8
Plasma Cell Myeloma with D-Myeloma Protein (IgD Myeloma)* JOHN L. FAHEY, M.D., PAUL P. CARBONE, M.D., Bethesda, Maryland DAVID S. ROWE, M.D.? and ROLF BACHMANN, M.D. Birmingham, England Malmi;, Sweden Plasma cell myeloma distinguished by a serum D-myeloma protein has been found in many parts of the world and more than two dozen cases have been identified. Noteworthy observations are the high frequency (80 per cent) of D-myeloma protein with lambda-light chains (D-myeloma protein-type L) and the almost invariable presence of Bence Jones proteinuria. D-myeloma protein levels rarely reach high serum concentrations because of their rapid rate of catabolism. Detection of serum D-myeloma protein, therefore, may be more difficult than G- or A-myeloma proteins or WaldenstrSm’s macroglobulins. D-myeloma protein should be suspected in serums containing anomalous immuno- globulin which cannot be classified as G- or A-myeloma proteins, WaldenstrBm’s macroglobulins or Bence Jones proteins. Immunoelectrophoresis with specific anti- IgD serum permits identification of D-myeloma protein. D-myeloma protein occurs in less than 1 per cent of patients with multiple myeloma. One patient with serum G- and D-myeloma proteins is described. ‘The clinical features and course of illness in fifteen patients here summarized are similar to those in patients with other types of myeloma proteins. Response to mel- phelan or cyclophosphamide therapy has been reported in patients with D-myeloma protein. A NEW type of myeloma protein, D-myeloma protein, and its normal counterpart, immunoglobulin-D (IgD, rD), were discovered recently [7,2]. Since there are differences in the clinical characteristics of patients synthesizing M-macroglobulins from those synthesizing G- and A-myeloma proteins, we were anxious to learn if the clinical manifestations of disease in patients with D-myeloma protein differed in any significant way from those occurring in pa- tients with other types of myeloma proteins. The present st d u y was undertaken to assess (1) the clinical and morphologic features of illness in patients with D-myeloma protein, (2) the frequency of D-myeloma protein among pa- tients with plasma cell myeloma, (3) the geo- graphic occurrence of the disease, (4) the prob- lems that might affect recognition of D-mye- loma, and (5) the relationship, if any, of D-myeloma protein to prognosis and response to therapy. Data from fifteen patients with D-myeloma protein form the basis of the present report. METHODS D-myeloma protein was identified as electro- phoretically discrete increases of immunoglobulin containing only delta (6) heavy chains and either kappa (K) or lambda (X) light chains. A minimum serum IgD concentration was not arbitrarily estab- lished as a prerequisite for identification of IgD myeloma protein for reasons which will be discussed. Immunoelectrophoresis was performed on ionagar plates in veronal buffer using polyvalent immuno- globulin antiserum as well as specific rabbit or goat antiserums for detection of human IgG (y chains), IgA ((r chains), IgM (II chains), IgD (6 chains), and for * From the Immunology and Medicine Branches, National Cancer Institute, Bethesda, Maryland 20014, the Department of Experimental Pathology, University of Birmingham, England, and the Department of Clinical Chem- istry, General Hospital, MalmG, Sweden. Requests for reprints should be addressed to John L. Fahey, M.D., Immunology Branch, National Cancer Institute, Bethesda, Maryland 20014. Manuscript received September 23, 1967. t Present address: WHO International Reference Centre for Immunoglobulins, Institut de Biochemie, 21 rue du Bugnon, Lausanne, Switzerland. VOL. 45, SEPTEMBER 1968 373

Plasma cell myeloma with D-myeloma protein (IgD myeloma)

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Page 1: Plasma cell myeloma with D-myeloma protein (IgD myeloma)

Plasma Cell Myeloma with D-Myeloma

Protein (IgD Myeloma)*

JOHN L. FAHEY, M.D., PAUL P. CARBONE, M.D.,

Bethesda, Maryland

DAVID S. ROWE, M.D.? and ROLF BACHMANN, M.D.

Birmingham, England Malmi;, Sweden

Plasma cell myeloma distinguished by a serum D-myeloma protein has been found in many parts of the world and more than two dozen cases have been identified. Noteworthy observations are the high frequency (80 per cent) of D-myeloma protein with lambda-light chains (D-myeloma protein-type L) and the almost invariable presence of Bence Jones proteinuria.

