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Simple Summary During the course of their disease, almost all multiple myeloma patients experience one or more relapses. Treatment options for relapsed/refractory multiple myeloma (RRMM) have largely increased in the last decades. The choice of when and how to treat in the relapsed/refractory setting can therefore be challenging. Since multiple myeloma (MM) typically affects elderly people, it is of importance to include specific, frailty-related comorbidities in the choice of treatment. The aim of this review was to present an update on treatment options for patients with RRMM, under consideration of today’s available literature, current guidelines and patient-, disease- and treatment-related factors. We focused on geriatric assessments (GA) and frailty scores such as the revised myeloma comorbidity index (R-MCI), international myeloma working group (IMWG-) frailty index and others as these allow obtaining a more accurate picture of the individual patient constitution than the numerical age alone. Abstract Treatment of relapsed/refractory multiple myeloma (RRMM) is more complex today due to the availability of novel therapeutic options, mostly applied as combination regimens. immunotherapy options have especially increased substantially, likewise the understanding that patient-, disease- and treatment-related factors should be considered at all stages of the disease. RRMM is based on definitions of the international myeloma working group (IMWG) and includes biochemical progression, such as paraprotein increase, or symptomatic relapse with CRAB criteria (hypercalcemia, renal impairment, anemia, bone lesions). When choosing RRMM-treatment, the biochemical markers for progression and severity of the disease, dynamic of disease relapse, type and number of prior therapy lines, including toxicity and underlying health status, need to be considered, and shared decision making should be pursued. Objectively characterizing health status via geriatric assessment (GA) at each multiple myeloma (MM) treatment decision point has been shown to be a better estimate than via age and comorbidities alone. The well-established national comprehensive cancer network, IMWG, European myeloma network and other national treatment algorithms consider these issues. Ideally, GA-based clinical trials should be supported in the future to choose wisely and efficaciously from available intervention and treatment options in often-older MM adults in order to further improve morbidity and mortality.

Background At Freiburg University Medical Center, chemotherapy prescriptions are processed via a computerized physician order entry (CPOE) tool and clinically checked by a designated chemotherapy surveillance team. Any error detected is reported instantly, corrected, and prospectively recorded. The objective of the current study was to gain insight into the causes, potential consequences, and future preventability of chemotherapy prescribing errors. Methods A detailed analysis of 18,823 consecutive antineoplastic orders placed in 2013 through 2014 was performed. In cooperation with information technology (IT) specialists, the intercepted errors were analyzed for effective future prevention using IT measures. Potential error consequences were determined by case discussions between pharmacists and physicians. Results Within 24 months, a total of 406 chemotherapy prescribing errors were intercepted that affected 375 (2%) of the total orders. Errors were classified as clinically relevant in 279 of the chemotherapy orders (1.5%). In these cases, reduced therapeutic efficacy (0.44%), the need for increased monitoring (0.48%), prolonged hospital stay (0.55%), and fatality (0.02%) were avoided as potential consequences. The most efficient conventional measures for error prevention comprised checking the order history and patient's medical record, and a detailed knowledge of chemotherapy protocols. Of all the errors analyzed, 61% would be avoided through further software development. The improvements identified are implemented through a validated next-generation CPOE tool. Conclusions The upgraded CPOE tool can be shared across other hospitals to raise safety standards and spread potential benefits across a wider patient population. The current analysis also highlighted that approximately 30% to 40% of errors cannot be avoided electronically. Therefore, pharmacovigilance initiatives remain indispensable.

BACKGROUND Because of the various therapeutic options available for multiple myeloma (MM), remarkable interest exists today in individualized therapeutic concepts based on patients' fitness. The main objectives of this study were to compare different comorbidity scores and functional tests with respect to their impact on survival (overall survival [OS] and progression-free survival [PFS]); develop a time-efficient, MM-specific functional assessment (FA); and evaluate changes in patients' FA during treatment. METHODS The authors performed a prospective FA in 266 consecutive patients with MM at their initial diagnosis. This included 5 comorbidity scores and 12 commonly used geriatric functional tests. To evaluate changes in the course of treatment, the authors reassessed these 17 tests after ≥6 months. The entire analysis included 7327 FA tests. RESULTS On the basis of univariate and multivariate Cox regression analyses, the authors identified 4 of the 17 evaluated scores and functional tests as most relevant: the Revised Myeloma Comorbidity Index (R-MCI), Activity of Daily Living (ADL), the Mini-Mental State Examination (MMSE), and the quality-of-life 12-Item Short Form Health Survey Physical Composite Scale (SF-12 PCS). These showed precise group differences for fit, (intermediate-fit), and frail patients in OS and PFS: the 3-year OS rates were 90%, 74%, and 43% via the R-MCI for fit, intermediate-fit, and frail patients, respectively (P = .0006); 80% and 66% via the ADL for fit and frail patients, respectively (P = .0159); 78% and 48% via the MMSE for fit and frail patients, respectively (P = .0001); and 86% and 66% via the SF-12 PCS for fit and frail patients, respectively (P = .0091). In follow-up analyses, 16 of 17 FA tests improved, mostly in younger patients (

