t(11;14) multiple myeloma: A subtype associated with distinct immunological features,immunophenotypic characteristics but divergent outcome

t(11;14)(q13;q32) is the most common chromosome translocation in multiple myeloma (MM), but a consensus of clinicopathological features and impact on survival is yet to be reached. We analyzed a cohort of 350 patients with various plasma cell malignancies, including newly diagnosed MM (NDMM, n = 253), relapsed/refractory MM (RRMM, n = 77), as well as primary and secondary plasma cell leukemia (PCL, n = 10 and n = 10, respectively). Results: A remarkably higher frequency of t(11;14) was observed in the PCL than in the NDMM. A high incidence of t(11;14) was detected in the IgD, IgM, and nonsecretory MM. The t(11;14) MM group was associated with a significantly higher positive rate of B-lineage associated antigens CD20 and CD79a as well as the lack of CD56 expression. t(11;14) was less likely to be accompanied by 13q14 deletion than 13q14 deletion frequency in non-t(11;14) population (p = 0.026), and fewer patients displaying t(11;14) were identified as belonging to the high-risk cytogenetic group due to the extremely low incidence of t(4;14) and t(14;16). As a whole, patients exhibiting t(11;14) had a comparable outcome with the control cohort in NDMM, but CD20 was able to identify two subsets of the disease with dissimilar outcomes. Among patients receiving bortezomib-based treatment, patients harboring t(11;14) without CD20 expression had a significantly shortened PFS (11.0 versus 43.0 months, p = 0.005) and OS (16.5 versus 54.0 months, p = 0.016) compared with patients displaying t(11;14) with CD20. Our findings suggest that although the t(11;14) plasma cell disorder displayed distinct biological, clinical and laboratory features, it was a heterogeneous disease with divergent outcome.     

伴t(11;14)的浆细胞肿瘤380例临床分析

目的 探讨伴t(11;14)浆细胞肿瘤患者的临床病理特征和t(11;14)对预后的影响.方法 回顾性分析380例初诊浆细胞肿瘤患者的临床资料,其中女性146例,男性234例,初诊多发性骨髓瘤(MM)370例,原发性浆细胞白血病(PCL)10例.采用双侧Fisher确切概率法评估分类变量之间的关系,置信系数为95 %.结果370例初诊MM患者中有101例(27.3 %)存在t(11;14);10例PCL患者中有8例存在t(11;14).t(11;14)在IgD、IgM型和不分泌型MM患者中的检出率为50.9 %(27/53),明显高于IgA型[21.6 %(16/78)]及IgG型[28.4 %(52/183)](均P=0.002).t(11;14) MM患者CD56表达比例低于非t(11;14)MM患者[51.6 %(48/93)比72.0 %(167/232),P=0.001],CD117抗原表达比例亦降低[23.7 %(22/93)比37.7 %(87/231),P=0.019].在269例不伴t(11;14)MM患者中有86例IgH重排阳性,主要为t(4;14)或t(14;16).伴t(11;14)的MM中,高危患者占11.9 %(12/101),而不伴t(11;14)者中占27.5 %(74/269),两者差异有统计学意义(P=0.001).结论 伴t(11;14)的MM患者具有独特的生物学行为、临床特征和实验室特征.     

Heterogeneous chromosome 12p deletion is an independent adverse prognostic factor and resistant to bortezomib-based therapy in multiple myeloma

The deletion of 12p (del(12p)) has been described as a novel negative prognostic marker in multiple myeloma (MM) and has gained increasing attention in recent years. However, its impact on MM is still controversial. In this study, we comprehensively evaluated the clinical impact of 12p13 deletion using fluorescence in situ hybridization (FISH) on 275 newly diagnosed MM cases treated in a prospective, non-randomized clinical trial (BDH 2008/02). The results showed that deletion of 12p13 was detected in 10.5% of newly diagnosed cases and associated with multiple indicators for high tumor burden including ISS III, BM plasmacytosis larger than 50%, and renal lesion. Moreover, the cases with 12p13 deletion typically had higher incidence of del(17p), IGH translocation and t(4;14). Patients with del(12p) conferred significantly adverse prognosis for PFS and OS, even in patients subjected to bortezomib-based therapy. When adjusted to the established prognostic variables including del(13q), del(17p), t(4;14), amp(1q21), ISS stage and LDH, del(12p13) remained the powerful independent adverse factor for PFS (P = 0.007) and OS (P = 0.032). In addition, del(12p13) combined with high β2-MG, high LDH and bone lesion can further identify subpopulations with high-risk features. Our results strongly supported that del(12p13) can be used as a valuable prognostic marker in MM.     