D-myeloma protein levels rarely reach high serum concentrations because of their rapid rate of catabolism. Detection of serum D-myeloma protein, therefore, may be more difficult than G- or A-myeloma proteins or WaldenstrSm’s macroglobulins. D-myeloma protein should be suspected in serums containing anomalous immuno- globulin which cannot be classified as G- or A-myeloma proteins, WaldenstrBm’s macroglobulins or Bence Jones proteins. Immunoelectrophoresis with specific anti- IgD serum permits identification of D-myeloma protein. D-myeloma protein occurs in less than 1 per cent of patients with multiple myeloma. One patient with serum G- and D-myeloma proteins is described.

‘The clinical features and course of illness in fifteen patients here summarized are similar to those in patients with other types of myeloma proteins. Response to mel- phelan or cyclophosphamide therapy has been reported in patients with D-myeloma protein.

A NEW type of myeloma protein, D-myeloma protein, and its normal counterpart,

immunoglobulin-D (IgD, rD), were discovered recently [7,2]. Since there are differences in the clinical characteristics of patients synthesizing M-macroglobulins from those synthesizing G- and A-myeloma proteins, we were anxious to learn if the clinical manifestations of disease in patients with D-myeloma protein differed in any significant way from those occurring in pa- tients with other types of myeloma proteins. The present st d u y was undertaken to assess (1) the clinical and morphologic features of illness in patients with D-myeloma protein, (2) the frequency of D-myeloma protein among pa- tients with plasma cell myeloma, (3) the geo- graphic occurrence of the disease, (4) the prob- lems that might affect recognition of D-mye-

loma, and (5) the relationship, if any, of D-myeloma protein to prognosis and response to therapy. Data from fifteen patients with D-myeloma protein form the basis of the present report.

METHODS

D-myeloma protein was identified as electro- phoretically discrete increases of immunoglobulin containing only delta (6) heavy chains and either kappa (K) or lambda (X) light chains. A minimum serum IgD concentration was not arbitrarily estab- lished as a prerequisite for identification of IgD myeloma protein for reasons which will be discussed.

Immunoelectrophoresis was performed on ionagar plates in veronal buffer using polyvalent immuno- globulin antiserum as well as specific rabbit or goat antiserums for detection of human IgG (y chains), IgA ((r chains), IgM (II chains), IgD (6 chains), and for

* From the Immunology and Medicine Branches, National Cancer Institute, Bethesda, Maryland 20014, the Department of Experimental Pathology, University of Birmingham, England, and the Department of Clinical Chem- istry, General Hospital, MalmG, Sweden. Requests for reprints should be addressed to John L. Fahey, M.D., Immunology Branch, National Cancer Institute, Bethesda, Maryland 20014. Manuscript received September 23, 1967.

t Present address: WHO International Reference Centre for Immunoglobulins, Institut de Biochemie, 21 rue du Bugnon, Lausanne, Switzerland.

VOL. 45, SEPTEMBER 1968 373

Page 2: Plasma cell myeloma with D-myeloma protein (IgD myeloma)

374 IgD Myeloma-Fuhey et al.

TABLE I

LABORATORY VALUES AT THE TIME OF DIAGNOSIS OF PLASMA CELL MYELOMA

Age Survival Per cent Blood Serum Abnormal

(ma) Hemo- Plasma Serum Urea Total Globulins Qualitative Case

‘,‘n’;l Diagnosis globin Cells in Calcium Nitrogen Protein Proteinuria Bence Jones

NO. Patient Sex to Death (gm.%) Marrow (mg.%) (mg.%) (pm.%) gm.% Mobility (gm./24 hr.) Test

8 A.A. (S)

9 H.L. (S) 10 F.H. (HK)

11 H.S. (J) 12 L.P. (US)

13 L.H. (US) 14 J.B. (US)

15 H.M. (S)

S.J. (N) J.F. (N) T.N. (N)

E.M. (GB)

B.M. (GB)

J.D. (US)

A.M.M. (S)

