Immunoglobulin D (IgD) myeloma is a rare isotype that comprises 1-2% of multiple myeloma (MM) patients [1-3], which has significantly inferior survival for a median overall survival (OS) between 13 and 21 months [4-6]. Given the lack of large cohort with comprehensive clinical and cytogenetic assessment, knowledge about IgD myeloma is obtained mostly from a limited sample size [7]. Therefore, we carried out a multicenter retrospective study to evaluate the prevalence, clinical features, prognosis, and to develop and validate a prognostic model, including 356 patients with IgD myeloma from 14 centers of Asian Myeloma Network (AMN). Data were collected from China, Korea, and Singapore diagnosed from 2002 to 2019 (Supplementary Table 1). Ethical committee approvals were obtained and study protocol was approved by the Institutional Review Board of each institution. To avoid clinical information leak, and get

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8036 Background: Multiple myeloma (MM) is a plasma cell malignancy characterized by chromosomal instabilities (CIN). Here we investigate the potential of cell-free DNA CIN as non-invasive biomarker to predict early response for MM treatments. Methods: In this prospective study, we recruited 11 relapsed/refractory (RRMM) and 19 newly diagnosed (NDMM) patients at Changzheng Hospital. Plasma samples were collected after finished two cycles or one month (RRMM) of therapy, with matched ones before the current regimen. cfDNA was extracted, followed by CIN analyses by using a customized bioinformatics workflow, ultrasensitive chromosomal aneuploidy detector (UCAD). Criteria for response and progression were according to the IMWG (Durie BG et al. 2006). Results: 7 (23%) patients (5 RRMM and 2 NDMM) showed high cfDNA CIN regard as strong positive after two cycles of treatment. Plasma cfDNA CIN profiling found complex clonal evolution compared two cycles to baseline. Multiple genomic regions, including chr7, 17p (TP53), 12q and 3p, were involved in clonal evolution. The degree of cfDNA CIN correlated with myeloma stage and overall survival. Remarkably, of the 5 heavily treated RRMM patients and 1 primary refractory newly diagnosed patient, 3 died within 60 days after the last time of cfDNA detection. Nine patients (30%) of patients showed positive cfDNA CIN after two cycles of treatment, which response rate was 11% (n=1) with SD, 33% (n=3) with MR, and 56% with PR, respectively. Fourteen patients with 5 RRMM and 9 NDMM were detected marginal or negative cfDNA CIN after two cycle’s treatment. The overall response rate in 14 patients was 100%, including 14.3% with a complete response, 14.3% with a very good partial response (VGPR), 57.1% with a PR, and 14.3% with a MR. Of these patients, 3 RRMM who received with more than six lines of therapy, showed positive cfDNA CIN. Subsequently, these three heavily treated RRMM patients have chance to enroll the chimeric antigen receptor T-Cell immunotherapy (CAR-T) therapy (enrolled NCT03093168). Surprisedly, all of them benefit from the CAR-T therapy to improve responses dramatically, meanwhile, the dynamics of total cfDNA concentration correlated with tumor burden to negative. Conclusions: We provide evidence that cfDNA level correlates with tumor burden and response rate in MM. For heavily pre-treated advanced RRMM patients with cfDNA CIN positive were benefit from the CAR-T therapy. Therefore, serial plasma cfDNA analysis is a robust and sensitive tool for monitoring response to therapy.

Background: Minimal residual disease (MRD) is becoming standard diagnostic care for multiple myeloma. Here we investigate cell-free DNA chromosomal instability as minimal invasive biomarker for minimal residual disease monitoring. Methods: 55 patients were recruited, including 47 newly diagnosed and 8 relapsed multiple myelomas. Plasma samples were collected before treatments, end of 2 cycle and 4 cycle of treatments. Treatment response was assessed by using IMWG criteria. Cell-free DNA was analyzed by illumine HiSeq X10, followed by chromosomal instability analyses by a customized bioinformatics workflow, ultrasensitive chromosomal aneuploidy detector (UCAD), and cfDNA CIN responding to treatment was summarized as cfDNA MRD INDEX. Results: In this cohort study, 53 (96.3%) patients were found with treatment responses after 4 cycle of treatments, including 16 (29.1%) complete, 13 (23.6%) very good partial, 17 (30.9%) partial and 6 (10.9%) marginal responses. The other 2 (3.64%) recurrent MM experiences disease progression. At baseline, plasma cfDNA chromosomal aberrations were found in 14/17(82.3%) multiple myeloma patients. Less patients were found with detectable chromosomal changes after treatments (58.8% after C2, 41.2% after C4, versus 82.3% before treatments, P<0.01). The treatment responses identified in plasma cfDNA were summarized as cfDNA MRD INDEX. Low cfDNA MRD INDEX predicts better treatment responses (Fisher exact test, Odds ratio=7.3, P=4.69e-05). And it predicts complete response with sensitivity 100% and specificity 83.3%, with cutoff value 0.044. Furthermore, cfDNA CIN MRD index were found linearly correlated with percentage of malignant plasma cells from bone marrow aspiration as examined by flow cytometry assay (R-square=0.883, P<0.01). Cutoff -0.06 predicts 100% MRD negatives at specificity 100%. Conclusions: Plasma cfDNA CIN might be used for monitoring multiple myeloma patients treatment responses, especially for predicting minimal residual diseases. Disclosures No relevant conflicts of interest to declare.