Smoking and the risk of leukemia, lymphoma, and multiple myeloma (Sweden)

While several epidemiologic studies have indicated a link between smoking and the risk of developing hema-tolymphoproliferative cancers (chiefly leukemias, lymphomas, and multiple myelomas), in particular myeloid leukemia, the role of tobacco in the etiology of these neoplasms remains unclear. To evaluate the potential impact of tobacco use on development of leukemia, lymphoma, and multiple myeloma, we conducted a cohort study of 334,957 Swedish construction workers using prospectively collected exposure-information with complete long-term follow-up. A total of 1,322 incident neoplasms occurred during the study period, 1971-91. We found no significant association between smoking status, number of cigarettes smoked, or duration of smoking and the risk of developing leukemias, lymphomas, or multiple myeloma. There was a suggestion of a positive association between smoking and the risk of developing Hodgkin's disease, although the rate ratios were not significantly elevated, except for young current smokers. No positive dose-risk trends emerged. Our study provides no evidence that smoking bears any major relationship to the occurrence of leukemias, non-Hodgkin's lymphomas, or multiple myeloma.     

Second malignant lymphomas and leukemias in the National Cancer Center from 1962 to 1987

Occurrence of second hematopoietic malignancies (SHM) among 49,163 patients with cancer, who had been admitted to the National Cancer Center Hospital from 1962 to 1987, was investigated. Forty-two cases of malignant lymphomas (38 non-Hodgkin lymphomas, 3 Hodgkin's diseases and 1 multiple myeloma) and 17 cases of leukemias (11 acute leukemias, 4 chronic leukemias and 2 myelodysplastic syndromes) developed as SHM. Second malignant lymphomas were 1.37 times more frequent than expected (P less than 0.05), whereas no excess incidence was seen in second leukemias. The incidence of malignant lymphomas was 2.2 times higher than expected in patients with initial stomach cancer (P less than 0.01). Two-thirds of second non-Hodgkin lymphomas occurred in extranodal regions. Nodal lymphomas were more prevalent in cases treated with chemotherapy and/or radiotherapy. Second leukemias were all of myeloid origin except one case of acute lymphoblastic leukemia. Etiological heterogeneity of SHM is discussed in relation to treatment and other risk factors.     

Second Malignant Lymphomas and Leukemias in the National Cancer Center from 1962 to 1987

Occurrence of second hematopoietic malignancies (SHM) among 49,163 patients with cancer, who had been admitted to the National Cancer Center Hospital from 1962 to 1987, was investigated. Forty-two cases of malignant lymphomas (38 non-Hodgkin lymphomas, 3 Hodgkin's diseases and 1 multiple myeloma) and 17 cases of leukemias (11 acute leukemias, 4 chronic leukemias and 2 myelodysplastic syndromes) developed as SHM. Second malignant lymphomas were 1.37 times more frequent than expected ( P <0.05), whereas no excess incidence was seen in second leukemias. The incidence of malignant lymphomas was 2.2 times higher than expected in patients with initial stomach cancer ( P <0.01). Two-thirds of second non-Hodgkin lymphomas occurred in extranodal regions. Nodal lymphomas were more prevalent in cases treated with chemotherapy and/or radiotherapy. Second leukemias were all of myeloid origin except one case of acute lymphoblastic leukemia. Etiological heterogeneity of SHM is discussed in relation to treatment and other risk factors.     

The clinical spectrum of pure Bence Jones proteinuria. A study of 66 patients

Sixty-six consecutive patients exhibiting isolated urinary excretion of monoclonal free light chains, i.e. Bence Jones protein (BJP), on screening investigation for serum and urine monoclonal immunoglobulins were studied in order to better define the spectrum of immunoproliferative disorders associated with such a protein abnormality. The typical plasma cell neoplasms accounted for only one third of the cases, multiple myeloma (MM) and systemic amyloidosis (AL) being diagnosed in 18% and 15% of the patients, respectively. Eighteen (27%) of the patients were recognized as having malignant nonHodgkin's lymphomas (NHL), 21 (32%) had chronic lymphocytic leukemia (CLL), and 2 (3%) had hairy cell leukemia (HCL). Three patients (5%) without apparent evidence of any malignant immunoproliferative disease were classified as having a monoclonal gammopathy of undetermined significance (MGUS). The greatest urinary concentrations of BJP were found in plasmacytic neoplasms, the daily excretion of MM patients being significantly higher than that of AL patients. Considerably lower BJP outputs were recorded in the other diseases, the lowest ones being associated with MGUS. NHL patients had a daily excretion four times higher as compared with that of CLL patients. The distribution of NHL by histologic type was: follicular center cell lymphomas (FCCL) 39%, small lymphocytic lymphoma (SLL) 33%, immunoblastic lymphoma (IBL) 17%, and plasmacytoid lymphocytic lymphoma (PLL) 11%. The highest BJP levels were found in PLL, and the lowest ones in FCCL. In CLL patients the amount of urinary BJP correlated significantly with the tumor load, as estimated by the number of enlarged lymphoid areas. The study suggests that detection and measurement of isolated urinary BJP may provide useful data for the clinical evaluation of a wide spectrum of immunoproliferative disorders.     