58,M 15 8.5

66,M 34 13.5

59,F 16 lo/29

42,F 51 10.2

45,M 22+ 10.3

40-M 18 6.1

43;F 34 8.2

65,M 27 9.4

55,F 51 9.1

53,M 31 9.7 48,M 3f 8

41,M 24+ 15.2

47,F 18+ 18.5 62,M 5 12.8 50,M 4f 10.2

20-80

65

95t <2

10-15

ND

Large

Large

34

45

54

13

1

19 14.8 32

11

11.3

10.2

9.0 9.9

9.8

9.0

12.8

11.4

10.2

10.3 . . . 9.3

21

16 14

41

58 42

NPN

36 NPN

156 55

54

19

21

8.7 4.3

6.6 NAP

6.4 B 6.7 ND

6.6 NAP

9.1 3.9

7.6 1.4

3.7 5.9

ND

4f ND

8.7 3.2 ND

7.0

7.0 10.4

N N 6.6 9.1

1.2

2.3

4.0

NAP NAP

NAP

0.9

l-2

3+ 6.6 ND

ND

15

NOTE: (N) = NIH; (GB) = Great Britain; (US) = United States; (S) = Sweden; (HK) 5 Hong Kong; (J) = Japan. NPN = nonprotein

nitrogen. ND = not performed. NAP = no abnormal peak.

K and h light polypeptide chains [2,3]. Quantitative determination of each immunoglobulin class was con- ducted in antibody-in-agar gel diffusion plates [4,5].

Serums were screened for increase of IgD globulin by Ouchterlony tests employing specific anti-IgD antiserum. Normal serum with a high IgD level and a serum with known D-myeloma protein were used

as reference materials. Serums which had more than

0.1 mg. per ml. IgD were tested for D-myeloma pro- tein by immunoelectrophoresis using specific anti- IgD antiserum.

Clinical and biochemical data were derived from three patients studied at the Clinical Center of the National Institutes of Health and twelve patients studied elsewhere, details of whom were generously made available to us.

ANTI-C.A.M.K.1 ANTI - ANTI -IgD

FE. 1. Immunoelectrophoretic identification of D- myeloma protein. Immunoelectrophoresis was carried out with a polyvalent antiserum reacting with G (y), A (a), M (EC), K (K) and L (X) determinants or with an anti- serum prepared against the D-myeloma protein from a patient (S.J.). The multiple IgD components seen in this patient’s serum reflect partial breakdown of the D- myeloma protein with an anodal (Fc) piece and cathodal (Fab) piece in addition to the intact D-myeloma protein.

Each patient having a serum D-myeloma protein was found to have multiple myeloma as defined by the presence of more than 10 per cent malignant plasma cells in the bone marrow, or jaw tumor (L.H.) and other symptoms and signs of plasmacytic malignancy. The analysis of clinical and laboratory features was similar to that reported previously [6].

RESULTS

Characteristics of Serums Containing D-Myeloma Protein. Serum total protein levels were ele- vated (greater than 8 gm. per cent) in only five of fifteen patients (Table I). Zone electrophoresis disclosed discrete anomalous peaks in most but not all cases. Serum from five patients showed no anomalous peak on paper electrophoresis. How- ever, immunochemical studies of these cases revealed D-myeloma protein which had not been distinguishable from the normal beta globulin peak on zone electrophoresis.

Immunoelectrophoresis with specific anti- IgD serum permitted identification of serum myeloma protein (Fig. 1). In each case the protein had restricted electrophoretic mobility and either kappa or lambda light chain de- terminants. Immunoelectrophoretic testing with polyvalent and specific antiserums allowed ready distinction of D-myeloma proteins from G-mye- loma proteins, A-myeloma proteins, M (Wal- denstrom)-macroglobulins and Bence Jones pro- teins (Fig. 2).

Immunoelectrophoresis with polyvalent anti- serum reacting with globulins G, A and M and

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Page 3: Plasma cell myeloma with D-myeloma protein (IgD myeloma)

IgD Myeloma-Fahey et al.

with kappa and lambda light chains occa- sionally failed to reveal an anomalous im- munoglobulin, as in the serum from L.H. (Fig. 1). More frequently (Fig. 1, S. J., J.B., L.P.) an anomalous immunoglobulin was apparent, with a reaction pattern similar to that observed in serum from patients with Bence Jones pro- teinemia [7]. Sometimes the anomalous im- munoglobulin detected with polyvalent anti- serum was a serum Bence Jones protein and the D-myeloma protein was detected only when specific anti-D serum was used (serum from L.P., Fig. 1). In one sample (T.N., Fig. 1) both D- and G-myeloma proteins and Bence Jones protein were present in the serum. This unusual case is further discussed subsequently.

