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Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) Plasma Cell Neoplasms Raymond Alexanian CA Cancer J Clin 1976;26;38-49 DOI: 10.3322/canjclin.26.1.38 This information is current as of September 8, 2010 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://caonline.amcancersoc.org To subscribe to the print issue of CA: A Cancer Journal for Clinicians, go to (US individuals only): http://caonline.amcancersoc.org/subscriptions/ CA: A Cancer Journal for Clinicians is published six times per year for the American Cancer Society by Wiley-Blackwell. A bimonthly publication, it has been published continuously since November 1950. CA is owned, published, and trademarked by the American Cancer Society, 250 Williams Street NW, Atlanta GA 30303. (American Cancer Society, Inc.) All rights reserved. Print ISSN: 0007-9235. Online ISSN: 1542-4863. Plasma Cell Neoplasms Raymond Alexanian, M.D. Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) Plasma cell neoplasms constitute a group of entities with marked variations in clinical manifestations, extent of dis ease, frequency and severity of compli cations and treatment requirements. These disorders are usually associated with increased production of a homo geneous globulin, recognized as a oepeakon serum or urine electro phoresis. Multiple myeloma is the most common plasma cell neoplasm, and must be distinguished from other closely related disorders such as localized plas macytoma, asymptomatic and indolent myeloma, idiopathic oepeaksand mac roglobulinemic lymphomas. Plasma cell dyscrasias may be classified in the fol lowing manner: Disorder Approximate frequency Plasma cell myeloma Multiple myeloma" symptomatic Multiple myeloma".asymptomatic and indolent Localized plasma- cytoma Idiopathicpeak Macroglobulinemia of Waldenstrom Heavy-chain diseases Primary amyloidosis (withouot vert myeloma) 65 2 5 20 8 <1 <1 Localized Plasmacytoma About five percent of patients with plasma cell neoplasms have evidence of only one or two plasmacytomas, without the major complications frequently as sociated with multiple myeloma. In these patients, myeloma proteins are low or absent and the serum concentra tion of nonmyeloma immunoglobulins is generally normal. Local radiotherapy to about 4,000 rads is usually effective. Such therapy may reduce the level of any myeloma protein present and ele vate the serum concentrations of non myeloma immunoglobulins to supranor mal levels, indicating that a large frac tion of tumor has been eliminated.' This elevation of normal immunoglobulins also suggests that a small number of ma lignant cells may have inhibited normal immunoglobulin production by means of a humoral mechanism.2 Clinical sta bility may be sustained for many years. However, some patients thought to have localized plasmacytomas soon de velop rising myeloma proteins, pointing to an incorrect disease classification at diagnosis and the need for chemo therapeutic management. The median survival for a group of patients with no Dr. Alexanian is Professor of Medicine, Department of Medicine, The University of Texas System Cancer Center, Texas Medical Center, Houston, Texas. Portions of the study summarized here were sup ported by Grants CA-03 195 and CA-0583 I from the National Cancer Institute, Bethesda, Maryland. 38 CA"A CANCER JOURNAL FOR CLINICIANS Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) more than two plasmacytomas was about eight years.1 Asymptomatic and Indolent Myeloma Rare patients with unequivocal multiple myeloma are asymptomatic; the diag nosis is then made by a bone marrow examination following a coincidental serum electrophoresis or the detection of mild anemia. Generally, there is a large IgG peak, greater than 3.0 grams per cent, with depression of normal IgA and 1gM immunoglobulins. Indolent mye loma must be differentiated from oeidiopathicpeaks by the demon stration of anemia due to bone marrow plasmacytosis, marked depression of normal immunoglobulins or lytic bone lesions. As long as the disease remains asymptomatic and the myeloma protein level does not increase, these patients may