abl oncogene expression in non-Hodgkin lymphomas: correlation to histological differentiation and clinical status

Eight reactive lymphatic tissues, 166 cases of non-Hodgkin lymphomas (NHL) and 11 cases of multiple myeloma were investigated for expression of the c-abl protein using the poly-clonal anti-abl antibody 4411 and an indirect peroxidase technique. In selected cases the results were compared to those obtained with a second polyclonal and 2 monoclonal anti-abl antibodies. In 7 cases, Northern blot analysis of abl-mRNA was performed in parallel. In reactive lymphatic tissues, cells positive for the 4411 antibody were confined to the B-cell areas, i.e., to the mantle zone and parts of the germinal center. In NHL, a positive staining of the cell membrane was predominantly detectable in lymphomas putatively originating in the germinal center or mantle zone (in particular in centrocytic NHL), independent of their proliferative activity. Clinically, 7 out of 8 abl-positive cases of chronic lymphocytic leukemia (CLL) had a more aggressive course of disease, whereas "progressive disease" occurred in only 7 out of 19 c-abl antigen-negative cases. When the clinical status of 78 patients with NHL and 11 patients with multiple myeloma was related to c-abl expression, c-abl-positivity was mostly confined to patients in advanced tumor stages [p less than 0.001 (NHL)].     

HTLV-I carriers among migrants from an ATL-endemic area to ATL non-endemic metropolitan areas in Japan

The prevalence of antibodies against HTLV-I among Kyushu natives aged 16 to 39 years who moved from Nagasaki and Kagoshima prefectures to Aichi prefecture (a non-endemic area for ATL) was compared by their cities or counties of birth. The positive rate of anti-HTLV-I antibody was 2.4% (II/400) among Nagasaki natives, 6.4% (20/312) among Kagoshima natives and 4.0% (31/772) for both combined. There was a slight difference in the positive rate of anti-HTLV-I antibody between Kyushu natives from cities (3.3%) and from counties (4.5%). In county areas, the prevalence of anti-HTLV-I antibodies among migrants from areas of relatively higher mortality for malignant lymphomas (7.5%) was significantly higher (p less than 0.01) than among persons from lower mortality areas (1.9%). Most "positive" persons had moved from Kyushu to Aichi prefecture between the ages of 15 and 18 years. The results of the present study suggest that: there is a considerable number of HTLV-I carriers among Kyushu natives who have settled in ATL non-endemic areas, especially among those born in regions of Kyushu district which have a high mortality rate for malignant lymphomas; and that Kyushu natives who had settled in metropolitan areas might have been exposed to HTLV-I during childhood in their birthplace.     

Malignant lymphomas in Japan: epidemiological analysis on adult T-cell leukemia/lymphoma

According to the Vital Statistics Japan Series in 1950-1981, the age-adjusted death rate for malignant lymphomas (ICDs, 200-202) in Japan has increased in recent years. A geographical clustering of malignant lymphomas in the Kyushu districts was observed both in the period 1969-1971 and more recently in 1979-1981. The excessive rate of malignant lymphomas in Kyushu was due to the high incidence of adult T-cell leukemia/lymphoma (ATLL). The distribution of healthy carriers of ATLV, a human retrovirus which is almost identical to HTLV, was closely related to that of patients with ATLL in Japan. Epidemiological features of the infectious mode of ATLV suggested two main routes of natural transmission, one from mother to child and the other from husband to wife. ATLV is considered to be a main causative agent of ATLL from virological and epidemiological evidence, but infection by this virus alone may not result in ATLL because the incidence of ATLL among ATLV carriers was apparently not very high even in endemic areas of ATLL. Thus, some risk factors other than ATLV, such as environmental and genetic factors, may contribute to the development of ATLL.     

