Seventeen-year survival in multiple myeloma

We report a case of multiple myeloma surviving 17 years since diagnosis and 13 years in continuous complete remission since a relapse 4 years after initial treatment. Despite the prolonged remission, multiple lytic bone lesions have not healed.     

多发性骨髓瘤患者抗凝血酶活性分析

目的:探讨多发性骨髓瘤患者抗凝血酶(AT)活性变化及临床意义。方法:回顾性分析72例多发性骨髓瘤患者AT活性水平,并比较不同临床分期AT活性的差异,分析初发、缓解、未缓解、复发不同阶段AT活性的变化。结果:多发性骨髓瘤Ⅱ、Ⅲ期患者AT活性较Ⅰ期患者降低(P<0.05),初发组、部分缓解组、复发组较缓解组AT活性显著性降低(P<0.05);复发组白蛋白较缓解组降低,初发组、复发组、部分缓解组β2-MG、球蛋白及LDH均较缓解组升高,均差异有统计学意义(均P<0.05)。AT活性水平与β2-MG的变化具有相关性(r=-0.441,P<0.05);AT活性水平与白蛋白、球蛋白及LDH水平的变化无明确相关性。结论:AT活性不仅反映多发性骨髓瘤患者抗凝系统功能,也可反映患者整体病情变化,而且AT活性水平变化与β2微球蛋白具有相关性,可能具有一定的预后评估意义。     

Bortezomib in multiple myeloma

Multiple myeloma (MM) remains an incurable disease, and novel agents are therefore needed to improve outcome. Bortezomib is the first proteasome inhibitor to be approved by the US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products for the treatment of refractory/relapsed MM. Bortezomib has demonstrated significant anti-myeloma activity as a single agent in refractory/relapsed MM. When used in combination with other agents, responses have suggested the possibility of chemosensitization and synergy. All these facts have been the rationale for the use of bortezomib-based regimens as upfront treatment in young and elderly newly diagnosed MM patients. Furthermore, bortezomib does not appear to have an adverse effect on subsequent stem-cell collection. Bortezomib is well tolerated; most side-effects are only mild to moderate and manageable. Practical management of these side-effects is given so that they can be recognized and minimized by dose modification or concomitant therapy.     

Improved long-term survival in multiple myeloma

50 patients were treated for multiple myeloma with 5-drug combination chemotherapy between Jan 1979 and Feb 1980. After 8 years 12 patients (24%) were alive. The relative age-adjusted survival rate was 27%. The risk of death was constant during the follow-up, and active myelomatosis was still the main cause of death during the 8th yr. Thus the treatment is not curative. All 7 long-term survivors initially at stages II or III had at least a 75% response to the primary treatment. The other 5 patients were initially in an early stage (I) of their disease. Acute leukaemia has developed in 2 patients.     

溶栓治疗对急性心肌梗死者纤维蛋白溶解指标的影响

目的 研究急性心肌梗死(AMI)患者溶栓治疗过程中,血浆纤维蛋白溶解系统各指标的变化.方法 首次AMI者26例,男性17例、女性9例,给予尿激酶150万单位(U)溶栓治疗,测定溶栓前、及溶栓后0.5、6、12、24、72小时的血浆总体纤维蛋白溶解活力(GFC)、纤维蛋白原(Fg)、纤维蛋白溶解酶原(PLG)、组织型纤维蛋白溶解酶原激活因子(t-PA)及其抑制因子(PAI)水平.结果(1)血浆Fg、PLG浓度在尿激酶静脉注射后6小时显著降低至治疗前的50%,在24～72小时又逐渐回升至治疗前水平,72小时Fg浓度超过治疗前(P<0.05);血浆GFC、PAI则在治疗后0.5小时立即升高至峰值水平,在6～72小时迅速下降甚至低于治疗前水平(P<0.05);而t-PA水平在治疗后有所升高但变化无显著差异(P>0.05).(2)溶栓治疗后临床再灌注与无再灌注组血浆GFC的峰值水平及时间存在显著差异(P<0.05).结论 血浆GFC水平比其他指标更能揭示纤维蛋白溶解药物对体内纤维蛋白溶解系统的作用机制,溶栓治疗后血浆总体纤维蛋白溶解活力被激活的程度及时间是决定临床再灌注的重要因素.     

