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REVIEWS

Multiple Myeloma and Chronic Lymphocytic Leukemia: Parallels and Contrasts BARTBARLOGIE,M.D., Little ROCK, Arkansas, ROBERTPETERGALE,M.D., Ph.D., Los Angeles, California

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) are closely related B-cell wncers. Parallel and divergent features of these diwases are reviewed, In MM, expression of multiple hemopoietic lineage-associated antigens on the ma&pant cells and the substantial likelihood of p&on to acute myelogenous leukemia suggest transformation of a pluripotent stem cell In CLL, transformation more likely involves a committed B-cell progenitor. Another difference is that clonal evolution with associated cytogenetic progre&on is common in MM but not CLL. Other data, including studies of proto-oncogenes and tumor suppressor genes, suggest that MM results both from increased proliferation and accumulation of tumor cells, whereas tumor cell accumulation is the predominant feature of CIA These differences may be reflected in the seemingly greater role of cytokine abnormalities in MM progression. For example, osteoclast-activating properties of some cytokines account for bone involvement in MM but not in CLL. MM and CLL share common features such as stage-dependent anemia and immune deficiency. Both d&ases respond to all&ting agents but vary markedly in their sensitivity to fludarabine (CIA greater than MM) and glucocorticoids (MM greater than CIA). Difference9 between these disegses in progression-free interval and survival may reflect different definitions of premabgnant and malignant phases rather than biologic differences. Detailed comparisons between MM and CIA may provide additional insights into these and related B-cell cancers. From the Division of Hematology-Oncology and the Arkansas Cancer Research Center (BB), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and the Division of Hematology-Oncology, UCLA School of Medicine (RPG), Los Angeles, California. Thisworkwassupported in part byGrantsCA37161 andCA28771 from the National Institutes of Health. Requests for reprints should be addressed to Bart Barlogie, M.D., University of Arkansas for Medical Sciences, Division of HematologyOncology, 4301 West Markham, Slot 508. Little Rock, Arkansas 72205, or Robert Peter Gale, M.D., Ph.D., Division of Hematology-Oncology, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, California 90024. Manuscript submitted January 9, 1992, and accepted in revised form May 11,1992.

ultiple myeloma (MM) and chronic lymphoM cytic leukemia (CLL) are clonal malignancies of bonemarrow-derivedB cells.Advancesin molecular and cellular biology have resulted in increased understanding of these diseases.There have also been recent modest advancesin therapy. In this review, we emphasizeparallel and contrasting features of MM and CLL (Table I) that may further our understanding of these and related B-cell cancers. ~TloLmy AND EPIDEMIOLOGY11-31 Etiologies of MM and CLL are unknown.In mice, MM can be induced by long-term exposureto paraffin oil8 like alkanepristane. Agricultural workers may be at increasedrisk of MM from fertilizers and pesticides,as are personsexposedto benzeneand other petroleum products. Radiation is associated with MM in atomic bomb survivors and persons exposedto diagnostic and therapeutic radiations. Sporadic reports of a viral etiology of MM in animals and humans are unconfirmed. In animals, especiallycows,leukemia resembling CLL is causedby non-acutelytransforming viruses [4]. However,a viral etiology of CLL in humans has not been convincingly demonstrated.Unlike MM, CLL is not increasedamongatomic bomb survivors or other personsexposedto radiation. However,as in MM, associationswith agricultural occupations and benzeneare reportedin CLL [3]. MM and CLL share several epidemiologic features. Both affect older persons and have modest male predominances.CLL is aboutfive times more commonthan MM. MM is more common in blacks than whites, whereasthe converseis true of CLL. CLL is more frequent in Jews of EuropeanversusMediterranean descent;no such difference is observedin MM. CLL is rare in Asia, whereasMM is common. CLINICALFEATURES The clinical courseof MM and CLL is sometimes stable for several years.The median therapy-free interval is about 3 yearsin smolderingMM and 4 to 6 yearsin stageI and II CLL (comparableto smolderingMM) [5]. Median survivalsfrom initiation of therapy for symptomatic diseaseare 2.5 to 3 years for MM (for review,see[2]>and 5 to 7 yearsfor CLL