Clinical effects of human lymphoblastoid interferon in patients with hematologic neoplasms

Sixteen patients with hematologic neoplasms were treated with Human Lymphoblastoid Interferon (HL-BI) derived from Namalwa cell line. They were 6 multiple myeloma, 8 acute leukemia and 2 malignant lymphoma patients. All patients were previously treated with anticancer agents except one case with multiple myeloma. HLBI, 3.0 X 10(6) IU/day, was daily administered by intramuscular injection at least for 4 weeks. Three of 6 multiple myeloma responded to HLBI with a decrease of more than 25% in serum myeloma protein level. A case with pleural effusion due to massive infiltration of myeloma cells treated with intrathoratic administration of HLBI, in whom complete disappearance of pleural effusion was recognized. On the other hand, no patients with acute leukemia and malignant lymphoma responded except one case with acute lymphocytic leukemia, in which bone marrow lymphoblasts decreased transiently. Fever episodes, 13 of 16 cases, were more frequently seen but were manageable. Transient leukocytopenia and thrombocytopenia were also observed in 4 and 7 of 8 cases, respectively. No anaphylactoid reaction was seen. Thus, HLBI was expected useful in the clinical management of multiple myeloma.     

Leukemia, lymphoma, and multiple myeloma in Alaskan natives

All Alaskan Native patients diagnosed with leukemia, lymphoma, multiple myeloma, and related cancers during the time period 1969-83 were identified. Of 72 biopsy-confirmed cases, lymphoma was diagnosed in 37 (including mycosis fungoides in 5), leukemia in 22, multiple myeloma in 11, and other lymphoreticular cancers in 2. Compared to the rates for U.S. whites, incidence rates were low for leukemia and lymphoma (especially Hodgkin's disease), but not for multiple myeloma in males. There was an apparent increase over time in lymphomas in males, while no increase occurred in females, nor for leukemia or multiple myeloma in either sex.     

Differential diagnosis of malignant lymphomas and related disorders by specific pattern of expression of immunophenotypic markers revealed by multiparameter flow cytometry (Review)

The introduction of monoclonal antibodies (mAbs) for cell immunophenotyping and use of flow cytometry with the progressively improving software for multivariate analyses have revolutionized the diagnosis and influenced the classification of hematologic neoplasms. In this review we focus on the practical application of flow cytometry in the diagnosis and classification of malignant lymphomas and related lymphoproliferative disorders with special emphasis on differential diagnosis. A general approach to the utilization of flow cytometry (FC) in hematopathology with an algorithm to diagnose the most common neoplasms is presented. We discuss precursor B-cell neoplasms, mature B-cell neoplasms (SLL/CLL, mantle cell lymphoma, marginal zone lymphoma, hairy cell leukemia, diffuse large B-cell lymphoma, plasma cell dyscrasias and lymphomas with plasmacytic differentiation), precursor T-lymphoblastic leukemia and mature (peripheral) T-cell neoplasms, including T-SLL/PLL, anaplastic cell lymphomas and large granular cell leukemia/lymphoma. The text is accompanied by characteristic FC scatterplots of the discussed entities.     

Antibody-dependent cellular cytotoxicity in some lymphoreticular diseases

Antibody-dependent cellular cytotoxicity mediated by K cells against chicken erythrocytes was measured in 113 patients with malignant lymphoreticular disorders and compared with 230 controls. The results were expressed as the specific cytotoxicity of a fixed number of cells and also by cytotoxic capacity, which measures the number of cytolytic units in 1 ml of blood. The values for cytotoxic capacity were normal in the group of untreated patients with non-Hodgkin's lymphomas, multiple myeloma or chronic lymphocytic leukemia and in most of the patients with Hodgkin's disease or acute lymphoblastic leukemia. However, decreased specific cytotoxicity was observed in these same lymphoid leukemia patients, which may be due to dilution of effector cells. The effect of chemotherapy in reducing K-cell activity is more evident in patients with multiple myeloma, followed by patients with Hodgkin's disease, and finally by patients with non-Hodgkin's lymphomas. No case of K-cell neoplastic disease was observed in this series.     