be followed without chemotherapy. Vertebral compression fractures or re current infection indicate the need for therapy. Long-term stability of both symptomatology and myeloma protein production may occur in patients with indolent myeloma, as in those with only one or two localized plasmacytomas. For reasons not yet clarified, the plasma cells in these patients have a low growth fraction, and the possibility of a superior immunosurveillance capacity must be evaluated. The median survival for a group of patients with indolent myeloma was about five years. In one-half of the patients, chemotherapy was not required for at least two years.' cent.' Normal immunoglobulins were not depressed, lytic bone lesions were not present and Bence Jones proteins were absent. A bone marrow examina tion is usually not required in patients with idiopathic monoclonal gammopathy of IgG or IgA type. Idiopathic peaks of 1gM type are rare, as most of these patients have an under lying lymphoma or chronic lymphocytic leukemia.4 The frequency of IgG or IgA peaks in patients with cancer was similar to that in a normal population of the same age; control of the cancer did not effect the level of the peaks.5 Thus, the relationship of serum peaks to cancers other than myeloma or macroglobuline mia is probably coincidental. The con centration of monoclonal globulin usu ally remains stable for many years and evolution into overt myeloma rarely occurs. Chemotherapy is not indicated unless there is evidence of an increasing mass of plasma cells. The lifespan of patients with this chemical abnormality depends on their age and the primary condition under evaluation at the time of discovery. MultipleMyeloma Multiple myeloma is a disseminated neoplasm of plasma cells frequently characterized by bone destruction, bone marrow failure and the production of unique immunoglobulins. (Fig. I.) About 96 percent of patients show evi dence of globulin peaks on serum or urine electrophoresis. Idiopathic Monoclonal Gammopathy Idiopathic peaks have been identified in the serum of about 0.5 percent of normal individuals over 30 years of age.3 These patients have no symptoms attributable to myeloma and serum electrophoresis was usually ordered to evaluate another disorder. In one large series, about 90 percent of the abnormal protein spikes were of IgG type, with a serum concen tration always less than 3.0 grams per Supportiveand AncillaryTherapy These patients may have a variety of dis ease complications that must be man aged concomitantly with chemotherapy for the myeloma. Back pain due to com pression fractures of the thoracic or lum bar spine, constitutes the most common presenting symptom. Increased physical activity should be expedited with the ra tional use of analgesics, corsets and walkers. Back braces are often not well VOL. 26, NO. 1 JANUARY/FEBRUARY 1976 39 Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) Bone Lesions Pathologic Fracture Palpable Plasmacytoma Hypercalcem ia 4 Pancytopenia 1@ Skeletal Destruction 4 Marrow Infiltration 1@ MALIGNANT PROLIFERATION OF PLASMA CELLS S Abnormal Proteins 0 Urine: MyelomaKidney Blood: Cryoglobulins Hyperviscosity BleedingDisorders Reduction of Normal Immunoglobulins S Infection Tissues: Amyloidosis Fig. 1. Common complications in multiple myeloma. tolerated. Radiation therapy is useful for disabling bone pain from pathologic fractures and is recommended for severe pain persisting after the first course of chemotherapy. Prompt radiotherapy to areas of cord compression will prevent the need for decompressive laminec tomy. Corticosteroids help prevent edema if emergency radiation therapy is administered to the spinal cord. Internal surgical fixation of long bone fractures assists in reducing pain and allowing ambulation. Sodium fluoride and cal cium continue to be under study for their role in increasing bone calcification and reducing bone pain. Certain metabolic complications must also be prevented or treated. Dehydra tion must be avoided and adequate hy dration is essential, since myeloma pa tients frequently have high calcium levels and increased excretion of Bence Jones protein. Hypercalcemia