The estimated glomerular filtration rate (eGFR) is clinically used to approximate renal function and adapt drug dosage. Multiple myeloma is a hematological disease; its prognosis is largely influenced by renal function. We evaluated two commonly used GFR estimations, CKD-EPI and MDRD (CKD Epidemiology Collaboration; Modification of Diet in Renal Disease) in myeloma patients undergoing treatment with lenalidomide, a renally excreted immunomodulatory drug. We prospectively studied 130 myeloma patients receiving lenalidomide treatment at our institution. At baseline and after 3 months, GFR estimations were performed based on the CKD-EPI and MDRD equations. We compared eGFR-dependent CKD staging and lenalidomide dosage assignments. Initially, most patients were classified as CKD stage I/II, using both equations. Comparison of baseline renal function via CKD-EPI and MDRD induced concordance of CKD staging in 83% of patients, while CKD-EPI improved CKD staging in 16% of patients (p = 0.11). CKD-EPI assigned 3% of patients to higher lenalidomide dosing as opposed to MDRD. Both equations showed improved eGFR after 3 months of lenalidomide treatment. In our multiple myeloma patient cohort, CKD-EPI and MDRD led to similar CKD staging with minor differences in lenalidomide dosage assignment. Consistent with previous studies, eGFR improved under lenalidomide treatment. To standardize GFR estimation in myeloma patients, we suggest using the CKD-EPI equation.

Background: In an interdepartmental cooperation, we investigated the feasibility and benefits of implementing dose banding of chemotherapy at our medical center. Based on this concept, chemotherapy doses are clustered into bands of similar dosage levels, thereby allowing the preproduction of frequently used standard doses of drugs, with sufficient physicochemical stability. Although established practice in the United Kingdom, there is little published evidence of its introduction elsewhere. Methods: We performed an analysis of local prescribing practice (22,310 chemotherapies) and identified gemcitabine, 5-fluorouracil, and carboplatin, among various others, as cytotoxic drugs suitable for dose banding. Results: First, we determined the physicochemical stability of the selected chemotherapy drugs during 12-weeks' storage by performing pH analysis and visual examination for color change or particles. No relevant changes were identified. Gemcitabine was selected for quantitative high-performance liquid chromatography analysis and we were able to show that ≥95% remained after 12 weeks' storage, in accordance with international guidelines. To simulate a worst case scenario, we performed microbiological stability testing of simulated cytotoxic compounding by replacing the cytotoxic drug with liquid media. Samples were incubated over defined storage time points (3, 6, and 12 weeks) and evaluated using the direct inoculation method. For the container integrity test, we deposited the samples into highly contaminated broth for 1 hour. Microbiological stability was demonstrated in both tests for the full storage period. Conclusions: Our data show that 12-weeks' storage of selected cytotoxic products is feasible from a microbiological perspective. Sterility of prepared products was maintained under extreme storage conditions. Gemcitabine content was in accordance with international guidelines after 12-weeks' storage. These results support the introduction of dose-banded gemcitabine products with the predicted advantages of optimized pharmacy workflow and reduced patient waiting times. We highlight the need for further research and consensus on the performance of purity analyses in dose-banded drug products.

With growing numbers of elderly multiple myeloma patients, reliable tools to assess their vulnerability are required. The objective of the analysis herein was to develop and validate an easy to use myeloma risk score (revised Myeloma Comorbidity Index) that allows for risk prediction of overall survival and progression-free survival differences in a large patient cohort. We conducted a comprehensive comorbidity, frailty and disability evaluation in 801 consecutive myeloma patients, including comorbidity risks obtained at diagnosis. The cohort was examined within a training and validation set. Multivariate analysis determined renal, lung and Karnofsky Performance Status impairment, frailty and age as significant risks for overall survival. These were combined in a weighted revised Myeloma Comorbidity Index, allowing for the identification of fit (revised Myeloma Comorbidity Index ≤3 [n=247, 30.8%]), intermediate-fit (revised Myeloma Comorbidity Index 4–6 [n=446, 55.7%]) and frail patients (revised Myeloma Comorbidity Index >6 [n=108, 13.5%]): these subgroups, confirmed via validation analysis, showed median overall survival rates of 10.1, 4.4 and 1.2 years, respectively. The revised Myeloma Comorbidity Index was compared to other commonly used comorbidity indices (Charlson Comorbidity Index, Hematopoietic Cell Transplantation-Specific Comorbidity Index, Kaplan-Feinstein Index): if each were divided in risk groups based on 25% and 75% quartiles, highest hazard ratios, best prediction and Brier scores were achieved with the revised Myeloma Comorbidity Index. The advantages of the revised Myeloma Comorbidity Index include its accurate assessment of patients’ physical conditions and simple clinical applicability. We propose the revised Myeloma Comorbidity Index to be tested with the “reference” International Myeloma Working Group frailty score in multicenter analyses and future clinical trials. The study was registered at the German Clinical Trials Register (DRKS-00003868).