Venous thromboembolism in multiple myeloma: Increasing evidence in support of direct oral anticoagulants

Venous thromboembolism (VTE) continues to cause significant morbidity and excess mortality in patients with multiple myeloma. The report by Costa and colleagues demonstrates superiority of direct oral anticoagulants over aspirin in terms of VTE prevention, without increased bleeding complications seen. Commentary on: Costa et al. Direct oral anticoagulants versus aspirin for primary thromboprophylaxis in patients with multiple myeloma undergoing outpatient therapy: A systematic review and updated meta-analysis. Br J Haematol 2023;203:395–403.     

Serum oncostatin M in multiple myeloma: impact on disease severity and prognosis

Since high levels of serum IL-6 predict a poor prognosis of patients with multiple myeloma (MM), we investigated if a related cytokine, oncostatin M (OSM), correlates with clinical or biochemical findings or has prognostic significance in patients with MM. Among 82 newly diagnosed MM patients, OSM was detected in the sera in 45 (55%). Serum OSM had a borderline statistical correlation with serum IL-6 (r = 0.198, p = 0.074) and C-reactive protein (r = 0.199, p = 0.074) concentrations. However, OSM did not have prognostic significance alone or in combination with other factors. The median survival of patients with detectable serum OSM concentration was 41 months (range 2-124 months) and of OSM negative patients 35 months (1-75 months). Serum OSM concentration was not associated with clinical factors or severity of bone disease at diagnosis. We conclude that serum OSM concentration is not a prognostic factor in MM patients.     

Glucocorticoid receptor in multiple myeloma

Glucocorticoid receptor levels of myeloma cells were quantitated in 7 patients with multiple myeloma. In 4 patients, glucocorticoid receptor levels were less than 10 fmol/10(6) cells. In 3 patients, receptor levels were from 17.6 to 21.4 fmol/10(6) cells. We further examined the correlation between glucocorticoid receptor levels and effect of dexamethasone on 14C-thymidine incorporation and cell viability using 2 myeloma cell lines, OPM-1 and OPM-2, established from a patient with multiple myeloma. Glucocorticoid receptor levels of OPM-1 and OPM-2 were 8.5 fmol/10(6) cells and 63.2 fmol/10(6) cells, respectively. The sensitivity of OPM-1 to dexamethasone in these studies was lower than that of OPM-2. These results suggest the possibility that the low level of glucocorticoid receptor in myeloma cells may be important for predicting a poor response to glucocorticoid therapy.     

Antitumor activity of fludarabine against human multiple myeloma in vitro and in vivo

Fludarabine, a nucleoside analogue, plays a major role in the treatment of B-cell lymphocytic leukemia, hairy cell leukemia, and indolent lymphomas. There is a controversy about antitumor activity of fludarabine in multiple myeloma (MM). The aim of this study was to evaluate the activity of fludarabine against human myeloma cells both in vivo and in vitro. We demonstrated that myeloma cell line RPMI8226 was efficiently inhibited by fludarabine, concomitantly with decreased phosphorylation of Akt, down-regulation of the inhibitor of apoptosis proteins (IAP) family, including XIAP and survivin, and induction of apoptosis related to activation of caspase cascade. Contrary to dexamethasone, the effect of fludarabine on RPMI8226 cells was independent of interleukin-6. Fludarabine also induced cytotoxicity in dexamethasone-sensitive (MM.1S) and -resistant (MM.1R) cells at 48 h with IC50 of 13.48 microg/mL and 33.79 microg/mL, respectively. In contrast, U266 cells were resistant to fludarabine. Moreover, RPMI8226 myeloma xenograft model was established using severe combined immunodeficient mice. The tumors treated with fludarabine at 40 mg/kg increased less than 5-fold in 25 d comparing with approximately 10-fold in the control tumors, demonstrating the antitumor activity of fludarabine in vivo. These results suggest that fludarabine may be an important therapeutic option for MM patients who are resistant to dexamethasone.     