Patterns of Ganglioside Expression in B Cell Neoplasms

Twenty seven B cell neoplasms were examined by high performance thin layer chromatography (HPTLC) and immune thin layer chromatography (ITLC) to determine ganglioside expression. Patterns of expression in the cells were compared with conventional morphology, genotype, and glycoprotein immunophenotype. Patterns of ganglioside expression were found for each of the tumor types analyzed (5 acute lymphoblastic lymphomas (ALL), 5 Burkitt's Lymphomas (BL), 4 chronic lymphocytic leukemias (CLL), 3 diffuse poorly differentiated lymphomas (DPDL), 7 diffuse histiocytic lymphomas (DHL), and 3 multiple myelomas (MM). GM3 was the predominant ganglioside found in all B cell neoplasms except multiple myeloma where GM2 was equivalent to GM3. GM1 was detected by ITLC in all B cell tumors, but significant amounts were found by HPTLC only in ALL, CLL, and DHL. Small amounts of GD3 and GD2 were found in several B cell neoplasms. Significant amounts of other gangliosides were not found. The expression of GM2 on the MM cell lines, a cell type derived from outside of the nervous system, is unusual. This high level of expression was also seen in metabolic labeling studies. GM2 was readily detectable in the SKMM1 human multiple myeloma cell line by flow cytometry and served as a target for human complement-mediated cytotoxicity. Although the functions of gangliosides are largely unknown, the patterns of gangliosides found for this system of human B cell malignancies may serve to provide targets for specific immunotherapy and clues to their functions.     

Neutral glycosphingolipid expression in B-cell neoplasms

The expression of neutral glycosphingolipids (GSL) in 37 B-cell neoplasms [7 acute lymphocytic leukemia (ALL), 5 Burkitt's lymphoma (BL), 7 chronic lymphocytic leukemia (CLL), 5 diffuse, poorly differentiated lymphoma (DPDL), 6 diffuse histiocytic lymphoma (DHL), 3 hairy-cell leukemia (HCL), and 4 multiple myeloma (MM)] was examined. Patterns of expression of simple (GlcCer, LacCer) and globo-series GSL (Gb3, Gb4) were found for each tumor type. In addition, pre-B ALL expressed the neo-lacto series GSL, paragloboside, which was not significantly seen at later stages of maturation. As a group, leukemias expressed about 10 times higher ratios of simple GSL to Globo-series GSL as compared to lymphomas, regardless of stage of differentiation. Significant amounts of GSL of other series were not found except in one CLL which contained asialo-GM2. GSL phenotype in these cells was not grossly affected by cell genotype since pre-B ALL containing Philadelphia chromosome t(9q;22q) translocations were similar to other ALL; and DHL with t(8q;14q) translocations had GSL patterns similar to other DHL samples and dissimilar to GSL patterns found in Burkitt's lymphomas with t(8q;14q). Differences in GSL expression among the different types of B-cell neoplasm suggested that GSL patterns form a phenotypic map that may complement the traditional glycoprotein immunophenotypic map and contribute to our understanding of the biology of these diseases and B-cell differentiation.     

Estimation of adult T-cell leukemia incidence in Kyushu District from vital statistics Japan between 1983 and 1982: comparison with a nationwide survey

To investigate the change in adult T-cell leukemia incidence between 1983 and 1992 and to evaluate the sensitivity of the nationwide adult T-cell leukemia survey, we estimated adult T-cell leukemia incidence in the Kyushu district, southern Japan, where adult T-cell leukemia is endemic. The incidence of adult T-cell leukemia was calculated from the difference between Kyushu and the rest of Japan in mortality from malignant lymphoid neoplasms, i.e., Kyushu's excess rate was assumed to be due to adult T-cell leukemia. In Kyushu, average annual adult T-cell leukemia cases aged > or = 20 years were estimated for men as 252 during the period 1983-87 and 341 during 1988-92, and for women as 201 and 246 respectively. The age-adjusted mortality rate tended to be higher in the latter period [6.29 per 100000 (95% confidence interval 5.59-7.00) vs. 5.25 (4.60-5.90) in men, and 3.33 (2.85-3.80) vs. 3.18 (2.71-3.66) in women]. By contrast, the registered number of adult T-cell leukemia cases nationwide during 1988-93 was only 35% (203/587) of the estimated number, and the number of registered versus estimated cases decreased with age, especially when cases were > 60 years old. In conclusion, the estimated adult T-cell leukemia incidence for 1983-92 increased in the latter half of the period. The estimation suggests that 65% of adult T-cell leukemia cases might be missed by a nationwide survey, and older cases were more likely than younger ones to be missed.      