This first validation of the International Myeloma Working Group geriatric assessment in 125 newly diagnosed multiple myeloma patients was performed using the International Myeloma Working Group score based on age, the Charlson Comorbidity Index and cognitive and physical conditions (Activities of Daily Living / Instrumental Activities of Daily Living) to classify patients as fit, intermediate-fit or frail. We verified the International Myeloma Working Group score’s impact on outcome, and whether additional tools complement it. Since our prior analyses determined renal, lung and Karnofsky performance impairment as multivariate risks, and the inclusion of frailty, age and cytogenetics complements this, we included the revised myeloma comorbidity index, the Charlson Comorbidity Index, the Hematopoietic Cell Transplantation-Comorbidity Index and the Kaplan-Feinstein Index in this assessment. Multivariate analysis confirmed cytogenetics, Activities of Daily Living, Instrumental Activities of Daily Living and the Charlson Comorbidity Index as risks: 3-year overall survival for fit, intermediate-fit and frail patients was 91%, 77% and 47%, respectively. Using the Charlson Comorbidity Index, the Hematopoietic Cell Transplantation-Comorbidity Index, the Kaplan-Feinstein Index and the revised Myeloma Comorbidity Index allowed us to define fit and frail patients with distinct progression-free and overall survival rates, with the most pronounced differences evidenced via the International Myeloma Working Group score, the Charlson Comorbidity Index and the revised Myeloma Comorbidity Index. Since the Charlson Comorbidity Index is included in the International Myeloma Working Group score, we propose the latter and the revised Myeloma Comorbidity Index for future frailty measurements. Both are useful instruments for identifying myeloma patients with a geriatric risk profile and have a strong prognostic value for functional decline and overall survival. The study was registered as: (clinicaltrials.gov Identifier: 00003686).

Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of Janus kinase (JAK) 1 and JAK2. Ruxolitinib has been approved for the treatment of myelofibrosis (MF) by the US Food and Drug Administration (FDA) in 2011 and by the European Medicines Agency (EMA) in 2012, followed by the approval for the treatment of hydroxyurea (HU)-resistant or -intolerant polycythemia vera (PV) in 2014. Both MF and PV are myeloproliferative neoplasms (MPNs) which are characterized by the aberrant activation of the JAK-STAT pathway. Clinically, MF features bone marrow fibrosis, splenomegaly, abnormal blood counts, and poor quality-of-life through associated symptoms. PV is characterized by the overproduction of primarily red blood cells (RBC), risk of thrombotic complications, and development of secondary MF. Ruxolitinib treatment results in a meaningful reduction in spleen size and symptom burden in the majority of MF patients and may also have a favorable effect on survival. In PV, ruxolitinib effectively controls the hematocrit and reduces splenomegaly. Since recently, ruxolitinib is also under investigation for the treatment of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Toxicities of ruxolitinib include myelosuppression, which results in dose-limiting thrombocytopenia and anemia, and viral reactivations. The metabolization of ruxolitinib through CYP3A4 needs to be considered particularly if co-administered with potent CYP3A4 inhibitors. Several further JAK inhibitors are currently under investigation for MPNs or other immuno-inflammatory diseases.

Pomalidomide (originally CC-4047 or 3-amino-thalidomide) is a derivative of thalidomide that is antiangiogenic and also acts as immunomodulatory. Pomalidomide, the recent immunomodulatory agent (IMiD), has shown substantial in vitro antiproliferative and proapoptotic effects. In vivo studies have suggested limited cross-resistance between lenalidomide and pomalidomide. Moreover, pomalidomide achieved very convincing responses in relapsed and refractory multiple myeloma (RRMM) patients, including those, who are refractory to both lenalidomide and bortezomib. Since pomalidomide plus low-dose dexamethasone has shown better responses, progression-free survival (PFS) and overall survival (OS) than high-dose dexamethasone or pomalidomide alone, subsequent trials have pursued or are still investigating pomalidomide triplet combinations, using cyclophosphamide or other novel agents, such as proteasome inhibitors (PI: bortezomib, carfilzomib) or antibodies, like elotuzumab or daratumumab. Pomalidomide has also been assessed in AL amyloidosis, MPNs (myelofibrosis [MF]), Waldenstrom's macroglobulinemia, solid tumors (sarcoma, lung cancer), or HIV, and-for AL amyloidosis and MF-has already been proven to be remarkably active. Due to its potency, pomalidomide was approved for RRMM by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) in 2013 and for drug combination with low-dose dexamethasone in 2015. In June 2017, the FDA further expanded approval for pomalidomide in combination with daratumumab and low-dose dexamethasone for patients with RRMM.

