clusions: These results demonstrate that relapsed multiple myeloma patients who respond to initial bortezomib treatment have a sustained susceptibility to bortezomib and do not experience uncommon toxicity to retreatment.

Previous studies have shown that retreatment of relapsed/refractory multiple myeloma (MM) with a second course of bortezomib therapy could be effective in heavily pre-treated patients. In this study, the results of a multicentre, retrospective survey were reported involving patients in Switzerland with MM who responded to initial bortezomib therapy; 43 patients were enrolled and 42 were evaluated for response. The overall response rate (complete response [CR] + near CR [nCR] + partial response [PR]) to bortezomib retreatment was 64.3%, and the clinical benefit rate (CR + nCR + PR + stable disease) for retreatment was 83%. The response rate to bortezomib retreatment in the subgroup with a first treatment-free interval (TFI) >6 months was higher than that in the subgroup with first TFI ≤6 months (74.1% vs. 46.7%) and lower in patients who received concomitant dexamethasone with bortezomib retreatment (57.1% vs. 78.6%). The median overall survival (OS) from first diagnosis of MM was 9.3 years, and after retreatment with bortezomib the median OS was 1.7 years. In total, 85.7% of patients who achieved CR or nCR with initial bortezomib treatment achieved CR or nCR with retreatment. Bortezomib as retreatment was well tolerated, and the safety profile was consistent with previous studies of bortezomib in relapsed MM. The most common adverse drug reaction attributed to bortezomib was peripheral neuropathy in 5 patients. In conclusion, bortezomib retreatment was a well-tolerated, effective therapeutic option for relapsed MM patients in the Swiss clinical setting who have previously responded to bortezomib, particularly for those who experienced an initial TFI of >6 months.

We present a 48-year-old patient who complained for 1 year about urticarial reactions which appeared always when he ingested alcoholic beverages. Skin prick tests with ethanol were negative but positive with 10% acetic acid in the patient. Normal controls tested negative with acetic acid. Skin prick tests to common immediate-type allergens were negative. The patient underwent a double-blind, placebo-controlled challenge test. A few minutes after challenge with ethanol but not with placebo, the patient developed erythema and wheals on the chest and the upper arms. The tryptase serum level rose from undetectable (0.1 U/ml) before challenge to 3.8 U/ml after skin lesions had appeared. This case demonstrates that increased tryptase serum levels can help in the diagnosis of ethanol-induced urticaria.

