del 17p and had a median OS of 23.5 months while those with < 50% survived a median of 33 months (P = 0.12). Seventy-three percent of patients responded to initial therapy and 32% had ≥ VGPR. Twenty-three percent had a cardiac response to initial therapy. There was no difference in OS between patients who had bortezomib-based therapy and those who did not, and no difference between the OS of cardiac stage 1/2 and stage 3 patients. One patient with 37% del 17p and a complex karyotype at baseline progressed at relapse to both advanced AL cardiac involvement and plasma cell leukemia with over 90% del 17p containing PC, suggesting that del 17p may confer risk in AL as in MM under certain circumstances. In the preliminary case-control analysis, OS was no different between cases and controls (Fig 1, P = 0.32). Recent data indicate that the more common cytogenetic abnormalities in AL, namely t(11;14) and gain 1q, are associated with differences in response to melphalan or bortezomib. In this series of AL cases with del 17p, we find suggestive evidence that high levels of clonal cells with del 17p may confer a poorer prognosis than already exists as a consequence of the tropism of AL light chains for the heart. We are seeking more cases for inclusion in this series and conducting both a multivariate analysis and a detailed case-control comparison which may shed light on this issue. References (1) Comenzo et al. Blood 2001;98(3):714-20. (2) Warsame et al. Blood Cancer Journal 2015;5, e-310, e-pub 1 May 2015 (3) Bochtler et al. Amyloid. 2014 Mar;21(1):9-17. (4) Bochtler et al. J Clin Oncol. 2015 Apr 20;33(12):1371-8. (5) Zhou et al. Clin Lymphoma Myeloma Leuk 2012;12(1):49-58. (6) An et al. Clin Cancer Res; 21(9); 2148-56. (7) Palladini et al. Blood 2015, e-pub 18 May 2015 Figure 1. Figure 1. Disclosures Hegenbart: Janssen: Honoraria. Landau:Prothena: Consultancy, Honoraria; Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria; Janssen: Consultancy; Onyx: Honoraria, Research Funding; Takeda: Research Funding. Avet-Loiseau:onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Hansen:Celgene GmbH: Honoraria. Schönland:Janssen, Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Comenzo:Janssen: Research Funding; Prothena: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Takeda Millennium: Research Funding; Karyopharm: Research Funding.

We analyzed the prognostic impact of the most frequent genetic abnormalities detected by fluorescence-in situ-hybridization combined with immunofluorescent cytoplasm immunoglobulin staining (cIg-FISH) in 101 patients with multiple myeloma, who underwent allogeneic stem cell transplantation after reduced melphalan/fludarabine-based conditioning from related (n=34) and unrelated (n=67) donors. The abnormalities were del(13q14) [62%], t(11;14)(q13;q32) [11%], t(4;14)(p16.3;q32) [16%], CMYC-gains (8q24) [17%], del(17p13.1) [16%], t(14;16)(q32;q23) [4%], whereas none of the patients had t(6;14)(p25;q32). Translocation t(4;14), CMYC-gains and del 17p were frequently associated with del(13q14): 64%, 80% and 92%, respectively. The complete remission (CR) rate was 45% for all patients. Patients with del(17p13) achieved fewer complete remission than others (7% vs. 56%; p=0.001), while no difference was seen for t(4;14) and other abnormalities. Univariate analysis revealed higher relapse rates for age > 50 years (p=0.002), del(13q14) (p=0.006) and del(17p13) (p=0.003). Patients with translocation t (4;14) had a similar four year event-free survival than others (50 vs 45%). In a multivariate analysis, only del(13q14) [HR: 2.34, p=0.03] and del(17p13) [HR: 2.24; p=0.04] influenced the risk of relapse, while for event-free survival, only age [HR 2.8; p=0.01] and del(17p13) [HR: 2.05; p=0.03] retained the prognostic value. These data seem to indicate that some adverse cytogenetic risk factors such as t(4;14) can be overcome by allogeneic stem cell transplantation, probably due to the graft versus myeloma effect. Del(17p13.1) is a significant factor for a lower chance of complete remissions and shorter event free survival following allogeneic stem cell transplantation. The presented data will have implications for risk-adapted strategies in the future.