Heterogeneous CD52 expression among hematologic neoplasms: implications for the use of alemtuzumab (CAMPATH-1H).

PURPOSE: CD52 is a GPI-linked glycoprotein expressed by B cells, T cells, monocytes, and macrophages. The humanized monoclonal antibody alemtuzumab (CAMPATH-1H) is specific for CD52 and is Food and Drug Administration - approved for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL). The utility of CAMPATH in the treatment of other hematologic neoplasms has been explored; however, a comprehensive survey of CD52 expression among a broad spectrum of WHO-defined tumor types has not been completed. EXPERIMENTAL DESIGN: We evaluated 294 hematologic neoplasms for the presence of CD52 using standard immunohistochemical techniques on paraffin-embedded biopsy specimens fixed with formalin, B-Plus, Zenker's acetic acid, or B5-formalin. RESULTS: The vast majority of low-grade B cell lymphoproliferative disorders (CLL/small lymphocytic leukemia, follicular lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, and mucosa-associated lymphoid tissue lymphomas) express CD52. In addition, we found that the majority of precursor B cell acute lymphoblastic leukemia/lymphomas express this antigen. In contrast, there is surprising heterogeneity in CD52 expression among more aggressive B cell lymphomas, with 25% of cases of diffuse large B cell lymphoma and Burkitt lymphoma demonstrating no detectable CD52. In addition, the majority of neoplasms of the T cell lineage are negative for the antigen, including most cases of precursor T cell acute lymphoblastic leukemia/lymphoma, anaplastic large cell lymphoma, and peripheral T cell lymphoma, not otherwise specified. Finally, the vast majority of cases of acute myeloid leukemia, Hodgkin lymphoma, and multiple myeloma are negative for CD52 expression. CONCLUSION: In contrast with CLL, the variable expression of CD52 among other hematologic malignancies suggests that target validation on a case-by-case basis will likely be necessary to guide the rational analysis of CAMPATH therapy.     

Monoclonal antibody against a membrane antigen characterizing leukemic human B-lymphocytes

In the diagnosis of non-Hodgkin's lymphomas, the ready characterization of the neoplastic cell lineage by analysis of cell surface markers is of great importance. We present evidence for the existence of a human B-leukemia-associated antigen recognized by a complement-fixing monoclonal antibody (anti-Y 29/55). A hybridoma was produced by fusing mouse myeloma cells and splenocytes of a mouse immunized against lymphoid cells of a patient with B-cell chronic lymphocytic leukemia. Characterization of anti-Y 29/55-reactive normal and malignant leukocytes was demonstrated by cytolysis and indirect immunofluorescence. This revealed reactivity with an antigen on B-lymphoma cells (11 patients), on leukemic lymphocytes in B-cell chronic lymphocytic leukemia (13 patients), and on malignant cells in hairy-cell leukemia (two patients) but not on leukemic cells of T-cell acute lymphoblastic leukemia (one patient), on T-lymphoma cells (one patient), on cells of acute myeloblastic leukemia (four patients), or of chronic myeloid leukemia (four patients). No specific cytolysis occurred with B- and T-peripheral blood lymphocytes from (a) healthy donors (16 individuals), (b) patient with reactive lymphocytosis (one patient), (c) nonleukemic multiple myeloma (six patients), or (d) Hodgkin's disease (three patients). Surface immunoglobulin-positive, sheep RBC-negative lymphocytes isolated from human spleen (three individuals), tonsils (seven individuals), and lymph nodes (one individual), however, were recognized. It is concluded that leukemic B-cells carry a marker characteristic of nonrecirculating sessile B-lymphocytes.     

Proportionate mortality study of workers in the grain industry

The proportionate mortality experience and proportionate cancer mortality experience were examined for 1,114 white male members of the American Federation of Grain Millers' life insurance plan. Mortality was significantly elevated for accidents and cancers of the lymphatic and hematopoietic systems, particularly from lymphosarcoma and reticulum cell sarcoma, other neoplasms of lymphoid tissue (i.e., giant follicular lymphoma and other primary malignant neoplasms of lymphoid tissue), and multiple myeloma. No increased mortality was seen for cancer of the respiratory tract, and nonmalignant diseases of the digestive tract were significantly lower than expected. Employees of grain mills showed higher mortality ratios of lymphatic and hematopoietic cancers as compared to other grain industry categories. A preliminary survey of pesticide usage suggested that grain mills were generally associated with greater use of pesticides than other industrial categories with considerable variation among the many facilities encompassed in this study.     