Additional malignancies in multiple myeloma patients after first-line and maintenance treatment have been observed, questioning whether specific risks exist. Second primary malignancies have also gained attention since randomized data showed associations to newer drugs. We have conducted this large registry analysis in 744 consecutive patients and analyzed: 1) frequency and onset of additional malignancies; and 2) second primary malignancy- and myeloma-specific risks. We assessed the frequency of additional malignancies in terms of host-, myeloma- and treatment-specific characteristics. To compare these risks, we estimated cumulative incidence rates for second malignancies and myeloma with Fine and Gray regression models taking into account competing risks. Additional malignancies were found in 118 patients: prior or synchronous malignancies in 63% and subsequent in 37%. Cumulative incidence rates for second malignancies were increased in IgG-myeloma and decreased in bortezomib-treated patients (P

Pomalidomide (originally CC-4047 or 3-amino-thalidomide) is a derivative of thalidomide that is antiangiogenic and also acts as an immunomodulator. Pomalidomide, as the newest immunomodulatory agent (IMiD), has shown substantial in vitro antiproliferative and proapoptotic effects. In vivo studies have suggested limited cross-resistance between lenalidomide and pomalidomide, and the response of pomalidomide in relapsed and refractory (RR) multiple myeloma (MM) patients, including those who are refractory to both lenalidomide and bortezomib, has induced notable enthusiasm. Several studies have evaluated continuous (2 mg/day) or alternate (5 mg/2 day) dose schedules of pomalidomide, as well as 2 versus 4 mg schedules, and pomalidomide alone versus in combination with dexamethasone or other antimyeloma agents. Since pomalidomide plus low-dose dexamethasone has shown better responses, progression-free and overall survival than high-dose dexamethasone or pomalidomide alone, subsequent trials investigating pomalidomide combination therapy have been initiated. Among these trials combinations with alkylating agents (cyclophosphamide, bendamustin), anthracyclins (pegylated liposomal doxorubicin), proteasome inhibitors (bortezomib, carfilzomib), and various others can be found. Pomalidomide has also been assessed in AL amyloidosis, MPNs (myelofibrosis [MF]), Waldenstrom's macroglobulinemia, solid tumors (sarcoma, lung cancer), or HIV and--for AL amyloidosis and MF--has already proven remarkable activity. Due to its potency, pomalidomide was approved by the US Food and Drug Administration (FDA) for RRMM in 2/2013 and has also been approved by the European Medicines Agency (EMA).