伴1q21扩增初治多发性骨髓瘤患者疗效及预后的回顾性分析

目的 探讨1q21扩增（1q21+）与初治多发性骨髓瘤（newly diagnosed multiple myeloma,NDMM）患者的治疗疗效及预后的关系,以及1q21+在MM危险分层中的优势。方法 回顾性分析选择2015年11月至2021年11月于首都医科大学附属北京潞河医院就诊的NDMM患者作为研究对象,采用iFISH技术检测细胞遗传学异常情况,分析1q21+与以硼替佐米为基础的诱导化疗及自体干细胞移植（autologous stem cell transplant,ASCT）疗效及预后的关系,比较MM R2-ISS与R-ISS的分层优势。结果 本研究共纳入159例NDMM患者,1q21+患者79例,非1q21+患者80例,其中41例患者接受RVD方案治疗,118例患者接受非RVD方案治疗。在1q21+的患者中,RVD组的完全缓解（complete remission,CR）率高于非RVD组（P<0.001）;RVD组中,1q21+的CR率低于非1q21+的患者（P=0.004）。多因素分析显示,1q21+是NDMM患者无进展生存期（progression-free su...     

Incidence and Prognostic Significance of High-Risk Cytogenetically Abnormalities in Multiple Myeloma Patients in Colombia

IntroductionMultiple Myeloma (MM) is the second most common hematological cancer, several cytogenetics abnormalities such as t(4;14), del (17p), and t(14;16) were identified as a high-risk for survival, in Latin America, we have very little data on cytogenetic alterations in MM. This study describes the incidence of high-risk cytogenetically abnormalities in a Colombian population and prognostic significance.MethodsIn a retrospective cohort of new diagnostic Multiple Myeloma between 2016 and 2020, we identified a high-risk cytogenetically abnormalities t(4;14), t(14;16), and 17p deletions by FISH techniques and described incidence. We followed patients until progression or death and comparing progression free survival (PFS) and overall survival (OS), according with high- risk cytogenetically features.ResultsWe included 135 newly diagnosed MM patients, the incidence of high-risk cytogenetically abnormalities were 30.3%, with 17.1% of 17p deletions, 14.1% of t(4;14) and 2.25% of t(14;16). According to the high risk cytogenetically abnormalities, the median PFS for the group of no abnormalities were 50.2 months 95% CI [25.2-62.4] and for the group of high-risk cytogenetic abnormalities 33.9 months 95% CI [23.6-NA] (P = .2). For OS the median were 76.9 months, 95% CI [67.5-NA] and 42.7 months 95% CI [33.3-NA], respectively (P = .009).ConclusionHigh-risk cytogenetically abnormalities were independent risk factor for OS but not PFS in this cohort of patients, and the incidence of del (17p) was slightly higher than the literature reports. MicroabstractPrognostic significance of high-risk cytogenetic abnormalities in Multiple Myeloma in Colombia is unknown. In a retrospective cohort study of 135 newly, diagnostic Multiple Myeloma we found incidence of high-risk cytogenetic abnormalities was 30.3%. The hazard ratio (HR) for disease progression or death compared high-risk cytogenetic group vs. control was 1.22, (95% CI, 0.73-2.05) (P = .2), and The HR for death for the group of high-risk cytogenetic abnormalities was 2.17, (95% CI, 1.19-3.97). In the group of high-risk cytogenetic abnormalities, if the patient received VRD as induction treatment the median PFS were 41.2 months 95% CI [13.3-NA] and 33.9 months 95% CI [24.9-NA] for patients with different induction treatment (P = .56)     

Chromosomal aberrations +1q21 and del(17p13) predict survival in patients with recurrent multiple myeloma treated with lenalidomide and dexamethasone

BACKGROUND:

In the era of novel agents such as lenalidomide and bortezomib, risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches in patients with multiple myeloma (MM).