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MM AND Cl.1 / BARLOGIE AND GALE TABLE I Parallels and ContrastsBetween Multiple Myeloma and Chronic Lymphocytic Leukemia -..--_ Chronic Multiple Lympmpgr Variable Myeloma -__ .~~--.~ Carcinogenesis Radiation Chemicals

t t

Demographics Mainly over age 50 Preva;r among:

t

t

-__-

t

t Ashkanazi Jews

t

-~

Disease evolution Preceding benign phase Transformation early in hemopoiesis Secondary acute myeloblastic leukemia Progression to higher-grade malignancy --Clin~n;f;tures

t t t t

t t

-

t Thrombcqtopenia lmmunodeficiency Bone lesions Renal failure Clonal B cells Monoclonal immunoglobulin secretion

------. Biology Cytogenetics Simple, without evolution Complex, with progression Oncogenes myc, ras bcl-2 Cytokines Multiple, involved in normal hemopoiesis Tumor staging Related to bone marrow infiltration Treatment Responsive to alkylating agents Responsive toffudarabine Cures not reported

t t t

t t t t tt

.-

A

t t

t t

t

t

-

t

t

t

t t t

t

-

(for review,see[3]). In both diseases,survival correlates with the diseasestageat diagnosisand the rate of progreseion(de infm). The seemingly more rapid pace of MM versus CLL may reflect different diagnosticcriteria of early disease.Thus, subjectsin whom the sole initial abnormality is a monoclonalimmunoglobulin in the blood are diagnosedas having monoclonalgammopathy of undeterminedsignificance(MGUS), rather than MM [6]. The annual progressionrate of MGUS to MM is only 1%to 2% [6].Whether MGUS alwaysprecedesMM is unknown sothat symptomand progression-freeintervals cannot be estimated. In contrastto the distinction betweenMGUS and MM, an increasein monoclonalB cells in the blood (greaterthan 5 X l@/L) is often immediately defined as CLL regardlessof diseasestage.Many sub-

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jecta with CLL never require therapy becausethe diseasedoesnot progressor becauseof antecedent death from unrelated causes.Thus, in contrast to MM, there is lessselectionof CLL caseswith progressive,symptomatic disease. Becauseof thesediagnosticdifferences,MM appearsto be moreaggressive,with shortersymptom-, progression-, and treatment-free intervals and briefer survival than CLL. Our impression is that comparably diagnosed and staged persons with both disordershavesimilar outcomes.Some investigators have proposedthe term monoclonal lymphocytosisof undetermined significance (MLUS) for personswith CLL without lymphadenopathy, hepatosplenomegaly,or bone marrow failure. Although the presenceof monoclonal B cells in the blood representsthe hallmark of CLL, circulating plasma cells are uncommon even in advanced MM. This differenceoccursdespitecomparabletumor infiltration of the bone marrow and likely reflects biologic featuresof the malignant cells. However,with the useof sensitivetechniques,immature B cells related to the malignant clone have been readily identified in the blood of most personswith MM [2,7,8].Conversely,plasma cells related to the malignant clonearesometimesdetectedin the bone marrow of personswith CLL. Anemia is common in both MM and CLL. In contrast, thrombocytopenia is rare in advanced MM but common in advancedCLL. Another example is autoantibodiesto red blood cells and platelets, which develop in about 10%of personswith CLL but only rarely in MM [9]. In CLL, theseantibodies are polyclonal and unrelated to the malignant B cell. In MM, autoantibodiesareproducedby the malignant plasma cells in rare cases[lO,ll]. Marked monoclonalimmunoglobulin secretionis the halhnark of MM but is rare in CLL. However, sensitivetechniquescan detect low levelsof secreted monoclonal immunoglobulin in most persons with CLL. Despite the marked hypergammaglobulinemia typical of MM, antibody responsesof residual, presumably normal B cells are markedly impaired [12,13].The same is true in CLL [14]. Destructive (lytic) bonelesionsand osteoporosis are common in MM but rare in CLL. This difference probably reflecta the secretion of cytokines with osteoclast-activatingproperties by malignant plasma cells [E-17] but not by CLL B cells. PHENOTYPE Almost all MM cellshavesubstantialcytoplasmic but not surface immunoglobulin [18]. Antigens of mature plasma cells, like CD38, are often detected [19]. MM cells alsoexpressdiverselineageand dif-