Alternative pathway of complement in multiple myeloma

The alternative pathway of complement was studied in 16 newly diagnosed and 2 previously treated patients with multiple myeloma. Functional activity of this pathway was abnormal in 10 of these 18 patients (55%). These abnormalities correlated with depressed levels of alternative pathway components in 3 of 10 patients, but in the remaining 7, no etiology was demonstrated. There was an inverse correlation between activity and concentration of the monoclonal protein. This defect is an additional factor that may predispose patients with myeloma to overwhelming infection.     

Genetic variations in multiple myeloma I: effect on risk of multiple myeloma

Few risk factors have been established for the plasma cell disorder multiple myeloma, but some of these like African American ethnicity and a family history of B-cell lymphoproliferative diseases suggest a genetic component for the disease. Genetic variation represents the genetic basis of variability in a population. The complex interplay between environment and genes for the development of cancer may therefore be influenced by genetic variations. A genetic variation may change the function of the gene, and if the genetic variation is associated with the risk of disease, that particular gene may be involved in the pathogenesis of disease. Genes of interest are genes involved in the normal development and function of the plasma cell and genes that protect us against exposures from the environment, for example, genes involved in the metabolism of xenobiotics, metabolism of folate and methionine, as well as genes involved in inflammation and DNA repair. Identification of genes with potential influence on cancer risk may help us to establish relevant laboratory studies on exposure and dose-response assessment and may help us to test the hypothesis in epidemiological studies. Knowledge of individual at high risk of cancer may offer promising insight for the prevention of cancer.     

HyperCVAD for VAD-resistant multiple myeloma

More effective and safer regimens are needed for patients who have advanced multiple myeloma resistant to or relapsing despite prior treatment with alkylating agents and VAD. We treated 58 such patients using the combination of twice daily cyclophosphamide (total dose 1.8 g/m²) and VAD (hyperCVAD). Treatment was given to outpatients followed by G-CSF at 5 μg/kg/d until granulocyte recovery. Twenty-three patients responded (40%), with a median duration of granulocyte depression to less than 500/μl of 4 days and a mortality rate of 2%. The median survival time for all patients was 15 months, and the median remission time of responding patients was 8 months. Patients who had low LDH, low B₂M, or primary resistant disease lived significantly longer than patients without these features. The combination of fractionated cyclophosphamide and VAD provided an effective and safe rescue treatment for many patients who had advanced myeloma resistant to standard therapies. © 1996 Wiley-Liss, Inc.     

VAD-based regimens as primary treatment for multiple myeloma

An alternating VCAD-VAD regimen, combining vincristine-doxorubicin by continuous infusion with cyclophosphamide and pulse dexamethasone, or VAD alone, was given to 175 previously untreated patients with multiple myeloma. The response rate with primary VAD-based regimens of 55% was virtually identical to the 54% in comparable patients treated previously with similar programs by using bolus vincristine-doxorubicin. Despite responses to VAD that were more rapid in onset than any previous treatment, remission and survival times were similar. This may be due to major differences in drug sensitivity between progenitor and differentiated plasma cells. A VAD-based regimen seems better for newly diagnosed patients when rapid control of multiple myeloma is necessary.     