METHODS:

The authors analyzed the prognostic value of deletion del(13q14), del(17p13), +1q21, translocation t(4;14), t(11;14), and t(14;16) by fluorescence in situ hybridization (FISH) in a series of 92 patients with recurrent MM who were treated with lenalidomide and dexamethasone (len/dex) at the study center.

RESULTS:

Patients carrying del(13q14) or t(14;16) were found to have a shorter median time to disease progression (TTP) of 5.1 months (vs 14.4 months; P = .009) and 2.0 months (vs 10.5 months; P <.001), respectively. However, no effect on TTP was observed in patients harboring del(13q14) as an exclusive chromosomal aberration without the concomitant presence of t(4;14) or del(17p13). The median overall survival (OS) for patients with del(17p13) or +1q21 was 6.7 months (P = .002) and 8.3 months (P < .001), respectively, whereas the median OS for patients carrying none of these abnormalities was not reached. Multivariate analysis revealed that the effects of del(17p13) and +1q21 on OS were independent of patient age as well as the type and number of regimens administered before len/dex.

CONCLUSIONS:

The results of the current study suggest that the prognostic significance of t(4;14) may be ameliorated or eliminated in patients treated with len/dex, whereas the presence of del(17p13) or +1q21 is still associated with a dismal OS. The presence of t(11;14) and del(13q14) as exclusive chromosomal aberrations indicates no impact on outcome. Because of its rarity in MM, a confirmation of the prognostic role of the t(14;16) aberration is still pending. Cancer 2011. © 2010 American Cancer Society.     

A Clinical and Correlative Study of Elotuzumab,Carfilzomib, Lenalidomide,and Dexamethasone (Elo-KRd) for Lenalidomide Refractory Multiple Myeloma in First Relapse

IntroductionTreatment of patients with multiple myeloma (MM) in first relapse remains a challenge. This phase II study combined elotuzumab (Elo) with carfilzomib, lenalidomide, and dexamethasone (KRd) for treatment of MM in first relapse with the aim of improving efficacy.MethodsEnrolled patients received Elo-KRd induction for 4 cycles, and Elo-lenalidomide maintenance until progression. The primary endpoint was VGPR or better (≥VGPR) postinduction. Secondary endpoints were MRD by flow cytometry, OS, PFS, and safety. Correlatives included characterization of the impact of Elo-KRd on NK and T cell subsets via flow cytometry. Target accrual of 40 patients was not met due to COVID-19 pandemic.ResultsOf 15 patients enrolled, 10 (67%) had high-risk features (del17p, t[4;14], t[14;16], 1q gain/amplification, plasma cell leukemia, extramedullary MM, or functional high risk), 12 (80%) were lenalidomide-refractory, and 5 (33.3%) bortezomib-refractory. Postinduction ≥VGPR was 7/15 (46.7%) and MRD-negative (10⁻⁵) rate 20%. Overall response during study was 80%, including ≥VGPR as best response of 53.3%. At median follow-up of 28.2 (range, 3.8 to 44.2) months, the median PFS was 11.5 months (95% CI 1.9, 18), and median OS not reached (95% CI 10.1, NA). No new safety concerns were reported. Elo-KRd treatment did not augment NK cell distribution or activity in blood or bone marrow. Effector CD4+ and CD8+ T cells significantly decreased postinduction, with concomitant acquisition of T central memory phenotype, particularly at a high rate in ≥VGPR group.ConclusionA short course of Elo-KRd induction followed by Elo-lenalidomide maintenance demonstrated activity in predominantly lenalidomide-refractory and / or high-risk MM. The results with this well-tolerated combination are comparable to other contemporary approved triplet combinations.     

t(11;14) and t(4;14) translocations correlated with mature lymphoplasmacytoid and immature morphology, respectively, in multiple myeloma.