Background: Most MM cells secrete an iIg and the corresponding FLC in excess. With its shorter half-life, FLC provides real-time information on tumor protein synthesis. In addition, immunoglobulin heavy chain/light chain analysis (HLC) is associated with a high sensitivity. Our study aimed to determine if early detection of response by FLC and HLC is predictive of outcome in patients with iIg MM. Methods: We prospectively studied 30 episodes of treatment in 24 patients with iIg MM measurable by serum protein electrophoresis (SPEP) ( 10 g/L) and FLC ( 100 mg/L). The M-spike, FLC (Freelite) and HLC (Hevylite) were measured before and after initiation of treatment weekly for the first 2-3 cycles. FLC and HLC assays were performed retrospectively by nephelometry and did not influence treatment. Patients were followed until next treatment or death. Response, based on IMWG criteria, was defined as at least partial response (PR). Criteria for HLC were the same as for FLC. Results: Median follow-up was 27.6 months (mos). Response by FLC preceded response by SPEP by a median of 3 weeks. By the end of cycle 1, PR was achieved in 23% of cases by SPEP, vs 63% by FLC. On cycle 2, median EFS for patients in PR by FLC compared to patients with stable disease (SD) was 17.5 vs 4.5 mos (p1⁄40.0039). After adjustment for age, line of treatment, ISS and cytogenetics, response by FLC on cycle 2 remained predictive of better EFS (HR 0.20 p1⁄40.008), in contrast to SPEP. On cycle 2, among patients with SD by SPEP, those with PR vs SD by FLC had a longer median EFS (17.5 vs 6.0 mos, p1⁄40.0441) and longer 1-year EFS (56 vs 22%) (figure 1). Among patients in PR by FLC, patients presenting with an unstable response (decrease in FLC by 50% followed by an unsustained increase in FLC by 25% and 25mg/L) had a significantly worse 1-year EFS compared to patients with a stable response by FLC (87.5% vs 30.8%, p1⁄40.0015). These paraprotein fluctuations within a cycle were not apparent with SPEP, reflecting the longer half-life of ilg. In our patients, HLC did not detect response earlier than FLC. Conclusion: Patients with ilg MM failing to respond by cycle 2 or with unstable response using FLC assay have significantly shorter EFS. However, addition of early HLC measurements is not more informative. Our results demonstrate that early FLC measurements after initiation of treatment are predictive of clinical outcome and could be used to better adjust therapy in patients to improve efficacy. PO-047 Assessment of time from onset of first symptoms to the final diagnosis of multiple myeloma (MM) possible risks and future solutions G. Graziani, J. Waldschmidt, G.W. Herget, M. Pandurevic, K. Henne, R. Selder, A.M. May, M. Moller, G. Ihorst, H. Reinhardt, W. Vach, J. Duyster, R. Wasch, M. Engelhardt Department of Medicine I Hematology and Oncology, Medical Center University of Freiburg (UKF); Comprehensive Cancer Center Freiburg e CCCF, Medical Center University of Freiburg; Department of Orthopedics and Trauma Surgery, Medical Center University of Freiburg; Department of Radiation Oncology, Medical Center University of Freiburg; Institute of Clinical Pathology, Medical Center University of Freiburg; Clinical Trials Unit, Medical Center University of Freiburg; Center for Medical Biometry and Medical Informatics, Medical Center University of Freiburg Introduction: The International Myeloma Working Group (IMWG) has recently updated the criteria for the diagnosis of MM, including definition of ultra-high-risk Smouldering Myeloma (SMM) and thereby revised the definition of active MM, which should be treated (Rajkumar et al. Lancet Oncol 2014). As a result, earlier diagnosis and treatment initiation of MM is proposed, albeit MM detection remains challenging due to the unspecificity of MM symptoms. Objective literature regarding the duration of diagnosis finding is lacking and possible risks which might lead to substantial latencies remain undetermined as yet. Methods: Here, 108 MM patients (pts) diagnosed between 1997-2014, treated within clinical trials at the Medical Center University of Freiburg and discussed in our MM tumor board, were meticulously analyzed via all medical records available. We assessed the duration and type of initial symptoms occurring until MM diagnosis and whether specific risks for possible delays could be determined. For the subsequent prospective analysis, we developed a concise MM-specific questionnaire to assess pts seen in our outpt clinic. Results: 102 of 108 pts showed symptoms before the diagnosis of MM. In 16 pts (15%), prior MGUS, SMM or solitary plasmocytoma were documented. The median time from first symptoms to the final MM diagnosis was 3 months (ms), albeit with large variation (0-120 ms). Pt frequencies diagnosed within 12ms are shown in Fig. 1A. Comparison of initial symptoms in pts diagnosed within 6 (n1⁄468) vs. >6ms (n1⁄434) did not reveal significant differences in the type of symptoms (Fig. 1B). Non-CRAB-related symptoms, like B-symptoms or infections, were more frequent with 35% and 25%, respectively, than previously reported (Engelhardt, Haematologica 2014). Of note, pts diagnosed in >6ms showed increased frequencies of light-chain-only MM, prior orthopedic or rheumatic comorbidities, residency in smaller communities and longer distance to tertiary centers compared to pts diagnosed within 6ms. Conclusions: The detection of possible risks for a delayed diagnosis finding is highly relevant, as our results show that 20% of MM pts experience latencies of 12ms. Differences in type of initial symptoms were not significant, whereas others, e.g. disease 15th International Myeloma Workshop, September 23-26, 2015 e107

In the era of high-dose chemotherapy and novel antimyeloma agents, the survival of multiple myeloma (MM) patients has substantially improved. Adverse effects, including infections, may however arise in the era of combination antimyeloma therapies. In general, MM patients have shown a risk of varicella zoster virus (VZV) infection of 1-4 %, increasing with bortezomib treatment or transplants, but whether immunomodulatory drugs also bear a risk of VZV/complicated herpes simplex virus (HSV) (e.g., VZV-encephalitis [VZV-E], disseminated VZV-infection [d-VZV-i], or conus-cauda syndrome [CCS]) has not been elucidated. We here assessed VZV, VZV-E, d-VZV-i, and CCS in 93 lenalidomide-treated MM patients, consecutively seen and treated in our department. Patients' data were analyzed via electronic medical record retrieval within our research data warehouse as described previously. Of the 93 MM patients receiving lenalidomide, 10 showed VZV or other complicated VZV/HSV infections. These VZV patients showed defined risk factors as meticulously assessed, including suppressed lymphocyte subsets, substantial cell-mediated immune defects, and compromised humoral immune response. Due to our findings-and in line with an aciclovir prophylaxis in bortezomib and stem cell transplant protocols-we introduced a routine aciclovir prophylaxis in our lenalidomide protocols in May 2012 to minimize adverse events and to avoid discontinuation of lenalidomide treatment. Since then, we have observed no case of VZV/complicated HSV infection. Based on our data, we encourage other centers to also focus on these observations, assess viral infections, and-in those centers facilitating a research data warehouse-advocate an analogue data review as an appropriate multicenter approach.