must be managed vigorously and is usually con trolled by a high fluid intake, increased physical activity, diuretics and corticos teroids. In previously untreated patients, alkylator-prednisone therapy should not bedelayed since it almost always reverses hypercalcemia. In disabled patients with drug-resistant myeloma, control of hypercalcemia is less likely, but Mithra mycin may provide brief relief. Hyperuricemia is managed by allopurinol. Short-term hemodialysis may be useful for severe renal failure, ei therdue to' ~myelomkaidney' ~amoryloi dosis; long-term hemodialysis has been continued in some patients with chronic uremia in remission. Symptomatic 40 CA"ACANCER JOURNAL FOR CLINICIANS Table 1. Multiple Myeloma Response Rates in Melphalan Treatment Programs Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) TreatmentNo. (months)Daily Rate TreatedRespoPnesrecent EvaluableMedianSurvival melphalan Intermittent meiphalan Intermittent melphalan + prednisone Intermittent melphalan + prednisone + procarbazine Intermittent melphalan + prednisone + procarbazine + vincristine23 54 132 226 12414 31 59 53 5915' 17 22 22 30 ~laArge fraction of these patients were subsequently treated with intermittent meiphalan prednisone when no responseto daily meiphalan was apparent. anemia is treated with packed red cell transfusions; androgens may be used in selected patients with chronic anemia who have adequate iron supply. Infec tion has not been successfully prevented with prophylactic gamma globulin. Evaluationof Remission Serial evaluations of myeloma protein levels are required to determine the ef fect of chemotherapy on tumor mass. Changes in myeloma protein production rate are calculated from: the myeloma protein concentration; the changing ca tabolic rate as related to the concentra tion of IgG proteins;6 the assumed or measured plasma volume.2 Simple com puter programs permit the rapid calcula tion of tumor mass change in individual patients.2 In the Southwest Oncology Group, reduction to less than 25 percent of the pretreatment serum rnyeloma pn) tein production rate (considered as 100 percent) indicates a oeresponse,afall to 25-50 percent signals oeimprove ment, and a reduction to only 50-100 percent of the initial value denotes oeno response. The level of abnormal serum protein is most precisely assessed by routine electrophoresis. Radial immun odiffusion measurements are helpful in evaluating tumor mass change only in those patients with marked reductions in IgA peaks. More sensitive techniques are needed to measure low myeloma protein levels in those 15 percent of treated patients with an apparent disap pearance of the serum peak. For patients with only Bence Jones protein excretion, the disappearance of abnormal protein is required to confirm a oeresponse.Bone marrow differen tials of plasma cell percentage are of lit tle value in assessing tumor mass change because of their low precision, com pared to abnormal protein quantitations, VOl 2 NO J~A1JUARYFEBPLIAR' 19@6 ~11 Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) F p r. changes in tumor mass in a patient receiving interrn@ttent courses of rnelphalan noun cr e@~Cde@ntr'p rm'ss,n oid chnh, it' r death and their poor correlation with other dis ease parameters. Clinical responses are usually of good quality and patients are able to resume most of their normal ac tivities. Unless there is persistent renal fail ure, the hemoglobin value increases to more than 10 grams percent; some pa tients also develop recalcification of lytic bone lesions7 or recovery of de pressed normal immunoglobulins 8 Nephelometric studies of serum have recently provided automatic and repro ducible assessments of normal immu noglobulin concentration in these pa tients. Chemotherapy(RemissionInduction) In 1958, Russian investigators reported that phenylalanine mustard was useful in myeloma. Clinical trials were initiated with the L-isomer of this drug (melpha Ian), and an intermittent schedule in maximal doses was evaluated by Berg sagel at M.D. Anderson Hospital, in collaboration with other members of the Southwest Oncology Group (SWOG). Bergsagel reported that disease remis sions were achieved in a large fraction of patients and significant survival pro longation first became evident.9 Between 1965-1972, the Southwest Oncology Group treated 559 patients 42 CA"ACANCER JOURNAL FOR CLINICIANS Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) with multiple myeloma using one of sev eral melphalan treatment programs in a series of controlled studies.