Deletions of chromosome bands 13q14 and 17p13 (P53) as well as t(4;14)(p16;q32) or overrepresentation of CMYC are known to be adverse prognostic factors for time to progression (TTP) and overall survival (OS) in myeloma patients receiving conventional or high-dose chemotherapy followed by autologous stem cell transplantation. We investigated the impact of these chromosomal abnormalities as detected by fluorescence in situ hybridization combined with immunofluorescent cytoplasm immunoglobulin staining (cIg-FISH) on outcome after dose-reduced melphalan/fludarabin based allogeneic stem cell transplantation (SCT) in 64 patients (pts) with multiple myeloma (MM). Median age was 52 years (34 – 67 ys.), 38 patients were male, 26 female. 45 pts received stem cell graft from an unrelated donor and 19 pts from HLA-identical sibling. Deletion of 13q14 was found in 35 out of 64 pts (55%), P53 deletion in 7 out of 64 pts (11%), t(4;14)(p16;q32) in 11 out of 56 pts (20%) and trisomy of CMYC in 12 out of 55 pts (22%). The following strong correlations among the genetic changes have been seen: six out of seven pts with P53 deletion also showed deletion in chromosome band 13q14 (86%), which was also found in nine out of eleven pts with t(4;14) (82% del 13) and nine out of twelve pts with CMYC trisomy (75% del 13). The estimated event-free (EFS) and overall survival (OS) at four years for the entire study population was 48% and 57%, respectively. No significant difference of the estimated event-free survival at 3 years was seen for pts with del 13 (42% vs 54%, p=0,4), with P53 deletion (43% vs 49%, p=0,27) and for pts with t(4;14) (46% vs 62%, p=0,69) or CMYC overrepresentation (37% vs 50%, p=0,35). Comparison of pts showing both del 13 and P53 deletion, del 13 and t(4;14), del 13 and trisomy of CMYC or t(4;14) and CMYC trisomy with the rest of the study population did not show a significantly reduced EFS either. Even the comparison of pts with any chromosomal abnormalities and pts without any genetic changes detected by FISH did not show a significant difference in EFS (48% vs 50%, p=0,8). These preliminary data suggest that the negative prognostic impact of chromosomal abnormalities such as deletion of 13q14, P53 deletion, t(4;14) and overrepresentation of CMYC may be overcome by allogeneic SCT probably due to the graft versus myeloma effect.

Deletion of chromosome band 17p13 (P53) is known to be an adverse prognostic factor for time to progression (TTP) and overall survival (OS) in myeloma patients receiving conventional or high-dose chemotherapy. In this retrospective multicenter study, we investigated the impact of P53 deletion as detected by fluorescence in situ hybridization combined with immunofluorescent cytoplasm immunoglobulin staining (cIg-FISH) on outcome after allogeneic blood stem cell transplantation (SCT) in 50 patients (pts) with advanced or relapsed multiple myeloma (MM). Median age was 51 years (34 – 67 ys.), 32 patients were male, 18 female. Thirty pts received a stem cell graft from an unrelated donor, and 20 pts from a HLA-identical sibling. P53 gene deletion was found in 5 out of 49 pts (10,2 %). Deletion 13 detected by cIg-FISH was found in 20 out of 47 pts (42%). There was a strong correlation between P53 deletion and deletion 13: four out of the five patients with P53 deletion also showed deletion in chromosome band 13q14. The estimated event-free (EFS) and overall survival (OS) at three years for the entire study population was 43% and 65%, respectively. For patients with del 13 only a trend for a worse 3 year EFS was seen (38% vs 42%, p=0.2), while pts with P53 deletion had a significant reduced EFS (0% vs 46%, p=0.0001). Three out of five pts with P53 deletion relapsed very early after allogeneic SCT (day 81, 108 and 287 respectively). These data suggest that P53 is a risk factor for patients with MM treated with allogeneic SCT which can not be overcome by this treatment strategy.