Background Most MM patients develop anemia with progression to symptomatic disease. Usually, this is normocytic/normochromic, with normal or low iron and elevated ferritin levels. Because ferritin levels alone do not correctly reflect iron stores, we performed a comprehensive analysis of iron parameters (iron, ferritin, transferrin, transferrin saturation [TRFS]) to more precisely assess patients' iron metabolism. Patients and Methods We analyzed: (1) the frequency of IO vs. ID in 136 consecutive MM patients; (2) the prognostic effect on progression-free (PFS) and overall survival (OS); and (3) specific risk groups according to patients' iron metabolism. Results Most patients had normal iron metabolism or ID: median iron, ferritin, transferrin, and TRFS values were 75 μg/dL, 446 μg/L, 195 mg/dL, and 26%, respectively. Ferritin levels of 1000 μg/L were observed in 46%, 30%, and 24%, and TRFS levels 45% in 32%, 46%, and 22% of patients, respectively. When patients with modified (ID or IO) vs. normal iron metabolism were compared, laboratory parameters (prohormone of brain natriuretic peptide, estimated glomerular filtration rate, c-reactive protein, reflecting cardiac, renal, or infectious impairment), and PFS and OS appeared impaired with modified metabolism, albeit age- and disease-specific differences were insignificant. Conclusion Normal iron metabolism and ID is more frequent in MM patients than IO. ID and IO correlate with organ impairment and impaired survival in MM. This knowledge should be incorporated into the design of future studies that will determine the benefit of iron supplementation with ID, and iron chelators with IO in MM.

The outcomes of MM patients vary considerably and depend on a variety of host- and disease-related risks. As yet, a comorbidity risk index in MM patients has neither been standardized nor validated.We conducted an initial analysis in 127 MM patients and developed the FCI, validating it in an independent cohort of 466 MM patients. The FCI includes patients' Karnofsky Performance Status, renal and lung disease status. We compared the prognostic information of this validated FCI with established comorbidity indices (Hematopoietic Cell Transplantation-Specific Comorbidity Index and Kaplan Feinstein), the International Staging System (ISS), MM therapy, and age.Our validation confirmed that patients with 0, 1, or 2 to 3 FCI risk factors display significantly different overall survival (OS) of not reached, 86, and 39 months, respectively (P.0001). Via multivariate analysis including the FCI, ISS, therapy, and age, the FCI retained its independent prognostic significance (P.0015). The combination of the FCI and ISS allowed definition of 3 distinct subgroups with low-risk (FCI 0 and ISS I-II), intermediate-risk (all remaining), and high-risk (FCI 1-3 and ISS III) with OS probabilities at 5-years of 85%, 74%, and 42%, respectively (P.0001).Our validation analysis demonstrated that the FCI remains a reliable comorbidity index, is simpler to generate than other available comorbidity scores, and contributes valuable information to the ISS. Their combination allows the definition of low-, intermediate-, and high-risk patients. These results advocate use of the FCI in future prospective studies and might guide personalized treatment strategies.