Recent studies have shown that two recurrent translocations, t(4;14)(p16;q32) and t(11;14)(q13;q32), define distinct entities with different prognosis in multiple myeloma (MM). We addressed the issue of whether these illegitimate IGH rearrangements could contribute to the morphological heterogeneity of the malignant plasma cells (PC). Bone marrow aspirates of 178 untreated MM cases with successful molecular cytogenetics analysis using fluorescence in situ hybridization were reviewed. PC of 25/48 (52%) patients with t(11;14) exhibited a lymphoplasmacytoid morphology. Moreover, 25/27 (93%) of the cases with this morphological profile bore the t(11;14). In addition, both cytogenetics and morphological subtypes shared higher incidence of nonsecretory MM. In contrast, 17 out of 28 cases (61%) with t(4;14) exhibited PC with diffuse chromatin pattern. Interestingly, both t(4;14) translocation and immature morphology correlated with higher incidence of high tumor mass and chromosome 13 abnormality. In conclusion, our results suggest that a particular morphology can be the signature of chromosomal abnormalities in MM.     

Efficacy of up-front treatment with a double stem cell transplantation in multiple myeloma

BACKGROUND: We report the outcome of 53 patients with multiple myeloma (MM), who received autologous stem cell transplantation (ASCT) from April 1996 to September 2004 at our institution and who survived for more than 3 months after the transplant. METHODS: Following the first ASCT, 36 patients underwent an up-front second SCT, which consisted of either an ASCT (n = 24) or a reduced-intensity conditioning allogeneic stem cell transplant (RIST) (n = 12). Seventeen patients were given maintenance treatment. RESULTS: Seventy-seven percent of the patients (n = 41) showed an objective response to the initial therapy prior to the first ASCT. Overall, 60.4% (32 out of 53) and 32.1% (17 out of 53) of the patients had a complete response (CR) and partial response (PR) after the first ASCT, respectively. At the time of analysis, 34 patients (64.2%) were still alive. With a median follow-up of 32 months (range 9-98), the estimated progression-free survival (PFS) and overall survival (OS) at 5 years were 17.0 and 34.9%, respectively. Multivariate analysis revealed that the second SCT, normal hemoglobin and <50% marrow plasma cells were associated with an improved PFS. A second SCT, CR to the first SCT, female gender and an absence of advanced bone lesions were associated with a better OS. CONCLUSIONS: A second SCT is the most significant factor for an improved PFS and OS after the first ASCT (P < 0.001, respectively). Up-front double SCT is needed to improve the OS and PFS in patients with MM.     

MicroRNA-15a/16-1 cluster located at chromosome 13q14 is down-regulated but displays different expression pattern and prognostic significance in multiple myeloma

MiRNA-15a/16-1 cluster located at chromosome 13q14 has been confirmed to regulate critical genes associated with cell proliferation, apoptosis and drug resistance in multiple myeloma (MM). However, little is known about their expression pattern and prognostic value in MM patients. In this study, we have analyzed the expression levels of miR-15a/16-1 in 117 MM patients (90 newly diagnosed, 11 relapsed and 16 remission patients) and 19 health donors (HDs) by quantitative real-time PCR. Our results indicated that the expression levels of miR-15a and 16-1 were down-regulated in newly diagnosed MM patients as compared to HDs (P = 0.025; P < 0.001) and independent of del(13q14). Downregulation of miR-15a was significantly associated with disease progression and poor prognosis while miR-16-1 seemed to be a good diagnostic marker to distinguish MM from HDs with area under the curve (AUC) of 0.864, sensitivity of 100% and specificity of 73%. Furthermore, patients with miR-15a < 2.35 (low expression group) had significantly shorter PFS (P < 0.001) and OS (P < 0.001). After adjustment of the established prognostic variables including del(13q), del(17p), amp(1q21) and high risk genetic abnormality, low miR-15a expression (<2.35) was still a powerful independent predictor for PFS (P = 0.008) and OS (P = 0.038). In addition, miR-15a combined with high β2-MG and high risk genetic abnormality can further identify the high-risk subpopulations. Therefore, our data suggest that the expression patterns of miR-15a/16-1 are different in MM patients, and miR-15a seems to be linked with disease progression and prognosis while miR-16-1 acts as a valuable diagnostic marker.     