*lO12 Re sponse rates and median survival times are summarized in Table 1. A higher frequency of response resulted from an intermittent melphalan schedule, com pared to a daily schedule, even though the total dose over a specific period was similar. The use of melphalan and pred nisone in combination enhanced the re sponse rate even further, so that about 55 percent of patients with evaluable trials achieved a 75 percent reduction in tumor mass. Serial changes in calculated intermittent courses of melphalan and prednisone repeated at four-week inter vals with periodic vincristine injections appears to provide the best initial treat ment for patients with multiple myeloma. both procarbazine and vincristine, was associated with the longest median sur vival time observed to date in patients with multiple myeloma (i.e., 30 months). 12 Thus, intermittent courses of melpha lan and prednisone repeated at four week intervals with periodic vincristine injections appears to provide the best initial treatment for patients with mul tiple myeloma. (Melphalan, 10 mg./m.2/day concurrently with predni sone, 60 mg./m.2/day for four days, and vincristine, 1 mg. intravenously every 14 days. Dose adjustments are made in accordance with blood counts and pa tient tolerance.) Other SWOG treatment combinations, that include adriamycin and cyclophosphamide are currently under evaluation for remission induction in these patients. tumor mass in a patient responding to melphalan-prednisone are shown in Fig. 2. Progressive relapse occurred despite continued therapy that included various investigational drugs. From 1968-1972, the value of adding procarbazine and vincristine to the mel phalan-prednisone regimen was studied. Procarbazine alone was active in several untreated myeloma patients; vincristine also reduced tumor mass, as shown by the further reduction of small myeloma protein peaks in some responsive pa tients. Unfortunately, there was no fur ther elevation of response rates follow ing the addition of procarbazine and yin cristine to the melphalan-prednisone combination. Although the use of pro carbazine did not improve survival, the quadruple drug combination, including * In addition to the author, the following medical centers and investigators participated in the SWOG trials summarized here, registering more than 75 percent of the patients: University of Arkansas Medical Center, Little Rock (Dr. A. Haut); Cleve land Clinic Foundation, Cleveland (Dr. J. Weick); Henry Ford Hospital, Detroit (Dr. R. Monto); Ohio State University College of Medicine, Columbus (Dr. S. Balcerzak); Scott and White Clinic, Temple (Dr. J. Bonnet). Chemotherapy (Remission Maintenance) The Southwest Oncology Group con ducted the first study on remission main tenance for multiple myeloma be tween 1969@7212@13Ninety-eight consecutive patients in remission after at least 12 months of chemo therapy were assigned to treatment regi mens either with: (A) continued melpha lan-prednisone; (B) 1,3-Bis (2- chloroethyl)-1-nitrosourea (BCNU) prednisone; or (C) no chemotherapy. More than 30 patients were placed in each maintenance group; more than 50 percent of each group have died. (Fig. 3.) Respondingpatientsreceivingindef inite melphalan-prednisone or BCNU prednisone had a higher frequency of pneumonia and herpes zoster. Patients relapsing without any chemotherapy had a high incidence of second remissions with resumption of melphalan-predni sone, but no patient relapsing on the BCNU-prednisone program responded to melphalan-prednisone. These results suggested that continued, indefinite al kylating agent chemotherapy after the first year may be more harmful than VOL. 26, NO. 1 JANUARY/FEBRUARY 1976 43 Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) Fig