In myeloma therapy retreatment after successful therapy is frequently considered. Here we present pooled data from a German and Swiss multicenter, retrospective survey (26866138MMY4014). The survey started in Germany and was later extended to Switzerland. German data have already been published before. Here we report on the entire cohort of patients for the first time. For inclusion into this analysis, patients with MM had to have had preceding bortezomib treatment, resulting in at least partial remission and a second therapy with Bortezomib on relapse. The intention of this trial was to provide further evidence of the value of a retreatment with bortezomib, description of predisposing factors and comparison of response quality and remission duration in this predefined patient group of bortezomib responders. Data from 36 centers and 94 patients were available for safety analysis. 34 patients had to be excluded from the efficacy analysis due to major deviations from the inclusion criteria, i.e. concomitant antineoplastic treatment, retreatment with bortezomib not being completed, no response during initial bortezomib treatment or missing information about MM-specific interim therapy. Thus 60 patients were left for the per protocol population (PP). Patients had a mean age of 65.5 years (40–89), 56.4% being male. Patients had received a mean of 3.7 prior therapies for multiple myeloma before initial bortezomib therapy, most frequently melphalan-prednisone (44.7%), dexamethasone (38.3%) and/or vincristine-adriamycin-dexamethasone (31.9%). Stem cell transplantation was undertaken in 26.6% of the patients. Mean cycle numbers for initial bortezomib therapy and retreatment were 5.8 and 4.5, respectively. The majority of patients (85.1% and 78.7%, respectively) received a bortezomib dose of 1.3 mg/m2. Concomitant dexamethasone therapy was administered to 43.6% and 62.8% of the patients, respectively. Between the initial bortezomib therapy and bortezomib retreatment 13.8% of the patients received other MM-specific interim therapy. The efficacy analysis was based on the PP population and revealed very encouraging responses. Overall response (OR) was defined as complete response (CR), nearly complete response (nCR) and partial response (PR). With a pre-defined OR of 100% for the initial bortezomib therapy, 63% (49.9–75.4%) responded again to retreatment. Best response is summarized in the table below. Subgroup analyses of the rates of clinical benefit (CR, nCR, PR or SD) were performed by treatment free interval (TFI) after initial bortezomib therapy (<= 6 months versus > 6 months) and by concomitant dexamethasone treatment. In patients with TFI > 6 months a higher rate of clinical benefit (89.7%) could be achieved as compared to TFI <= 6 months (61.9%). Concomitant dexamethasone treatment was associated with a lower rate of clinical benefit (76.5%) than without (84.6%). For 44 patients (46.8%) a total of 125 adverse drug reactions (ADRs) were documented. 21 serious ADRs were documented in 11 (11.7%) patients. 30 patients had died at the time of analysis. 2 patients died due to adverse events (pneumonia and pulmonary oedema) assessed as at least possibly related to bortezomib. For one fatal outcome (pneumonia) causality assessment has not been provided. This binational retrospective survey suggests that the safety profile is in line with the current summary of product characteristics of Velcade and that high remission rates and durable TFIs can be achieved by bortezomib retreatment. A TFI > 6 months could be a good clinical marker for a higher rate of clinical benefit. Results of an ongoing prospective trial on bortezomib retreatment are awaited to confirm these results. Initial bortezomib therapy (N=60) Bortezomib retreatment (N=60) * based on n=47 patients responding to bortezomib retreatment. Complete response (CR) 12 (20%) 8 (13.3%) Nearly complete response (nCR) 7 (11.7%) 3 (5%) Partial response (PR) 41 (68.3%) 27 (45%) Stable disease (SD) - (not allowed by selection criteria) 10 (16.7%) Progressive disease (PD) - (not allowed by selection criteria) 12 (20%) Median time to response 3.1 months 3.3 months* Median duration of response 6.9 months 6.1 months* Median treatment free interval 8.6 months 5.7 months

The combination of clinical knowledge (applicable for a majority of patients, published in the form of review articles), real world evidence (describing more nuanced outcomes for small cohorts) and innovative artificial intelligence algorithms opens potent avenues to re-examine clinical findings and uncover new biomarkers for the prognosis / prediction of therapeutic responses--in a manner that can directly be incorporated in clinical decision support tools. In this work, neural networks are first developed to reproduce clinical guidelines with >95% accuracy. After mastering the complex knowledge that is generally expected from human doctors, a transfer learning technique was used to sift through de-identified longitudinal data of 9267 patients with multiple myeloma-related conditions at the Vanderbilt University Medical Center using progression free survival (PFS) to quantify therapeutic outcomes. The "precision medicine neural networks" obtained as a result can be compared with conventional and less portable survival model algorithms, using Shapley values to explain prediction differences. Testing a first hypothesis that "lytic bone lesions are a prognostic factor for poor PFS", a study involving 1530 patients confirmed that the median PFS of 54 ± 6 months (684 censored patients showing progression) in the presence of bone lesions is significantly lower than the 107 ± 40 months (90 censored patients) in the absence of lesions. Keeping only 179 patients for which a full range of cytogenetic factors are available and using a Cox regression & Random Survival Forests that provide the best fit of the data, we confirmed previous findings for high-risk trisomies 1 and 7, monosomy 13, deletion 12p and translocation t(11;14)(q13;q32). We furthermore uncovered new additional adverse factors del6q, 2+, 21-, 16- to formulate a model that achieves a statistically significant concordance of 0.72 ± 0.07. Comparing therapeutic effects for patients in a real-world hospital setting with clinical trials, we found that lenalidomide + bortezomib + dexamethasone used in a first-line therapy resulted in lower median PFS of 17-47 months than the 39-52 months published in the SWOG S0777 trial, most likely because comorbidities contributed to shortening the PFS in real-world settings. We conclude with an analysis of concrete examples where therapeutic recommendations differ from guidelines, explaining the reason with statistically significant cohorts observed in the data. Disclosures No relevant conflicts of interest to declare.