The 4th nation-wide study of adult T-cell leukemia/lymphoma (ATL) in Japan: estimates of risk of ATL and its geographical and clinical features. The T- and B-cell Malignancy Study Group

To estimate the annual incidence of adult T-cell leukemia/lymphoma (ATL) by district in Japan, a large-scale nationwide survey of ATL and of non-Hodgkin's lymphoma was performed in 1988. Questionnaires for the registration of ATL and of T-cell and non-T-cell lymphoma were distributed to the physicians in charge of this survey in 1,287 hospitals with 200 or more beds throughout Japan. From the positive rate of anti-HTLV-I antibody in adults, the annual incidence of ATL was estimated at 697, independently of the present survey. In fact, 657 cases (47% of the estimated number), newly diagnosed during the 2 years January 1986 to December 1987, were registered from 191 general hospitals throughout Japan. Major results obtained from the present survey are as follows: (1) among all ATL cases registered, 51% were from Kyushu and 29% were from metropolitan areas (Kanto, Chubu and Kinki) and most, but not all, patients with ATL in the metropolitan areas had come from the ATL-endemic areas and settled in the metropolitan areas; (2) the estimated annual incidence rates of ATL per million adults were 40.4 in males and 26.4 in females in Kyushu, the overall risk of ATL being 1.5 times as high in males as in females; (3) the age-specific incidence rate in Kyushu increased steeply with age until the age of 70, and then decreased markedly in both sexes; (4) the ratio of T-cell versus non-T-cell lymphomas was 2.9 in Kyushu but 0.5 in other districts of Japan, however, this difference regressed to the average for the whole of Japan if ATL cases were excluded; (5) 26.5% of patients with ATL had a family history of cancer, and among these, 14 (8.2%) were ATL, 21 (12.2%) were lymphoma and 17 (9.9%) were hematopoietic malignancies, the incidence of which was markedly higher than in the general population; (6) with regard to clinicopathological features of ATL, there were more advanced cases in south Kyushu than in other districts, however, these differences were not statistically significant. To clarify the chronological changes and geographical variations in the annual incidence of ATL in Japan, continuous systematic nationwide surveillance is necessary and further nation-wide studies are being prepared.     

Second malignancies in patients with multiple myeloma.

Seven patients with multiple myeloma who developed a second neoplasm are presented. There were four patients with acute leukemia and three patients with non-hematologic neoplasms. The patients with acute leukemia were among the longest survivors (median duration approximately 72 months) and the response to anti-leukemic therapy in these patients was generally poor. Of the three patients with non=hematologic neoplasms, one patient was observed with simultaneous renal cell carcinoma and the other two patients developed adenocarcinoma of the colon and lung subsequently. In addition, two patients with mammary carcinoma who subsequently developed multiple myeloma were included. Literature was reviewed and the possibility that multiple myeloma itself might be a risk factor for the development of other malignancies was discussed.     

苯达莫司汀治疗复发/难治性多发性骨髓瘤的研究进展

多发性骨髓瘤（multiple myeloma,MM）是一种浆细胞恶性克隆性疾病。随着自体造血干细胞移植（autologous stem cell transplantation,ASCT）、免疫调节剂(immunomodulatory drugs,IMiDs)和蛋白酶抑制剂(proteasome inhibitors,PIs）等药物的应用,患者的整体生存期显著延长。但患者常因疾病复发、耐药及进展而死亡,MM至今仍无法治愈。苯达莫司汀（bendamustine,Ben）是一种古老的双功能氮芥衍生物,具有独特的作用机制,与其他烷化剂无交叉耐药性。在东欧地区,该药已广泛应用于慢性淋巴细胞白血病、恶性淋巴瘤、MM等淋巴系统肿瘤及乳腺癌的治疗。近年来,国外开展了一系列Ben单药或联合化疗治疗复发/难治性多发性骨髓瘤（relapsed/refractory multiple myeloma,RRMM）的临床研究,并显示出良好的疗效。本文就Ben单药或联合化疗治疗RRMM的疗效进行综述。