P Survivul of or ijomicirrf continued nnielpfraian-prednisonie her iy (dashed ne resporinive patieritn rnointa,riiI (sotH line) BCNU prrornsne after he tnt 12 norrtts or.. open n'ni ~uso)r no (demo helpful to myeloma patients in remis sion. A similar conclusion may apply to myeloma patients who are clinically sta ble but who have not responded in ac cordance with the SWOG myeloma pro tein criteria. Nevertheless, these studies justified the evaluation of other drugs during remission in order to reduce tumor mass maximally. Unfortunately, no further reduction occurred in mye loma protein peaks with cytosine arabin oside, methotrexate and hydroxyurea, although only modest doses were used in the ambulatory patients that were treated. Other maintenance treatment combinations are being evaluated by the SWOG, including azathioprine, BCG, BCNU and vincristine. Preliminary re sults are encouraging and a median sur vival time of almost three years is pro jected for currently treated patients. Thus, patients who achieve a 75 per cent reduction of myeloma proteins should not receive indefinite alkylating agent treatment since their clinical course appears to be just as stable with out any chemotherapy. This may lead to improved immunocompetence in pre venting both infection and tumor re lapse. Reinduction therapy with mel phalan-prednisone-vincristine is indi cated for patients on unmaintained re missions when a significant increase in myeloma protein level becomes evident. 44 CA"A CANCER JOURNAL FOR CLINICIANS Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) In myeloma patients resistant to melpha lan-prednisone, numerous drugs have been evaluated by the SWOG and found inactive, such as BCNU, cyclophospha gressive slowing of the growth rate with increasing tumor mass.'4 The extent of disease may also be assessed by a com bination of routine laboratory tests. The mide, podophyllin derivatives and ymca alkaloids. Adriamycin-prednisone was effective in about 15 percent of patients and one patient responded to bleorny cm. (This individual excreted 15 grams/day of Bence Jones protein despite six months of intermittent mel phalan-prednisone in maximal doses. After the administration of a total of 90 following represents a simple system now used in myeloma patients treated by the Southwest Oncology Group:'56 Hnohtumormass ( .2 10@ plasma cedsJm.2) Confirmed when any of the fol lowing is present: mg. bleomycin, abnormal protein disap peared from the urine for 12 months only to reappear and increase shortly before death.) - 1. Hemoglobin percent. <8.5 gms. .2. Corrected calcium >11.5 mg. percent.* Prognosis Marked variability in disease manifesta tions, clinical course and sensitivity to chemotherapy have prevented an accu rate estimate of prognosis in individual patients. No major disease parameters effecting the likelihood of remission have been identified, but several factors have now been shown to influence sur vival time. Thus, increasing degrees of anemia, hypercalcemia and renal failure are associated with progressively shorter lifespan. Very old patients and those producing IgA monoclonal proteins have a poorer prognosis than other pa @ tients. Early death, within one month after the first course of chemotherapy, still occurs in four percent of patients. An assessment of prognosis must con sider the myeloma tumor mass before 3.' Serum lgG peak >7 gms. percent or IgA peak >5 gms. percent. 4. Extensive lytic bone - lesions Low tumor mass ) 0.6 1012 piasma cells/rn.2) Confirmed when all of the fol lowing are present: 1. Hemoglobin >10.5 gms. percent. 2. Correctedcalcium<11.5 mg.percent.' Serum lgG peak <5 gms. percent or IgA peak <3 gms. percent. 4 None or few lytlc lesions chemotherapy and the magnitude of tumor reduction after treatment. The ab solute number of plasma cells in patients with myeloma may be derived from the Intermediate tumor mass (0.6-1.2 . 10@@plasma cells/rn.2) @ relationship between the in vitro produc tion rate of globulin per cell2 and the in other patients who do not for high or low tumor vivo turnover rate of myeloma globulin .