Additional genetic abnormalities significantly worsen poor prognosis associated with 1q21 amplification in multiple myeloma patients

We investigated the prognostic value of amp(1q21) alone and in combination with other abnormalities in newly diagnosed myeloma patients. The study group consisted of 104 patients treated with various induction regimens, mostly thalidomide based (87 patients). Amp(1q21) was detected in 49 (47.1%) of patients; in 26 (25.0%) cases, it was combined with del(13q14), in 7 (6.7%) with del(17p13) and in 15 (14.4%) with t(4;14)(p16;q32). The response rate was significantly better in amp(1q21)‐negative than in amp(1q21)‐positive patients (74.5% vs 55.1%, p = 0.025; complete response 18.2% vs 4.1%, p = 0.024). The median progression‐free survival (PFS) was 33.9 months in patients without amp(1q21) and 10.3 months with this aberration (p = 0.002). The presence of additional abnormalities resulted in significantly shortened PFS when compared with patients with isolated amp(1q21): coexisting del(13q14) resulted in 7.8 vs 29.0 months of PFS (p = 0.024) and del(17p13) resulted in 4.0 vs 24.9 months of PFS (p = 0.034). The presence of amp(1q21) significantly influenced overall survival (OS) as well as PFS resulting in the median OS of 26.6 vs 62.4 months (p = 0.018) in patients without amp(1q21). The presence of additional genetic abnormalities significantly affected OS when compared with patients carrying isolated amp(1q21): for del(13q14) 18.9 vs 58.4 months (p = 0.004) and for del(17p13) 12.0 vs 46.5 months (p = 0.036). On multivariate analysis amp(1q21), del(13q14) and del(17p13) were found to be an independent adverse predictors of shorter PFS and OS. Our results showed that the presence of amp(1q21) was associated with poor prognosis. Moreover additional genetic abnormalities made PFS and OS further shortened. Copyright © 2012 John Wiley & Sons, Ltd.     

Impact of cytogenetics in patients with relapsed or refractory multiple myeloma treated with bortezomib: Adverse effect of 1q21 gains

We investigated the influence of genetic risk factors on the clinical response to bortezomib in 85 relapsed/refractory multiple myeloma (MM) patients. Interphase cytoplasmic fluorescence in situ hybridization (cIg-FISH) detected del(13q), del(17p), del(1p21), t(4;14), and 1q21 gain in 38%, 22%, 26%, 18% and 39% of evaluable cases. Forty-nine patients (49%) responded to bortezomib with median progression free (PFS) and overall survivals (OS) of 5.0 and 12.6 months, respectively. Patients with 1q21 gain had a significantly shorter OS (5.3 months vs. 24.6 months, p = 0.0006) and PFS (2.3 months vs. 7.3 months, p = 0.003) than patients without such abnormality. There was no significant difference in response rate, response duration, PFS or OS for any of the other genetic risk factors tested. Multivariate analysis confirmed that 1q21 gain is an independent risk factor for PFS (p = 0.03) and OS (p = 0.009) of bortezomib-treated relapsed/refractory myeloma.     

Single-center Experience in Treating Patients With t(4;14) Multiple Myeloma With and Without Planned Frontline Autologous Stem Cell Transplantation

Background

Translocation t(4;14) has traditionally been classified as a high-risk cytogenetic feature in patients with multiple myeloma with shortened progression-free (PFS) and overall survival (OS) despite initial response to treatment. Recent data have shown an improved long-term survival in these patients treated with novel agents, such as bortezomib.

Treatment of Multiple Myeloma: A Comprehensive Review

Multiple myeloma (MM) is a neoplastic plasma cell disorder that results in end-organ damage (hypercalcemia, renal insufficiency, anemia, or skeletal lesions). Patients should not be treated unless they have symptomatic (end-organ damage) MM. They should be classified as having high-risk or standard-risk disease. Patients are classified as high risk in the presence of hypodiploidy or deletion of chromosome 13 (del[13]) with conventional cytogenetics, the presence of t(4:14), t(14;16), t(14;20) translocations or del(17p) with fluorescence in situ hybridization. High-risk disease accounts for about 25% of patients with symptomatic MM. If the patient is deemed eligible for an autologous stem cell transplantation (ASCT), 3 or 4 cycles of lenalidomide and low-dose dexamethasone, or bortezomib and dexamethasone, or thalidomide and dexamethasone are reasonable choices. Stem cells should then be collected and one may proceed with an ASCT. If the patient has a complete response or a very good partial response (VGPR), the patient may be followed without maintenance therapy. If the patient has a less than VGPR, a second ASCT is encouraged. If the patient is in the high-risk group, a bortezomib-containing regimen to maximum response followed by 2 additional cycles of therapy is a reasonable approach. Lenalidomide and lowdose dexamethasone is another option for maintenance until progression. If the patient is considered ineligible for an ASCT, then melphalan, prednisone, and thalidomide is suggested for the standard-risk patient, and melphalan, prednisone, and bortezomib (MPV) for the high-risk patient. Treatment of relapsed or refractory MM is covered. The novel therapies—thalidomide, bortezomib, and lenalidomide—have resulted in improved survival rates. The complications of MM are also described. Multiple myeloma is a plasma cell neoplasm that is characterized by a single clone of plasma cells producing a monoclonal protein (M-protein). The malignant proliferation of plasma cells produces skeletal destruction that leads to bone pain and pathologic fractures. The M-protein might lead to renal failure, hyperviscosity syndrome, or through the suppression of uninvolved immunoglobulins, recurrent infections. Anemia and hypercalcemia are common complications.     