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ferentiation antigenslike early B (mainly CDlO), T, NK, myeloid, erythroid, and megakaryocyticmarkers.These areoften presenttogetherwith cytoplaamic immunoglobulin on aneuploid cells [2,20]. Phenotypic features of CLL cells differ from thoseof MM cells. CLL cells often expressearly Bcell antigenslike CD19, CD20,CD21, CD24,CD37, and CD23 but not mature plasma cell antigenslike CD38 (for review, see[3,21]).About half of the patients expressCD25 about one fourth CDll, and about one tenth FMCll, CD22, and CDlO. CLL B cells expressCD5 (see [22,23]),a putative T-cell antigen that, in fact, defines a specific subset of human B cells [24]. Most CLL cells lack cytoplasmic immunoglobulin but havescant surfaceimmunoglobulin [25]. Myeloid differentiation antigens are alsosometimesdetectedin CLL; their frequency and diversity are considerablylessthan in MM WI -

Shared idiotype reactivity of monoclonal immunoglobulin from different personswith MM suggestednonrandomimmunoglobulin variable region (V) geneuse similar to that of CLL [27]. Although Vu4 and VH~predominate in both diseases,Vu4 usageis especiallyfrequent in MM [28]. The phenotype-independentbiasedVu genefamily usagemay point to similar stagesof B lymphopoiesis from which these diverse B-cell malignancies arise or evolve. SITE OF TRANSFORMATION Data regarding cell phenotype suggestdifferent sitesof transformation in MM and CLL. The greater diversity and higher frequency of expressionof myeloid antigensin MM suggesttransformation of a pluripotent stem cell with both lymphoid and myeloid potentialities [20]. This is consistentwith the substantial risk of developing acute myelogenous leukemia (AML) and myelodysplasia(MDS) in personswith MM [29]. In CLL, in contrast, most data suggesttransformation of a relatively committed B cell; AML and myelodysplasiaare uncommon. Several personswith coincident MM and CLL have been described [30]. Usually this is metachronous,but somecasesare synchronous.In most instances,MM developsafter CLL. Whether this reflects the biology of the transformed cell or the seemingly briefer survival of personswith MM is unknown. In about half of the cases,the two diseasesare geneticallyrelated, other casesare probably coincidence.Interestingly, CLL cells mature to plasmacellsafter in vitro treatment with differentiating agentslike phorbolesters[31]. Personswith MM sometimesdevelopplasma cell leukemia [32] or immunoblastic lymphoma (“high-

grade myeloma”) [33]; large cell lymphomas are rare. In CLL, developmentof large cell lymphoma (Richter’s syndrome)is not uncommon (for review, see[21]), whereasplasma cell leukemia and immunoblastic lymphoma are rare. In the relatively few casesof progressionof MM and CLL to other disorders studied, about half showeda genetic relationship between the original diseaseand the transformed phenotype.In the other cases,development of both diseasesis presumably coincidental. CYTOGENETICS MM and CLL cells grow poorly in vitro. Consequently, metaphasesare difficult to obtain. Cytogenetic aberrationsare present in about one third of personswith MM. However,most casesof MM have distinct nuclear DNA abnormalities on flow cytometric examination [34].This discrepancyis due to the low tumor cell proliferative activity sothat diploid metaphasesfrom residual normal hemopoietic cells are studied cytogenetically.About half of the casesof CLL have cytogeneticabnormalities [35]. In contrast to MM, CLL cells are diploid by DNA analysis; DNA aneuploidy usually suggestsdevelopment of a large cell lymphoma. Cytogeneticanalysesin MM indicate trisomies of almost all chromosomesexcept chromosomes10 and 13 [36,37].Gainsare frequently associatedwith lossof chromosome7, a finding common in therapyand chemical-relatedAML and in myelodysplasia. Most frequent monosomiesinvolve chromosomes 13and 16.Structural abnormalities are detectedin chromosomes1,6,7, and 14at diagnosis.Additional aberrations of chromosomes3, 5, 11, and 14 are observedin previously treated persons[38].Translocationscommonin B-cell lymphomas,like t(8;14), t(11;14),and t(14;18),occurin lessthan 5%of cases of MM [37]. Rearrangementsof proto-oncogenes associatedwith thesetranslocationsin personswith lymphomas, like b&l, bcl-2, and myc, occur infrequently in MM [2,39]. Some cytogenetic abnormalities correlate with diseasemanifestation and outcome in MM. Abnormalities of chromosome6q areassociatedwith lytic bone lesions [40]. Hypodiploidy, detectedby DNA flow cytometry or by cytogeneticstudies, is associated with Bence-Jonesprotein secretionand resistance to therapy [37,41].Abnormalities of chromosomes 5 and 7, commonly associated with therapy-linked MDS and AML, arenoted in about 25%of personswith MM, including somewithout prior therapy. The demonstration of suchchromosomeaberrationsin both MM and hemopoieticcells by phenotype-correlatedcytogeneticstudies would suggest a clonal relationship between MM and