@_..,~ in the plasma.6 Salmon has calculated that the oeaveragepatient with multiple myeloma has about 1012 cells/rn.2 This number is probably reached within three years, during which time there is pro *Coffected calcium (mg/lOU ml.) = serum Calcium (mg./100 ml.) s"erum albu min(g/100ml.) + 4.0 VOL. 26, NO 1 JANUARY/FEBRUARY 1976 45 Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) In a large number of myeloma pa ported the concept that progressive tu tients treated by the SWOG with alkyla mor growth was associated with a tor-prednisone combinations between steadily declining proliferating fraction. 1965-1972, about 45 percent had a The kinetics of tumor mass change oehighmass, about 30 percent an oein following chemotherapy were analyzed termediate mass, and about 25 percent by assuming the presence of varying a oelowmass. The response rate ranged proportions of oedrug-sensitiveand from 50-60 percent for patients in each oedrug-resistantcells. Thus the median group who received adequate trials, in half-time was about one month for the dicating that when large numbers of pa elimination of sensitive cells, as calcu tients are considered, there is a constant lated from the kinetics of initial tumor fractional cell-kill regardless of the ab reduction in responding patients. In solute cell number.'6 most cases, the entire population of sen Both the pretreatment tumor mass sitive cells would be eliminated within grade and the degree of remission had three years, assuming a constant expon a major influence on prognosis.16 Sur ential rate of cell destruction. Therefore, vival times were longest for those pa the duration of maintenance or rein tients with lower numbers of plasma forcement treatments with alkylating cells and proportionately shorter for chemotherapeutic agents could be indi those with a larger tumor mass after an vidualized from the initial rate of tumor optimum treatment regimen of melpha reduction. lan-prednisone. (Table 2.) Other studies have shown that the pro longation of survival in respondmg pa tients can be accounted for by the dura tion of remission.'7 These observations The clinical course of Waldenstrom's macroglobulinemia is highly variable with about 20 percent of patients not requiring chemotherapy for long periods. not only provide a more valid prognosis for individuals, but also form the basis for stratifying patients into different SWOG treatments according to tumor mass. In addition, they emphasize the importance of achieving a maximal re duction in absolute numbers of malig nant cells. After a maximum tumor reduction had been achieved with chemotherapy, responding patients showed varying du rations of a stable plateau in cell num ber. Most had evidence of relapse after less than one year of stability, due pri marily to the emergence of a resistant Cell Kinetics tumor population with a median dou In most patients responding to melpha bling time, during the early phases of lan-prednisone chemotherapy, an ap relapse, of about two months. This fig proximate one-log reduction in cell ure was much shorter than the six to 12 number has been associated with a short months calculated by Flobbs2and was plateau phase, preceding eventual re consistent with the short evolution of lapse of a resistant cell population. (Fig. human myeloma as suggested by 2.) During the period of remission, the Salmon 2,14 fraction of plasma cells labelled in vitro Of interest is that most patients ob with tritiated thymidine usually in served during relapse failed to demon creases. I8.@9 strate a slowing phase of tumor growth The change from a median 2.5 per before death. This emphasized the cent for untreated patients to a median marked variability in tumor growth; five percent for patients in remission some tumors with a high mass continued suggested that an increased growth frac to grow rapidly while others with a low tion had developed. These findings sup mass (localized or indolent) remained 46 CA"A CANCER JOURNAL FOR CLINICIANS Table2. Effect of Pretreatment Tumor Mass on Survival and Remission* DGergardeeeHoifghRIenmteisrsmloenTduiamtoerLowAll Mass Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) patients Unresponsive 