Introduction: Multiple myeloma (MM) relapse is common and may eventually lead to highly refractory/relapsed MM (RRMM). Therefore, novel treatment combinations are crucially needed for this highly challenging subgroup of patients (pts). The aim of the here presented phase I/II IIT was to test the tolerability and activity of a novel, so-called VBDD schedule within an outpatient regimen for extensively pretreated RRMM pts. In addition to Bortezomib, Doxorubicin and Dexamethason, which are all active and approved drugs in RRMM, Vorinostat has shown promising anti-tumor effects as a histone deacetylase inhibitor (HDACi). It inhibits the enzyme activity of HDAC 1, 2, 3 and 6, thereby allowing the activation of tumor suppressor genes. MM cells have been shown to escape from bortezomib treatment by formation of aggrosomes which desensitize cells to proteasome inhibitors and by microtubule mediated protein shuttling to lysosomes, where proteins are degradaded in order to prevent cytotoxic stress and ultimately escape from apoptosis (Fig.A). Albeit vorinostat has shown moderate activity when given alone, it has promising additive effects when combined with other antimyeloma agents, and was therefore used as an add-on agent within this RRMM regimen as it blocks microtubule coppling and aggrosome building and thereby may antagonize escape mechanisms in bortezomib-refractory pts. Methods: Vorinostat was escalated from 100mg (dose level 0), to 200mg (+1) and 300mg (+2). Primary objectives (MTD; 3+3 dose escalation), secondary objectives (safety, IMWG responses, PFS, OS) and supplementary endpoints (organ function, prognostic factors, QoL, comorbidity and HDAC-activity in PBMCs/BM) were assessed throughout the trial. Dose limiting toxicities (DLTs) were defined as any possibly drug-related adverse event (AEs) ≥grade 3 (CTCAE) during the 1st cycle. After completing 6 cycles, patients could receive either a bortezomib maintenance therapy or next-line treatment (e.g. 2nd ASCT). Results: 34 pts with RRMM with a median age of 63 years (47-78) and KPS of 90% (70-100%) have been enrolled, of which 33 received therapy according to the study protocol (1 pt deceased prior to study start due to aggressive MM progression and was therefore not included in the evaluation). The number of prior therapy lines was substantial with a median of 3 (1-8; with prior bortezomib, SCT and IMiDs in 88%, 94% and 42%, respectively). 3 pts each were treated in dose levels 0 and +1, and the remaining 27 pts in dose level +2. No DLTs were observed. In our current analysis, SAEs amounted to 15 and occurred in 9/33 pts (27%): Amongst them, 2 nonfatal SAEs were judged to be related to the investigational therapy (1 bacteraemia, 1 herpes zoster), for the others, no causal relationship to VBDD was found. The response according to IMWG criteria was rewarding with best ORR (>PR) and clinical benefit rate (CBR; >SD) of 42% and 94% (Fig. B), and end of treatment (EoT) ORREoT and CBREoT of 36% and 88%, respectively (Fig.C). Our data also revealed that the response was independent of the presence or absence of unfavorable cytogenetics. Comorbidity assessments assured no decline in pts' mental or physical condition and pts reported preserved or improved QoL with this well-tolerated 4-agent treatment regimen. Pharmacodynamic analyses in peripheral blood (PB) MCs showed substantial and early HDAC downregulation between VBDD cycles 1 and 2 in 11/16 pts (69%): median HDAC activity decreased to 52% of pre-treatment levels. Thereby, we were able to distinguish 3 groups of pts with substantial, more subtle or no PB HDAC decreases in 8, 3 and 5 pts, respectively. Of note, these HDAC changes correlated well with pts' serological and clinical responses, except in 2 pts. These intriguing results are currently further assessed and will be presented at the meeting. Conclusions: VBDD demonstrated to be an effective and well-tolerated outpatient regimen with promising response rates in heavily pretreated RRMM pts. The employed VBDD regimen, with a continuous, rather than pulsed vorinostat-schedule, constitutes a promising treatment option, expands current standard therapies and, similarly to other HDACi (i.e. panobinostat), suggests HDACi as a valuable add-on within this combination schedule in order to stabilize the disease and/or bridge RRMM patients to next-line treatments (i.e. autologous/allogenic stem cell transplantation) or novel clinical trial drugs. *AK and JW contributed equally Figure 1. Figure 1. Disclosures Off Label Use: We report on results of an Phase I/II IIT, in which the HDACi Vorinostat is used to treat relapsed or refractory Multiple Myeloma pts . Engelhardt:MSD: Research Funding; Janssen-Cilag: Research Funding; Comprehensive Cancer Center Freiburg: Research Funding; German Cancer Aid: Research Funding. Wäsch:German Cancer Aid: Research Funding; Janssen-Cilag: Research Funding; Comprehensiv Cancer Center Freiburg: Research Funding; MSD: Research Funding.