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MDS and hence support their derivation from a common hemopoietic stem cell [2,20]. These studies have not been reported. The most common chromosome abnormalities in CLL are trisomy 12 and structural aberrations of chromosomes 13 and/or 14 [35,42]. Persons with a normal diploid karyotype and aberrations of chromosome 13q have the most favorable prognosis; trisomy 12, an intermediate prognosis; and 14q+ abnormalities, a poor prognosis [35]. The few t( 11;14) chromosomal aberrations reported in CLL are usually associated with prolymphocytic leukemia rather than typical CLL [21]. An additional difference between MM and CLL relates to clonal evolution. This occurs more often in MM [38], whereas cytogenetic abnormalities in CLL seem relatively stable [35].

CYTOKINES There is considerable recent interest in cytokines and cancer. In some instances, abnormal cytokine expression is thought to cause neoplasia, in others to enhance growth of cancer cells. In MM, autologous bone marrow stromal cell cultures elaborate interleukin-6 (IL-6) and other cytokines [43]. These molecules support growth of monoclonal B lymphocytes and plasma cells from the blood. Together with other recent data on osteoclast activation in MM (but not MGUS) [44], these data support the notion that cytokines released from stromal cells are important in MM. Details of their interaction are unknown [45,46]. However, IL-6 is currently thought to be the most important cytokine in MM. The importance of IL-6 in MM is underscored by elevated serum levels in advanced disease [47]. This increase results in high levels of acute-phase reactants, especially C-reactive protein, and decreased albumin synthesis by hepatocytes [48]. Increased IL-6 levels, which stimulate megakaryopoiesis, may explain why platelet levels are normal in MM [49]. IL-6 also activates osteoclasts and may be partially responsible for osteolytic bone disease and hypercalcemia. Therapy with antibodies to IL-6 decreases MM cell proliferation, reverses hypercalcemia, and decreases serum monoclonal immunoglobulins and C-reactive protein [50]. Mice transfected with an IL-6 gene construct develop features resembling Castleman’s disease [51]. Transgenic mice carrying the human IL-6 genomic DNA fused with the human immunoglobulin heavy chain enhancer develop massive plasmacytosis [52]. There are relatively few studies of cytokines in CLL. Some recent data indicate abnormalities of IL-2, IL-lo, TNF-a, and TNF-8; increased levels of TNF may contribute to anemia in some cases of CLL [53]. 446

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In summary, growth of MM cells seems enhanced, at least in part, by cytokines secreted mainly within the bone marrow environment [43]. Similar data have not been reported in CLL, but this is less well studied. One view of these data is that MM results from transformation and abnormal growth of B-precursor cells. IL-6 promotes their expansion and possibly terminal differentiation to plasma cells. Their longevity and consequently accumulation may be explained by increased bcl-2 expression, common to both MM and CLL cells [54,55].