50-100 25-49 Responsive 10-24 4<6(13021)*7*** 9 14 17 ( 8) 33(21)27 13 22 25 ( 9) 34(24)39 27 34 40(21) Each figure indicates median survival for all patients/group, indicating median remission duration for responders. with parentheses * * Percent.of control for serum peaks only. * All patients in this group showed dtsappearance of their serum peak. stable or showed slow growth for pro longed periods.' One can only speculate on the role of immunosurveillance or other factors in the regulation of growth patterns. Macroglobulinemia of Waldenstrom Waldenstrom's macroglobulinemia, a chronic lymphoprol iferati ye disorder, may cause lymph node enlargement, bone marrow infiltration by pleomorphic lymphoid cells and hepatosplenomeg aly. All patients have an increased pro duction of a monoclonal gamma globu lin of 1gM type. The major clinical and laboratory features of Waldenstrom' s macroglobulinemia are demonstrated in Fig. 4. Since the lymphocytes of pa tients with chronic lymphocytic leuke mia or certain lymphomas usually show evidence of monoclonal 1gM produc tion, these disorders should also be con sidered a monoclonal gammopathy of bone marrow-derived lymphocytes. In about four percent of patients with lym phoma and diffuse histologic infiltration of lymph nodes, the production rate was so high that a monoclonal 1gM peak was confirmed on serum electrophoresis .@ The clinical course of Waldenstrom's macroglobulinemia is highly variable with about 20 percent of patients not re quiring chemotherapy for long periods. Immunological manifestations, such as increased cold sensitivity or autoim mune hemolytic anemia, may dominate the clinical course. Treatmentof Complications As with multiple myeloma, optimum VOL 26, NO 1 JANUARY/FEBRUARY1976 47 Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) Lymphadenopathy Splenomegaly Chronic Lymphocytic Leukemia 4 Tumor Masses S Pancytopenia 1@ Marrow Infiltration 1@ Blood: MONOCLONAL LYMPHOCYTIC PROLI FERATION 0S Abnormal Proteins Reduction of Normal 0 Hyperviscosity Cold Agglutinins Bleeding Disorders Hemolytic Anemia Immunoglobulins S Infection Urine: Myeloma Kidney (rare) Fig. 4. Commoncomplicationsin monoclonalmacroglobulinemia. management includes the simultaneous control of complications and the reduc tion of tumor mass with chemotherapy. A hyperviscosity syndrome that may produce neurologic symptoms or an in creased bleeding tendency requires prompt plasmaphoresis. This may be conducted rapidly and efficiently with an IBM separator. Symptomatic levels of hyperviscosity are uncommon unless monoclonal 1gM peaks exceed five gm. percent. Anemia may require packed red cell transfusions, but a markedly in creased plasma volume may account for much of the apparent reduction in hemo globin or hematocrit. Hypercalcemia is rare since skeletal lesions are uncom mon; because the degree of Bence Jones proteinuria is usually low, renal failure is also infrequent. Patients with macro globulinemia usually do not have as marked a depression of normal immuno globulins as those patients with mul tiple myeloma. Chemotherapy with intermittent courses of leukeran and prednisone in maximally tolerated doses will reduce tumor mass by more than 50 percent in about 80 percent of adequately treated patients.4 (Chiorambucil is initiated in a dose of 8 mg./m2/day concurrently with prednisone, 40 mg./m.2/day for 10 days, and repeated at six to eight week intervals. Dose adjustments are made according to blood counts and patient tolerance.) Evaluation of Response Evaluation of remission is based pri marily on changes in monoclonal ma 48 CA"A CANCER JOURNAL FOR CLINICIANS Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) croglobulin production rate. As in mul tiple myeloma, serial determinations of the serum concentration of abnormal globulin and of measured plasma vol ume provide the most precise index of tumor mass reduction. Serial evalua tions of lymph node size, blood lympho cyte count and hemoglobin concentra tion are also helpful. Control of these overt clinical manifestations will usually occur with only a 50 percent reduction in tumor mass, as assessed from the pro