Zhengang Yuan

Polymorphisms of nuclear factor-κB family genes are associated with development of multiple myeloma and treatment outcome in patients receiving bortezomib-based regimens

Background The nuclear factor-κB pathway is an important signaling pathway activated in multiple myeloma cells. Bortezomib inhibits nuclear factor-κB activation and is an important antimyeloma agent. Nevertheless, patients treated with this drug eventually relapse. We hypothesized that the nuclear factor-κB pathway may be associated with multiple myeloma and patients’ responses to bortezomib. Design and Methods In this study we analyzed 26 polymorphism sites of nuclear factor-κB family member genes, IKBα, NFKB2, and TRAF3, in 527 unrelated Chinese Han subjects (252 with multiple myeloma and 275 controls) using a Sequenom MassARRAY genotyping assay, and examined the outcome of 83 patients treated with a bortezomib-based regimen. Results Single nucleotide polymorphisms in the TRAF3 rs12147254 A allele and a specific haplotype 1 of TRAF3 [GAACAG] are associated with a decreased risk of multiple myeloma (odds ratio 0.709, P<0.001, and odds ratio 0.543, P<0.0001), while TRAF3 haplotype 4 [GGACAG] was associated with an increased risk of development of multiple myeloma (odds ratio 2.099, P=0.001). Moreover, the TRAF3 rs11160707 GA+AA genotype was significantly associated with a better progression-free survival (P=0.018). Patients with the NFKB2 rs12769316 GA+AA genotype had a superior overall survival (P=0.020), while those with the rs1056890 CT+TT genotype had an inferior overall survival (P=0.037). In an exploratory analysis, patients with the GA+AA/CC/GG genotype at the rs12769316, rs1056890, and rs11160707 sites had a significantly superior overall survival compared to patients with a wild-type genotype (P=0.007). In the multivariable analysis, TRAF3 rs11160707 was found to be an independent favorable factor for progression-free survival (hazard ratio 0.428, P=0.028). Conclusions Nuclear factor-κB family member gene polymorphisms play a role in the development of multiple myeloma and in the response to bortezomib therapy.

Polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide based regimens in multiple myeloma.

In this study, CYP2C19 genotypes were tested by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 92 patients with multiple myeloma (MM). Sixty-two patients were treated with thalidomide plus dexamethasone (Thal+Dex) and 30 with thalidomide combined with chemotherapy (Thal+CC). The overall response rate of extensive metabolizers (EMs) was statistically higher than that of poor metabolizers (PMs) (62.6% vs. 33.3%, p<0.05). Similar results were also observed in the Thal+Dex cohort. For the first time, our primary data suggested that the polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide based regimens in MM.

Extramedullary plasmacytoma in the presence of multiple myeloma: clinical correlates and prognostic relevance

Objective We studied the clinical and laboratory features and outcomes of multiple myeloma (MM) with extramedullary plasmocytoma (EP) disease both at diagnosis and during the course of MM. Patients and methods Forty-two patients of 467 patients with MM were retrospectively analyzed from both the 100th Hospital of the People’s Liberation Army and Shanghai Changzheng Hospitals. The clinical characteristics, laboratory parameters, responses, risk factors, and outcomes were analyzed. Results The median age was 53 years with a male/female sex ratio of 34:8. Twenty-six patients had EP disease at the time of diagnosis, and 16 patients developed EP during the course of the disease. We found that the Durie–Salmon stage, serum lactate dehydrogenase level, beta-2-microglobulin, complete blood counts, albumin, and the type of immunoglobulin (Ig) were not associated with the development of EP disease. Patients who developed EP during the course of MM had a higher ratio of plasmocytes and premature plasmocytes in the bone marrow with lower C-reactive protein level and earlier stage of International Staging System for Lung Cancer at the diagnosis of MM compared with patients who presented with EP at diagnosis. Once the patients developed EP disease, they frequently showed resistance to chemotherapy. With a median follow-up of 30 months, 19 patients were alive. Log-rank univariate analysis showed that patients with EP who had normal C-reactive protein, higher hemoglobin, lower serum lactate dehydrogenase, and stage I of International Staging System for Lung Cancer had longer survival. However, cyclooxygenase multivariate analysis failed to show statistical significance for any factor. Conclusions EP disease is the MM end-phase and is not a rare manifestation of MM with a cumulative incidence of 9% of MM. The prognosis is very poor once the diagnosis of EP disease is concurrent with MM.