PROTO-ONCOGENES AND TUMOR SUPPRESSORGENES Abnormalities of proto-oncogenes occur in variable proportions of persons with MM and CLL. Increased myc-related mRNA and protein are reported in about 25% and more than 90% of cases of MM, respectively [39,56]. Although normal plasma cells were not studied, myc expression is typically down-regulated during normal B-cell differentiation. In contrast to Burkitt’s lymphoma, myc is rarely rearranged in MM, and the immunoglobulin loci are rarely involved [39]. About one third of persons with MM have mutations in N-rus [57]. This is similar to the frequency reported in several other hematologic cancers like AML and acute lymphoblastic leukemia (ALL). N-rus mutations are generally regarded as a relatively late step in carcinogenesis. However, transfection of mutated N-rus sequences into Epstein-Barr virus-transformed human B cells results in plasma cell differentiation [58]. Stabilization of cytokine mRNA transcripts by ras mutations could explain elevated IL-6 levels in MM. Rearrangement of b&l, common in intermediate-grade lymphomas, is rare in MM [2]. As indicated, bcl-2 is strongly expressed in more than 90% of the cases of MM [54,55]. Studies of tumor-suppressor genes, like Rb and ~53, have not been reported. Abnormalities of myc, bcl-1, and/or N-rus are rare in CLL, whereas bcl-2 expression is common (F. Caligaris-Cappio, unpublished observations). The latter is of special interest since transgenic mice with a human bcl-2 transgene develop features resembling CLL, including an increased number of lymphocytes and enhanced autoimmunity [59]. This appears to result from the immortalization of B cells. In contrast to follicular lymphoma (and similar to MM), there is no consistent bcl-2 rearrangement in CLL. Abnormalities of tumor suppressor genes, like Rb and ~53, occur in up to 25% of persons with CLL [60]. Rb abnormalities are often associated with cytogenetic aberrations of chromosome 13. However, molecular techniques suggest that deletions and/or rearrangements of Rb are more frequent than sug93

MM AND CL1 /BARLOGIE

gested by cytogenetic analyses (G. Juliusson, unpublished observations). Abnormalities of Rb and ~53 in CLL rarely inactivate both alleles. Because tumor suppressor genes are typically recessive, the importance of heterozygous aberrations is unknown. Rb abnormalities are often associated with the development of a large cell lymphoma.

IMMUNE DEFICIENCY MM and CLL are associated with recurrent infections. This results from impaired antibody responses by residual, presumably normal, B cells [12-141. Why these B cells, genetically unrelated to the malignant clone, should function abnormally is unknown. Possibilities include an antecedent B-cell disorder, physical displacement of normal B cells by their malignant counterparts, impaired interactions with possibly abnormal T cells (uide infra), and others. We discuss these concepts elsewhere

WI.

T-cell abnormalities are also reported in MM and CLL, including quantitative aberrations, imbalances in T-cell subsets, and increased autoreactive T cells with Fc receptors for concordant immunoglobulin heavy chain isotypes (for review, see [2,3,21]). Interestingly, binding of shed Fc receptors to monoclonal immunoglobulin on the surface of malignant plasma cells inhibits their growth and protein secretion [61]. The opposite has been reported in CLL [62]. Since there are no data to suggest that T cells are involved in the malignant process in either disorder, these abnormalities presumably result from the disease. Alternatively, a nonmalignant T-cell disorder may antedate MM and CLL. Whether and how abnormalities of T [63] and other host cells such as monocytes [12] and NK cells [64,65] impart immune deficiency in myeloma and CLL are unknown. Bacterial infections in MM and CLL are decreased by the administration of prophylactic intravenous immunoglobulin [66]. Similar results have been observed with prophylactic antibiotics. Direct comparisons of intravenous immunoglobulin versus antibiotics used singly or in combination have not been reported.

STAGING Staging systems have been developed for both diseases and may help select appropriate therapy. The Durie and Salmon system [67] in MM is based on the degree of bone and bone marrow involvement with resulting hypercalcemia and anemia, respectively. More recently, myeloma cell proliferative activity [68], serum levels of /32-microglobulin [69], C-reactive protein (perhaps an indirect measure of IL-6 levels) [48], and lactic dehydrogenase

AND GALE

are reported to more accurately predict the response to therapy and survival [33]. The Rai [70] and Binet [71] systems for CLL use involvement of lymph nodes, spleen, and bone marrow with resulting anemia and thrombocytopenia to predict the need for therapy and survival. Other useful parameters include the pattern of bone marrow infiltration [72,73], indicators of proliferation [74], phenotype [75], and lymphocyte doubling time [76]. In contrast to MM, serum µglobulin and C-reactive protein levels are not useful predictors in CLL. The prognostic import of cytogenetic abnormalities in these diseases is discussed above.