tein data.4 Thus, oecompleteremis sions in chronic lymphoid cancers occur with relatively slight tumor reductions, emphasizing the need for more effective treatment of these disorders. The utility of other drug combinations must be evaluated in responding patients who have achieved a maximum reduction of tumor mass. The median survival time for a group of patients with macroglobu linemia was about three years,4 similar to survival of patients with multiple myeloma. Perspectives for Patient Care Plasma cell neoplasms are no longer considered rare diseases, and increasing numbers of patients are now being rec ognized. Optimum management re quires close collaboration between the private physician and a referral center familiar with this group of disorders. Specialized studies such as immunolec trophoretic typing, serial quantitation of normal and abnormal immunoglobulins and precise calculations of tumor mass change contribute substantially to im proved patient care. A high frequency of tumor response, marked degrees of re mission and remissions of long duration provide a better opportunity for longer survival times of good quality for many patients. Optimum control of initial complications, rational therapy for ad vanced and remission phases of disease, as well as the development of new chemotherapeutic agents for the treat ment of relapsing patients with tumor resistance are essential. References I. Conklin, R., and Alexanian, R.: Clinical classi fication of plasma cell myeloma. Arch. Intern. Med. 135:139-143, 1975. 2. Salmon, SE.: Immunoglobulin synthesis and tumor kineticosf multiplemyeloma. Semin. He matol.10:135-144,1973. 3. Axeisson, U.; Bachmann, R., and Hallen, I.: Frequency of pathological proteins (M-components) in 6,995 sera from an adult population. Acta. Med. Scand. 179:235-247, 1966. 4. Alexanian, R.: Monoclonal gammopathy in lymphoma. Arch. Intern. Med. 135:62-66, 1975. 5. Migliore, P.J., and Alexanian, R.: Monoclonal gammopathy in human neoplasia. Cancer 21:11271131, 1968. 6. Waldmann, TA., and Strober, W.: Metabolism of immunoglobulins. Progr. Allerg. 13:1-110, 1969. 7. Rodriguez, L.H., Finkelstein, lB.; Shullen berger, CC., and Alexanian, R.: Bone healing in multiple myeloma from meiphalan chemotherapy. Ann. tnt. Med. 76:551-556, 1972. 8. Alexanian, R., and Migliore, P. J.: Normal immunoglobulins in multiple myeloma: effect of melphalan chemotherapy. J. Lab. Clin. Med. 75:225-233,1970. 9. Bergsagel, D.E.; Sprague, CC.; Austin, C., and Griffith, KM.: Evaluation of new chemo therapeutic agents in the treatment of multiple mye loma. IV. L-Phenylalanine mustard (NCS-8806). Cancer Chemother. Rep. 21:87-99, 1962. 10. Alexanian, R. et al: Treatment for multiple myeloma: Combination chemotherapy with dif ferent melphalan dose regimens. J.A.M.A. 208:1680-1685, 1969. 11. Alexanian, R. et al: Combination chemo therapy for multiple myeloma. Cancer 30:382-389, 1972. 12. Alexanian, R.; Balcerzak, S.; Gehan, E. A.; Haut, A., and Hewlett, I. S.: Remission mainte nance therapy for multiple myeloma. Arch. Intern. Med. 135:147-152, 1975. 13. Alexanian, R.; Balcerzak, S.; Gehan, E.A.; Haut, A., and Hewlett, iS.: Unmaintained remis sions in multiple myeloma. Cancer Chemotherapy: Year Book Medical Publishers, 1975; pp. 155-171. 14. Sullivan, P.W., and Salmon, SE.: Kinetics of tumor growth and regression in IgG multiple myeloma. I. Clin. Invest. 51:1697-1708, 1972. 15. Dune, B.G.M., and Salmon. SE.: Clinical staging system for multiple myeloma. Cancer 36:842-854,1975. 16. Alexanian, R. et al: Prognostic factors in multiplmeyeloma. Cancer(InPress). 17. AlexanianR,.;BergsagelD,. E.;MiglioreP,. J.; Vaughn, W., and Howe, CD.: Melphalan then apyfor plasma cell myeloma. Blood 31:1-10, 1968. 18. Drewinko, B.; Brown, B.W.; Humphrey, R., and Alexanian, R.: Effect of chemotherapy on the labelling index of myeloma cells. Cancer 34:526531, 1974. 19. Salmon, SE.: Expansion of the growth fraction in multiple myeloma with alkylating agents. Blood 45;119-129, 1975. 20. Hobbs, JR.: Growth rates and responses to treatment in human myelomatosis. Brit. I. Haemat. 16:607-617, 1969. VOL. 26, NO. 1 JANUARY/FEBRUARY 1976 49