Prolonged survival after second autologous transplantation and lenalidomide maintenance for salvage treatment of myeloma patients at first relapse after prior autograft

Autologous stem cell transplantation (ASCT) as part of the primary therapy in multiple myeloma (MM) is standard practice. In contrast, the role of a second ASCT (ASCT2) and subsequent lenalidomide maintenance for relapsed disease remains unclear. In this study, we analysed 86 consecutive MM patients with a first relapse after prior ASCT receiving either a second ASCT or conventional chemotherapy. After a median follow‐up of 37.7 months since first relapse, 54 (62.8%) patients were still alive and 29 (33.7%) without progression. Sixty‐one (71.0%) patients received ASCT2 and had better progression‐free survival (PFS) (30.2 versus 13.0 mo; P = .0262) and overall survival (OS) rates (129.6 versus 33.5 mo; P = .0003) compared with 25 (29.0%) patients with conventional treatment. Patients relapsing later than 12 months after ASCT1 benefitted from a second ASCT with better PFS2 (P = .0179) and OS2 (P = .0009). Finally, lenalidomide maintenance after ASCT2 was associated with longer PFS (41.0 vs 21.6 mo; P = .0034) and better OS (not yet reached vs 129.6 mo; P = .0434) compared with patients without maintenance. Our data suggest that a second ASCT and lenalidomide maintenance given at first relapse in MM after prior ASCT are associated with better survival rates.     

Favorable Long-Term Outcomes with Autologous Stem Cell Transplantation for High-Risk Multiple Myeloma Patients with a Positive Result On 18F-FDG PET/CT at Baseline

Background18F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) is a useful tool for identifying high-risk features in patients with newly diagnosed multiple myeloma (NDMM). This study evaluated the role of autologous stem cell transplantation (ASCT) in patients presenting with positive results on PET/CT scans.Materials and MethodsThe medical records of 210 patients who underwent PET/CT at diagnosis were retrospectively reviewed. Eligible patients for transplantation proceeded to upfront ASCT with high-dose chemotherapy (HDT) after induction therapy with novel agents.ResultsThe presence of a number of focal lesions (FL) >3 and extramedullary disease (EMD) occurred in 111 and 35 patients, respectively. ASCT was performed in 54 patients. Among patients with FL > 3, those treated with ASCT showed a prolonged 2-year progression-free survival (PFS) and overall survival (OS) rates compared to those not treated with ASCT (PFS, 60.2% vs. 23.5%, P < 0.001; OS, 91.7% vs. 63.6%, P = 0.005). In patients with FL ≤ 3, treatment by ASCT was associated with a higher 2-year PFS rate than no treatment by ASCT (74.0% vs. 54.9%, P = 0.040). The OS of patients treated with ASCT was not significantly longer than that of patients not treated with ASCT (P = 0.115). In multivariate analysis, FL > 3, Revised International Staging System (R-ISS), and upfront ASCT were independent prognostic factors for PFS and OS.ConclusionPresenting FL > 3 on baseline PET/CT represents a high-risk feature in patients with NDMM. Frontline ASCT with HDT prolonged the survival of patients with FL > 3.     