Introduction The combination of bortezomib, doxorubicin and dexamethasone (BDD) is well tolerated and induces a high overall response rate (ORR). Preclinical studies have demonstrated that vorinostat, a histone deacetylase inhibitor, is synergistic with bortezomib and doxorubicin. The aim of this phase I/II study was to determine the tolerability and activity of the combination of BDD with vorinostat (VBDD) in relapsed/refractory multiple myeloma (MM). Methods Patients received escalated vorinostat-doses (provided by MSD) at 100mg (dose level 0), 200mg (dose level +1) and 300mg (dose level+2) on days 1-4, 8-11, 15-18, combined with bortezomib 1.3mg/m2 day 1,8,15 (provided by Janssen), dexamethasone 40mg day 1,8,15,22 and doxorubicin on 9mg/m2 day 1+8. The primary objective was the maximum tolerated dose (MTD; 3+3 dose escalation design). Secondary objectives were safety, response assessed by EBMT and IMWG criteria, progression-free survival and overall survival. Correlative endpoints include prognostic MM-parameters, organ function, QoL-, comorbidity-assessments and translational studies (e.g. HDAC-activity in PB MNCs, Figure 1). Dose limiting toxicities (DLTs) were defined as any possibly drug related adverse events (AEs) ≥grade 3 (CTCAE) within the 1st cycle. After completion of 6 cycles, patients could continue with bortezomib maintenance therapy or proceed to (most often 2nd) ASCT. Results To date, 18/30 patients have been enrolled (median age 63 years [range 54-75], 55% men). The median Karnofsky Performance Status was 90% (range 70-100%). Median prior therapy lines were substantial with 3 (range 1-8): bortezomib, thalidomide or lenalidomide were given in 88% and 24% each, respectively; 94% of patients had undergone prior SCTs. Cytogenetic abnormalities included del(17p) (n=2), t(4;14) (n=2), gain(1q) (n=2), t(11;14) (n=4) and hyperdiploidy (n=7). No DLTs have been observed to date; with 3 patients each being included in dose level 0 and dose level +1 and the following patients safely proceeding to dose level +2. Six SAEs occurred in 4/18 patients (22%): bacteraemia (n=1) and herpes zoster reactivation (n=1) were suspected to be related to all VBDD-drugs. No causal relationship to study drugs was suspected for pneumonia (n=2), 1 syncope and 1 death due to PD with persisting plasma cell leukemia. The ORR (>PR) and clinical benefit rate (SD, PR, CR) was 65% and 89%, respectively. At a median follow-up of 8 months (range 3-23), there have been only 2 patients with PD (refractory MM + plasma cell leukemia). The analysis of HDAC activity after VBDD initiation demonstrated downregulation in 6/8 (75%) patients (Figure 1). Further analyses will determine, whether HDAC activity and treatment response may correlate and whether this HDAC downregulation may precede and/or indicate depth of response Conclusions VBDD is a well tolerated and effective regimen in heavily pretreated relapsed/refractory MM patients. There have been no observed DLT and the MTD of vorinostat was set at 300mg, with all reported SAEs being in line with the known safety profile of the investigated drugs. Our alternative vorinostat-schedule (dosing of 4 days on and 4 days off) induced excellent tolerability and seems to enhance the antimyeloma response, warranting completion of this study. Disclosures: Kleber: MSD, Janssen-Cilag: Research Funding. Off Label Use: Preclinical studies have demonstrated that vorinostat, a histone deacetylase inhibitor, is synergistic with bortezomib and doxorubicin. The aim of this phase I/II study was to determine the tolerability and activity of the combination of BDD with vorinostat (VBDD) in relapsed/refractory multiple myeloma. Vorinostat is off-label use for MM patients, all other drugs are in label use. Waesch:MSD, Janssen-Cilag: Research Funding. Engelhardt:MSD, Janssen-Cilag: Research Funding.

Abstract 5119 Introduction: It has been previously reported that both short and long term vascular and thromboembolic events (TEE) occur following cisplatin containing chemotherapy for germ-cell cancer (GCC) (Bokemeyer et al. 1998, Weijl et al. 2000, Diekmann et al. 2010). It has also been shown that patients with GCC are at higher risk of TEE than patients with non-GCC, while on cisplatin-based chemotherapy (Piketty et al. 2005). Method: We reviewed all GCC patients treated in our department from 2008 until 2010 with cisplatin-based chemotherapy and assessed the incidence of TEE. Cases were analyzed with respect to risk factors for vascular events (obesity, diabetes, nicotine abuse, prior cardiovascular disease, prior TEE), tumor characteristics (low- vs. intermediate/high-risk GCC) and age. In addition, further analysis of hemostasis laboratory tests of these patients is being performed. Result: Eight patients (8/50=16%) treated with cisplatin-containing chemotherapy developed TEE. Of these TEE, two were myocardial infarctions, four pulmonary embolisms, one patient showed thrombosis of the jugular vein and one a peripheral (femoral) arterial thrombosis. TE-risk factors included: nicotine abuse in two patients, obesity and nicotine abuse in one patient and no identifiable factors in the others (hemostasis laboratory tests are currently being performed). The median age of these 8 patients was 42 years (range 16–61). Patients were treated with PEB (cisplatin, etoposide, bleomycin) or PIV (cisplatin, ifosfamide, etoposide) initially applying continuous heparin prophylaxis with 15000IE/day (d), d1-5 only during PEB or PIV, but no low-molecular weight heparin (LMWH-) and/or aspirin (ASS-) medication for venous and arterial TEE prophylaxis thereafter. With these clinically very relevant and severe TEEs, we have adapted our PEB- and PIV protocols, adding a LMWH prophylaxis (enoxaparin 40mg d6-21 after chemotherapy). Conclusion: We observed an increased risk of major thromboembolic and vascular events with an incidence rate of 16% in GCC patients after cisplatin-containing chemotherapy. Prior studies have identified TEE-risks in GCC and with cisplatin-chemotherapy, albeit LMWH- and/or ASS-prophylaxis - without clinical trials - has not been recommended as yet. Prospective studies investigating thrombosis prophylaxis measures are currently performed in order to achieve the best standard of care for these patients. Currently an extensive hemostasis diagnostic testing from all patients with TEE is being performed. Disclosures: No relevant conflicts of interest to declare.