Monocyte or white blood cell counts and β₂ microglobulin predict the durable efficacy of daratumumab with lenalidomide

BACKGROUND: Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab. OBJECTIVES: We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status. DESIGN: We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database. METHODS: We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database. RESULTS: In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower β2 microglobulin (B2MG < 5.5 mg/L) or fewer prior regimens (<4). No parameters were correlated with TTNT under the DBd regimen. CONCLUSION: We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/μl; 1 point for <200/μl) or WBC counts (0 points for ⩾3500/μl; 1 point for <3500/μl) plus B2MG (0 points for <5.5 mg/L; 1 point for ⩾5.5 mg/L). Patients with a score of 0 showed significantly longer TTNT and significantly better survival compared to those with a score of 1 or 2 (both p < 0.001). To confirm this concept, our results will need to be validated in other cohorts

Postazacitidine clone size predicts long-term outcome of patients with myelodysplastic syndromes and related myeloid neoplasms

Azacitidine is a mainstay of therapy for MDS-related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their post-treatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pre- (n=449) and post- (n=289) treatment bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their post-treatment clone size on treatment outcomes. In Cox proportional hazard modeling, multi-hit TP53 mutation (HR, 2.03; 95% CI, 1.42-2.91; P<.001), EZH2 mutation (HR, 1.71; 95% CI, 1.14-2.54; P=.009), and DDX41 mutations (HR, 0.33; 95% CI, 0.17-0.62; P<.001), together with age, high-risk karyotypes, low platelet, and high blast counts, independently predicted OS. Post-treatment clone size accounting for all drivers significantly correlated with International Working Group (IWG)-response (P<.001, trend test), except for that of DDX41-mutated clones, which did not predict IWG-response. Combined, IWG-response and post-treatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, IPSS-M (c-index, 0.653 vs 0.688; P<.001, likelihood ratio test). In conclusion, evaluation of post-treatment clone size, together with pre-treatment mutational profile as well as IWG-response have a role in better prognostication of azacitidine-treated myelodysplasia patients

Efficient enumeration of stereoisomers of tree structured molecules using dynamic programming

Nonredundant and exhaustive generation of stereoisomers of a chemical compound with a specified constitution is one of the important tools for molecular structure elucidation and molecular design. In this paper, we deal with chemical compounds composed of carbon, hydrogen, oxygen and nitrogen atoms whose graphical structures are tree-like graphs because these compounds are most fundamental, and consider stereoisomers that can be generated by asymmetric carbon atoms and double bonds between two adjacent carbon atoms. Based on dynamic programming, we propose an algorithm of generating all stereoisomers without duplication. We treat a given tree-like graph as a tree rooted at its structural center. Our algorithm first computes recursively the numbers of stereoisomers of the subgraphs induced by the descendants of each vertex, and then constructs each stereoisomer by backtracking the process of computing the numbers of stereoisomers. Our algorithm correctly counts the number of stereoisomers in O(n) time and space, and correctly enumerates all the stereoisomers in O(n) space and in O(n) time per stereoisomer, where n is the number of atoms in a given structure. The source code of the program implementing the proposed algorithm is freely available for academic use upon request

Significance of maintenance therapy after HDT/ASCT in symptomatic multiple myeloma: A multicenter retrospective analysis in Kansai Myeloma Forum

Abstract A total of 129 symptomatic patients with multiple myeloma (MM) who underwent high‐dose chemotherapy with autologous stem cell transplantation (HDT/ASCT) were analyzed. The 4‐year overall survival (OS) of patients with maintenance (n = 82) was 80%, whereas that of patients without maintenance (n = 47) was 72% (p = 0.426). The 4‐year progression‐free survival (PFS) of patients with maintenance was 38%, whereas that of patients without maintenance was 27% (p = 0.088). Multivariate analysis revealed that an International Staging System score ≥2 was associated with worse PFS (hazard ratio 1.62, p = 0.043). Among the 129 patients, two were excluded owing to early relapse, 50 patients achieved complete response (CR), and 77 patients failed to achieve CR. Patients who achieved CR showed better 4‐year PFS than those who failed to achieve CR (41% vs. 30%, p = 0.027); however, 4‐year OS was not different (76% vs. 82%, p = 0.971). In patients who achieved CR, 4‐year OS with/without maintenance was 74%/81% (p = 0.357), 4‐year PFS with/without maintenance was 42%/40% (p = 0.954). In patients who failed to achieve CR, the 4‐year OS with/without maintenance was 97%/91% (p = 0.107), and 4‐year PFS with/without maintenance was 36%/16% (p < 0.001). In patients who failed to achieve CR, maintenance significantly improved the PFS. Maintenance after HDT/ASCT can prolong PFS in patients who fail to achieve CR in real‐world settings