THERAPY Therapies of MM and CLL differ considerably. For example, most persons with MM ultimately require treatment, whereas many persons with CLL (or perhaps better MLUS) require no therapy for several years, if ever. There are, however, similarities. Both diseases respond to alkylating drugs active against hematopoietic stem cells, like melphaIan [77] and chlorambucil, but less so to drugs sparing such early hematopoietic progenitor cells, like cyclophosphamide. Glucocorticosteroids are especially active in MM [78,79]; their role in CLL is less certain, except in treating autoimmune features. In contrast, antimetabolites, like fludarabine [80], and purine nucleosides, like 2’-chlorodeoxyadenosine [81], are active in CLL but not MM. Interferon appears active in about one quarter to one third of persons with MM [82] and CLL [21], but mainly when the tumor stage is low and before there is resistance to cytotoxic agents.

DISEASEEVOLUTION As discussed, both MM and CLL undergo evolution from seemingly premalignant stages of MGUS and MLUS, respectively. Progression probably occurs at similarly slow paces, less than 5% per year. Persons with MM and CLL can develop more aggressive diseases, like plasma cell leukemia and immunoblastic lymphoma in MM as opposed to prolymphocytic leukemia and large cell lymphoma in CLL. Both MM and CLL are incurable with current therapies. Preliminary results of intensive therapy followed by autologous or allogeneic bone marrow transplants are promising in MM [83,84]. In CLL, encouraging results are also reported with allografts; there are few data with autotransplants [85].

SUMMARY AND CONCLUSIONS MM and CLL are clonal B-cell malignancies sharing many features including onset in older per-

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sons and a sometimes indolent course. Both are associated with premalignant or smoldering phases. However, these are currently regarded differently. In MM, MGUS is typically distinguished from MM. Persons with MGUS who survive for prolonged periods without progressing to MM are excluded from survival analyses in MM. In contrast, persons with early or low-stage CLL (MLUS) are included in CLL survival curves, even though many never develop disease progression, require no therapy, and die from causes unrelated to CLL. There is no biologic basis for these different concepts of MGUS versus MLUS. However, this distinction explains some perceived clinical differences between MM and CLL. Although both diseases involve B cells, the phenotype of the malignant cells differs considerably. MM cells have features of mature B cells (plasma cells), early B cells, and myeloid cells. This suggests that transformation of a pluripotent stem cell may underly MM and is consistent with the occasional evolution of MM to MDS or AML, even in untreated persons. This contrasts with the phenotype of CLL cells, which resembles immature B cells. Here, there is little evidence of involvement of myeloid cells; evolution to MDS or AML is rare. Considerable data suggest that the pathogenesis of MM and CLL differs. For example, complex cytogenetic aberrations are common in MM but rare in CLL. Furthermore, cytogenetic data suggest clonal evolution in MM but not CLL. This is consistent with the notion of a stem cell origin for MM but not CLL. Compatible with this is the notion of MM as a disease in which pre-plasma cells proliferate abnormally under the influence of an abnormal bone marrow microenvironment versus CLL, which is often regarded as an accumulation of B cells. These concepts of proliferation and accumulation are also reflected in studies of proto-oncogenes and cytokines in these disorders. Proto-oncogene abnormalities typical of MM, increased expression of myc and N-m mutations, characterize cancers in which cells proliferate abnormally. In contrast, bcl-2 expression, which causes a disease resembling CLL in transgenic mice, is associated with immortalization of B cells. As a possible consequence or parallel feature, cytokine abnormalities appear more important in MM than in CLL. Staging, prognosis, and treatment of these disorders are similar when adjusted for divergent classification of early cases (uide supra). Both diseases respond to alkylating drugs; however, antimetabolites and purine nucleosides, like fludarabine and 2’-CDA, are active in CLL but not MM. These contrasts and parallels in the biology and therapy of MM and CLL are important in under448

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standing the pathogenesis of these and related Bcell disorders. Future studies should be complementary: insights into MM may prove useful in understanding CLL and vice versa. Recent advances in molecular and cellular biology provide new research directions. Much remains to be learned about these interesting and common cancers.

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