Phase 2 study of tabalumab,a human anti‐B‐cell activating factor antibody,with bortezomib and dexamethasone in patients with previously treated multiple myeloma

In this double‐blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N  = 72), tabalumab 100 mg (N  = 74), or tabalumab 300 mg (N  = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m² on a 21‐day cycle. No significant intergroup differences were observed among primary (median progression‐free survival [mPFS ]) or secondary efficacy outcomes. The mPFS was 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR ) [95% confidence interval (CI )] = 1·13 [0·80–1·59], P  =  0·480; tabalumab 300 mg vs. placebo HR [95% CI ] = 1·03 [0·72–1·45], P  =  0·884). The most commonly‐reported treatment‐emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF 13B) expression (n  = 162) had significantly longer mPFS than those with high BAFF expression (n  = 55), using the 75th percentile cut‐off point (mPFS [95% CI ] = 8·3 [7·0–9·3] months vs. 5·8 [3·7–6·6] months; HR [95% CI ] = 1·59 [1·11–2·29], P  =  0·015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma.     

Generalized cutis laxa and fibrillar glomerulopathy resulting from IgG Deposition in IgG‐lambda Monoclonal Gammopathy: pulmonary hemorrhage during stem cell mobilization and complete hematological response with bortezomib and dexamethasone therapy

The case of a 52‐years‐old man with generalized acquired cutis laxa associated with IgG‐lambda monoclonal gammopathy and nephrotic syndrome with renal failure (due to fibrillar glomerulopathy resulting from IgG deposition) is reported. A peripheral blood autologous stem cell transplant was planned, but the procedure was complicated by severe pulmonary hemorrhage during stem cells mobilization with granulocyte colony‐stimulating factor (G‐CSF). Treatment with bortezomib and dexamethasome was subsequently started and a complete hematological response was achieved. Finally, the complete hematological response with the disappearance of the toxic M‐protein allows the possibility of a long‐term benefit with a kidney transplant followed by an autologous bone marrow transplant.     

Bortezomib induces thrombocytopenia by the inhibition of proplatelet formation of megakaryocytes

Bortezomib is a potent proteasome inhibitor that has been extensively used to treat multiple myeloma. One of the most common grade 3 adverse events is cyclic thrombocytopenia. In this study, we studied the mechanism by which bortezomib induces thrombocytopenia in a mouse model. After the intravenous administration of bortezomib (2.5 mg/kg) via tail vein, platelet counts significantly decreased on days 2–4 and recovered to the normal range on day 6. Bortezomib (2.5 mg/kg) injected into mice in vivo did not affect colony‐forming unit‐megakaryocytes (CFU‐Mk) or megakaryocytes in the bone marrow. However, proplatelet formation (PPF) significantly decreased on days 2 and 4, after bortezomib administration to mice. Meanwhile, CFU‐Mk formation and the ploidy distribution of cultured megakaryocytes in vitro were not affected by bortezomib used at concentrations of ≤1 ng/mL. The PPF of megakaryocytes in vitro significantly decreased with 0.1, 1, 10, and 100 ng/mL bortezomib. Considering the bortezomib concentration in clinical studies, these data strongly suggest that decreased PPF activity induces thrombocytopenia. To elucidate the mechanism behind decreased PPF, Western blot was performed. Activated Rho expression increased after the incubation of murine platelets with bortezomib. Decreased PPF activity was eliminated by the addition of Y27632, a Rho kinase inhibitor, in vitro. Given that the Rho/Rho kinase pathway is a negative regulator of PPF, bortezomib increases activated Rho, inducing decreased PPF, which results in decreased platelet count.     

Role of a pre‐existing neuropathy on the course of bortezomib‐induced peripheral neurotoxicity

Abstract We investigated a series of bortezomib‐treated patients and correlated the course of bortezomib‐induced peripheral neurotoxicity with the presence or absence of peripheral neuropathy at baseline. Forty‐eight patients were examined with the total neuropathy score reduced version (TNSr), visual analogue score (VAS) for pain, and nerve conduction studies at baseline and after two and four cycles of chemotherapy. Twenty‐three patients had a baseline TNSr = 0–2, and 25 patients had a baseline TNSr >2 (median = 6, range 3–13). The course of bortezomib‐induced peripheral neurotoxicity was generally more severe in those patients with the highest baseline TNSr. However, among those subjects with a normal baseline TNSr, two patients developed a clinically relevant peripheral neuropathy with a marked increase in TNSr as early as after two cycles of bortezomib treatment (TNSr = 10 and 15, respectively), while after four cycles, three other patients with normal baseline TNSr had a TNSr of 11, 12, and 13. VAS reporting confirmed that painful neuropathy is frequent after bortezomib administration. Our results indicate that the course of bortezomib‐induced peripheral neurotoxicity can be severe in subjects with normal neurological examination at baseline, and therefore, careful monitoring during treatment is suggested in these patients.     