Efficacy of elotuzumab for multiple myeloma in reference to lymphocyte counts and kappa/lambda ratio or B2 microglobulin

Abstract Novel therapeutic drugs have dramatically improved the overall survival of patients with multiple myeloma. We sought to identify the characteristics of patients likely to exhibit a durable response to one such drug, elotuzumab, by analyzing a real-world database in Japan. We analyzed 179 patients who underwent 201 elotuzumab treatments. The median time to next treatment (TTNT) with the 95% confidence interval was 6.29 months (5.18–9.20) in this cohort. Univariate analysis showed that patients with any of the following had longer TTNT: no high risk cytogenic abnormalities, more white blood cells, more lymphocytes, non-deviated κ/λ ratio, lower β2 microglobulin levels (B2MG), fewer prior drug regimens, no prior daratumumab use and better response after elotuzumab treatment. A multivariate analysis showed that TTNT was longer in patients with more lymphocytes (≥ 1400/μL), non-deviated κ/λ ratio (0.1–10), lower B2MG (< 5.5 mg/L) and no prior daratumumab use. We proposed a simple scoring system to predict the durability of the elotuzumab treatment effect by classifying the patients into three categories based on their lymphocyte counts (0 points for ≥ 1400/μL and 1 point for < 1400/μL) and κ/λ ratio (0 points for 0.1–10 and 1 point for < 0.1 or ≥ 10) or B2MG (0 points for < 5.5 mg/L and 1 point for ≥ 5.5 mg/L). The patients with a score of 0 showed significantly longer TTNT (p < 0.001) and better survival (p < 0.001) compared to those with a score of 1 or 2. Prospective cohort studies of elotuzumab treatment may be needed to validate the usefulness of our new scoring system

Impact of cytogenetic abnormalities in symptomatic multiple myeloma; a Japanese real-world analysis from Kansai Myeloma Forum

To evaluate the specific prognostic value of CAs, we conducted an analysis of 923 symptomatic multiple myeloma patients. Among this cohort, 480 patients had complete data set of high-risk CAs by interphase fluorescent in situ hybridization at diagnosis. In the high-risk group analysis, the median OS of patients without CAs (n = 338, 72 %) was 6.5 years, patients with del(17p) (n = 42, 9 %) was 4.4 years, patients with t(4;14) or t(14;16) (n = 72, 15 %) was 4.4 years, and patients with double-positive CAs(del(17p) and t(4;14) or t(14;16)) (n = 18, 4 %) was 2.1 years (p = 0.032). Patients with double-positive CAs had a significantly worse prognosis

Surface environment of Phobos and Phobos simulant UTPS

International audienceThe Martian Moons eXploration (MMX) mission will study the Martian moons Phobos and Deimos, Mars, and their environments. The mission scenario includes both landing on the surface of Phobos to collect samples and deploying a small rover for in situ observations. Engineering safeties and scientific planning for these operations require appropriate evaluations of the surface environment of Phobos. Thus, the mission team organized the Landing Operation Working Team (LOWT) and Surface Science and Geology Sub-Science Team (SSG-SST), whose view of the Phobos environment is summarized in this paper. While orbital and large-scale characteristics of Phobos are relatively well known, characteristics of the surface regolith, including the particle size-distributions, the packing density, and the mechanical properties, are difficult to constrain. Therefore, we developed several types of simulated soil materials (simulant), such as UTPS-TB (University of Tokyo Phobos Simulant, Tagish Lake based), UTPS-IB (Impact-hypothesis based), and UTPS-S (Simpler version) for engineering and scientific evaluation experiments