Sex Differences in Multiple Myeloma Biology but not Clinical Outcomes: Results from 3894 Patients in the Myeloma XI Trial

BackgroundSex differences in the incidence and outcomes of several cancers are well established. Multiple myeloma (MM) is a malignant plasma cell dyscrasia accounting for 2% of all new cancer cases in the UK. There is a clear sex disparity in MM incidence, with 57% of cases in males and 43% in females. The mechanisms behind this are not well understood and the impact of sex on patient outcomes has not been thoroughly explored.Patients and MethodsWe investigated the association of sex with baseline disease characteristics and outcome in 3894 patients recruited to the phase III UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated.ResultsFemales were significantly more likely to have the molecular lesions t(14;16) and del(17p) and were more likely to meet the cytogenetic classification of high-risk (HiR) or ultra-high-risk disease (UHiR). There was no difference in progression-free survival (PFS) or overall survival (OS) between the sexes in the overall population.ConclusionOur data suggest that the genetic lesions involved in the initiation and progression of MM may be different between the sexes. Although females were more likely to have the poor prognosis lesions t(14;16) and del(17p), and were more likely to be assessed as having HiR or UHiR disease, this was not associated with reduced PFS or OS. In female patients the trial treatment may have been able to overcome some of the adverse effects of high-risk cytogenetic lesions.MicroAbstractMultiple myeloma (MM) is more common in males compared to females but the reasons behind this are not well understood and the impact of sex on patient outcomes is unclear. This study demonstrates fundamental differences in genetic lesions underlying the biology of MM between males and females. However, we found that progression-free survival and overall survival were the same in both sexes.     

Exploratory analysis of intensified conditioning as first line treatment for patients with high risk multiple myeloma

Multiple myeloma has extremely heterogeneous outcomes. Among prognostic factors, t(4;14) and del(17p) are rare oncogenic events associated with very poor prognosis. In an exploratory case-control study, we compared the combination of Busulfan-Melphalan or TBI-Melphalan with high dose Melphalan as a conditioning regimen in a series of 48 patients with del(17p) or t(4;14). These regimens were preceded by a Bortezomib-containing induction. Progression-free survival (PFS) was the primary endpoint whereas overall survival (OS) and complete response (CR) rate were the secondary endpoints. Twenty consecutive cases of high-risk myeloma received a reinforced conditioning regimen of Busulfan 0.8 mg/kg x4/j IV from day-6 to day-3 pre- graft (BuMel) or total body irradiation (TBI) 12 Gy (TbiMel), having received Melphalan 140 mg/m² at day-2 pre-graft. These cases were matched to 28 controls treated with Melphalan 200 mg/m² at day-2 (Mel200). After intensification ± consolidation, with a median follow-up of 6.3 years, the CR rate was higher in the BuMel/TbiMel group (65% vs 50%, P = .006). No differences were observed between both groups in terms of PFS and OS (P = .96). PFS in patients with a del(17p) mutation tended to be superior in the BuMel/TbiMel group. Our exploratory study shows that reinforcing the intensification regimen with Busulfan or TBI does not seem to improve the prognosis associated to t(4;14) and del(17p) abnormalities.     

Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis

Venetoclax is efficacious in relapsed/refractory t(11;14) multiple myeloma, thus warranting investigation in light-chain amyloidosis (AL). This retrospective cohort includes 43 patients with previously treated AL, from 14 centers in the US and Europe. Thirty-one patients harbored t(11;14), 11 did not, and one t(11;14) status was unknown. Patients received a venetoclax-containing regimen for at least one 21- or 28-day cycle; the median prior treatments was three. The hematologic response rate for all patients was 68%; 63% achieved VGPR/CR. t(11;14) patients had higher hematologic response (81% vs. 40%) and higher VGPR/CR rate (78% vs. 30%, odds ratio: 0.12, 95% CI 0.02–0.62) than non-t(11;14) patients. For the unsegregated cohort, median progression-free survival (PFS) was 31.0 months and median OS was not reached (NR). For t(11;14), median PFS was NR and for non-t(11;14) median PFS was 6.7 months (HR: 0.14, 95% CI 0.04–0.53). Multivariate analysis incorporating age, sex, prior lines of therapy, and disease stage suggested a risk reduction for progression or death in t(11;14) patients. Median OS was NR for either subgroup. The organ response rate was 38%; most responders harbored t(11;14). Grade 3 or higher adverse events occurred in 19% with 7% due to infections. These promising results require confirmation in a randomized clinical trial.Subject terms: Myeloma, Myeloma