'Senile' myeloma: a possible variant form of multiple myeloma

Fifty-four patients were recognized as having multiple myeloma after the coincidental finding of a serum and/or urine M component on agarose gel electrophoresis during a survey for monoclonal gammopathies of a large random hospital population sample over 70 yr of age. Analysis of the presenting features and the clinical characteristics revealed that about two-thirds of the myeloma patients over 80 yr were asymptomatic at the time of the discovery of their monoclonal gammopathy. Follow-up studies and serial evaluations of changes in the myeloma cell mass without chemotherapy showed a subset of the older patients exhibiting a distinct pattern of slow tumor growth. The results of the study would suggest the possible existence of a variant form in the advanced age group of myeloma patients. This 'senile' type of myeloma would appear to be characterized primarily by non-specific presenting features, a fairly symptom-poor status, and a relatively protracted and benign course without chemotherapy.     

External validation of the SAVED score for venous thromboembolism risk stratification in patients with multiple myeloma receiving immunomodulatory drugs

Selective patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiD) are at high risk for venous thromboembolism (VTE). The SAVED score is a VTE risk prediction model recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines. Using retrospective data from 501 MM patients with new IMiD initiation between 2010 and 2019, we performed the first independent external validation of this model. The cumulative incidence of VTE after IMiD initiation at 6 and 12 months was 32% and 42% in the high-risk group, versus 6% and 9% in the low-risk group respectively. The C-statistic of the SAVED score to predict VTE within 12 months of IMiD-based treatment start was 0.74 [95% confidence interval (CI): 0.69–0.78], which outperformed several other VTE risk models in MM patients. Our findings suggest that the SAVED score is an accurate risk assessment tool for VTE stratification in patients initiating IMiD-containing regimens.     

Bendamustine in multiple myeloma

The advent of high‐dose melphalan with autologous stem‐cell transplantation (ASCT), the availability of novel agents such as thalidomide, lenalidomide (immunomodulatory drugs or IMiDs) and bortezomib (proteasome inhibitor) and improvements in supportive care have allowed to increase overall survival in multiple myeloma (MM) patients; nevertheless, MM remains an incurable pathology. For this reason, newer agents are required for continued disease control. Bendamustine is an old drug rediscovered in the last decade. In fact, its unique mechanism of action with structural similarities to both alkylating agents and antimetabolities, but which is not cross‐resistant to alkylating agents, has reawakened interest in the use of this drug in the treatment of MM. Studies have proven the safety and efficacy of bendamustine administered alone or in combination with new drugs in both upfront and relapse/refractory settings of MM patients, including those with renal impairment. Moreover, bendamustine has been successfully used as conditioning for autologous stem‐cell transplantation. Finally, the use of bendamustine does not compromise peripheral blood stem‐cell collection. This drug is generally well tolerated, with the majority of adverse events being due to myelosuppression. Non‐haematological adverse events are infrequent and usually mild.     

Cytomegalovirus reactivation in patients with multiple myeloma

The introduction of novel antimyeloma agents has improved the outcome of multiple myeloma (MM) dramatically. However, it has also led to an increasing incidence of Herpesviridae family virus infections, including a high incidence of post‐transplant cytomegalovirus (CMV) reactivation after treatment with novel agents. We herein retrospectively assessed the CMV reactivation in all 120 newly diagnosed patients with MM consecutively seen and treated at our hospital. CMV antigenemia tests were ordered in 58 patients depending on the clinical context, and the incidence of CMV reactivation and proven/suspected CMV disease requiring antiviral therapy was 20% (24 of 120) and 11% (13 of 120) respectively, including those without stem cell transplantation (SCT). The clinical and laboratory characteristics of these patients were compared with those in 34 CMV antigenemia‐negative (CMV‐negative) patients. Patients with extramedullary disease or a low absolute lymphocyte count (ALC) had a higher risk of developing CMV reactivation. In addition, the median duration from the time of MM diagnosis to CMV reactivation was 5.0 months. These results suggest that, regardless of whether or not undergoing SCT, elderly patients with MM receiving novel agents should be monitored for CMV reactivation to allow for the timely diagnosis and treatment, especially for those with extramedullary disease.