Role of the TNF-α promoter polymorphisms for development of multiple myeloma and clinical outcome in thalidomide plus dexamethasone

The role of TNF-α promoter polymorphisms in the development of multiple myeloma (MM) were tested in 210 patients and 218 healthy individuals and their impact on the clinical outcome were evaluated in 98 patients treated with thalidomide and dexamethasone (Thal+Dex) regimen. MM patients carrying the GA genotype (P=0.01) or GA+AA genotypes (P=0.02) at the TNF-α -308 polymorphism were associated with a reduced risk for MM. The TNF-α -238 GA+AA genotypes were associated with a significant enhancement in the progression-free survival (PFS) (P=0.009) and a better overall survival (OS) (P=0.088).

Treatment of multicentric Castleman's Disease accompanying multiple myeloma with bortezomib: a case report

Multicentric Castlemans disease (MCD) is a rare lymphoproliferative disorder of unknown etiology and characterized by various clinical manifestations and multiple organ involvement. It has been reported in association with POEMS syndrome and can progress to Kaposis sarcoma or malignant lymphoma. The disease runs a more aggressive course and a poor prognosis. Optimal therapies have not been well established up to now. We here reported a case of rare MCD complicated with multiple myeloma who received bortezomib and achieved very good remission. To our knowledge, this is the first report on MCD in the setting of multiple myeloma with good response to bortezomib.

Thyroid function and its clinical significance in POEMS syndrome

POEMS syndrome, also known as Crow-Fukase syndrome, represents a rare multisystem syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. Hypothyroidism is one of the common endocrine abnormalities which are central features of POEMS syndrome. The clinical data associated with the measurement of thyroid function and its clinical significance in POEMS syndrome is still rare. Herein, we report 24 cases with POEMS syndrome which were studied thyroid function and clinical manifestations and performed an associated analysis between hypothyroidism and edema/effusions. Of the 24 patients with POEMS syndrome, 17(70.8%) had a recognized hypothyroidism (including 11 clinical hypothyroidism and 6 subclinical hypothyroidism). Fourteen patients (58.3%) had some form of extravascular volume overload. In 14 patients with edema/effusions, 12 were diagnosed as having hypothyroidism. Hypothyroidism may be one of causes of edema/effusions. After thyroid hormone treatment and chemotherapy, symptoms of hypothyroidism and edema /effusions were improved greatly.

Prognostic factors for the efficacy of thalidomide in the treatment of multiple myeloma: A clinical study of 110 patients in China

Thalidomide (Thal) has been used for a few years as salvage treatment for patients with multiple myeloma (MM). However, the response rate in Chinese patients treated with Thal has not been determined and the prognostic factors for response rate (RR), progression-free survival (PFS) and overall survival (OS) not yet well identified. This study enrolled 110 Chinese patients with MM who received either Thal alone, Thal plus dexamethasone (Thal + Dex) or Thal plus conventional chemotherapy (Thal + CC). Their laboratory and clinical parameters were retrospectively analysed. The overall RR was 63.6% (complete response rate 6.4%, partial response rate 57.3%). Patients aged < 65 years, time from diagnosis to the start of Thal treatment < 6 months or combined therapy had a significantly higher RR (p < 0.05). In univariate analysis, age < 65years predicted a longer PFS (p = 0.008). Age < 65 years, serum creatinine < 176.8 µmol L−1 and serum beta 2 microglobulin (β2M) < 3.5 mg L−1 were associated with longer OS (p = 0.028, 0.045 and 0.019, respectively). Multi-factor analysis suggested that serum β2M was the only independent prognostic factor for OS (p = 0.025).