改良PAD方案治疗初发多发性骨髓瘤的疗效及安全性

目的:探讨不同硼替佐米剂量的PAD方案(硼替佐米+表阿霉素+地塞米松)治疗多发性骨髓瘤(multiple myeloma,MM)的疗效和安全性。方法:回顾性分析PAD方案治疗的32例MM患者的临床资料。其中,硼替佐米1.3mg/m~2静脉注射(d 1、d 4、d 8、d 11)+表阿霉素20mg静脉滴注(d 1~4)+地塞米松20mg静脉滴注(d 1~4、d 8~11)治疗20例(PAD 1组);硼替佐米1.6mg/m~2静脉注射(d 1、d 8、d 15)+表阿霉素20mg静脉滴注(d 1、d 8、d 15)+地塞米松20mg静脉滴注(d 1~2、d 8~9、d 15~16)治疗12例(PAD 2组)。两组均以28d为1个疗程,化疗3~6疗程。比较两组MM患者完成3个疗程后的疗效与不良反应。结果:PAD 1组总有效率为80.0%,PAD 2组为83.3%,两组差异无统计学意义。PAD 1组带状疱疹(30.0%vs 0%)患者多于PAD 2组,差异有统计学意义(P0.05);PAD 1组与PAD 2组胃肠道反应(20.0%vs16.7%)、周围神经炎(25.0%vs 16.7%)、粒细胞减少(15.0%vs 16.0%)、血小板减少(10.0%vs 8.0%)患者差异无统计学意义。结论:硼替佐米1.6mg/m~2每周1次静脉注射的PAD方案治疗与硼替佐米1.3mg/m~2每周2次静脉注射的PAD方案疗效相似,且硼替佐米1.6mg/m~2每周1次静脉注射的PAD方案不良反应更少,更为安全。     

蛋白酶体抑制剂对白血病作用的研究进展

蛋白酶体负责细胞内蛋白的降解,其活性的异常改变是肿瘤发生的标志。研究证实,蛋白酶体抑制剂对许多恶性肿瘤有抗癌活性,第一个获准临床试验和上市的蛋白酶体抑制剂硼替佐米治疗多发性骨髓瘤患者获得了较高的总体有效率和完全缓解率。国外学者也开展了一系列蛋白酶体抑制剂对白血病细胞治疗作用的研究,本文就蛋白酶体抑制剂对浆细胞白血病、慢性淋巴细胞白血病、成人T细胞淋巴瘤/白血病、慢性髓系白血病、急性髓系白血病作用的研究进展作一综述。     

Treatment of AL Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement 2020 Update

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder leading to progressive and life-threatening organ failure. The heart and the kidneys are the most commonly involved organs, but almost any organ can be involved. Because of the nonspecific presentation, diagnosis delay is common, and many patients are diagnosed with advanced organ failure. In the era of effective therapies and improved outcomes for patients with AL amyloidosis, the importance of early recognition is further enhanced as the ability to reverse organ dysfunction is limited in those with a profound organ failure. As AL amyloidosis is an uncommon disorder and given patients’ frailty and high early death rate, management of this complex condition is challenging. The treatment of AL amyloidosis is based on various anti–plasma cell therapies. These therapies are borrowed and customized from the treatment of multiple myeloma, a more common disorder. However, a growing number of phase 2/3 studies dedicated to the AL amyloidosis population are being performed, making treatment decisions more evidence-based. Supportive care is an integral part of management of AL amyloidosis because of the inherent organ dysfunction, limiting the delivery of effective therapy. This extensive review brings an updated summary on the management of AL amyloidosis, sectioned into the 3 pillars for survival improvement: early disease recognition, anti–plasma cell therapy, and supportive care.     

Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma

The Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma (CREST) demonstrated substantial activity with two dose levels of bortezomib (1.0 and 1.3 mg/m(2)), alone or with dexamethasone, in relapsed or refractory multiple myeloma. We present updated survival analyses after prolonged follow-up (median >5 years). One- and 5-year survival rates were 82% and 32%, respectively, in the 1.0 mg/m(2) group (n = 28), and 81% and 45%, respectively, in the 1.3 mg/m(2) group (n = 26). Notable survival, response, and time-to-progression data suggest that a bortezomib starting dose of 1.3 mg/m(2) is preferred. If bortezomib dose reduction is required, the 1.0 mg/m(2) dose still offers patients a substantial survival benefit.