D-myeloma protein is easily altered in stored serum and may show multiple components. This change had occurred in three serums (S. J., J.D. and H.M., Fig. 1). In these serums the D-myeloma protein had split into a more anodal Fc piece and a cathodal Fab piece. The Fc and Fab pieces, as well as intact D-myeloma protein, were seen in one serum sample (S.J.), but only intact myeloma protein and faster migrating Fc piece were detected in two others

POLYVALENT ANTISERUM NORMAI

D-MI

G-MI

A-MI

W-Macrc

BJ

NORMAL

FIG. 2. Immunoelectrophoretic comparison of serums with different classes of anomalous imnluno,gloh~~lins. Left column: polyvalent antiserum reacting with y, o(, p, K and X determinants is used in the troughs. Kqht column: antiserum reacting specifically with delta ch;iin (IgD) is used in the troughs.

(J.D. and H.M.). It is probable that no intact D-myeloma protein remained in one serum (E.M., Fig. 1) and that only the Fc piece from the D-myeloma protein was detected.

Most (80 per cent or sixteen of twenty D-myeloma proteins) were found to have light

TABLE II

SERUM IMMUNOCLOBULINS IN PATIENTS WITH D-MYELOMA PROTEIN

Light-Chain of D-Myeloma

Serum Immunoglobulin Levels (mg./ml.)

Patient Protein IgG kM k” Case No.

Normal 1 2 3 4 5 6 7 8 9

10 11 12 13 14 15 16 17 18 19 20

12.4 2.8 1.2

3.6 6.36 0:;; 18.0 0.3 0.1 7.2 0.83 0.36

4.8 0’.2j 0:;; . . . .

0.03 S.J. J.F. T.N. E.M. B.M. J.D. A.M.M. A.A. H.L. F.H. H.S. L.P. L.H. J.B. H.M. C.E. Ba Pa Ni La Go V.G. J.M. M.S.

Lambda Lambda Lambda Lambda Lambda

Kappa Lambda Lambda Lambda

Kappa Lambda Lambda

. . . Lambda Lambda Lambda

Kappa Lambda Lambda Lambda Lambda

Kappa Lambda Lambda

2:;

3.; O'.;! 0:;; 3.5 0.23 0.22 6.5 0.7 0.22 3.1 1.05 0.16

.

2:0 0.84

0.8

0:i‘i 3:, 0.16 33.0 0.075 2.1

. . .

‘ii 5.2 3.7

d.i.2 0.97 0.21

. . 1.6 0142 0.83 0.18

7.2 5.6 21

22 . . . . 23 24

. . . . . . . . .

VOL. 45, SEPTEMBER 1968

Page 4: Plasma cell myeloma with D-myeloma protein (IgD myeloma)

IgD Myeloma-Fahy et al.

&JD MYELOMA: SEPHAOEX G 200 CHROMATOGRAPHY Clinical Data. Ciinical summaries of fifteen patients with D-myeloma protein are given in Tables I and III. Of this group of patients, ten (67 per cent) were male, and the median age was fifty-three. The median time in months from the onset of symptoms to diagnosis was two months.

0.8

UG m&/ml.

0.4

0

2.0

1.0

I% 0 IO 20 30 40

TUBE NUMBER

FIG. 3. Sephadex G200 chromatography of serum from a patient (T.N.) containing G- and D-myeloma proteins; 3 ml. of serum was separated on a 4 by 46 cm. column of Sephadex G200 equilibrated with 0.2 sodium chloride, 0.2M pH8 tris hydrochloride. The immunoglobulin con- tent of effluent fractions was determined by quantitative radial diffusion technics with antibody in agar. The ter- minal peak was identified as Bence Jones protein, type L.

chains of antigenic type L in a series of twenty serums in which the light polypeptide chains of the D-myeloma protein could be typed (Table II). The remainder were type K.

Quantitative measurement of the other serum immunoglobulins revealed that the serum IgG, IgA and IgM levels were reduced in serums with D-myeloma proteins (Table II). Serum albumin levels also were low in the serums when these were measured.

G- and D-Myeloma Proteins in One Patient. One patient (T.N.) had both G-myeloma and D-myeloma proteins in the serum. The presence of two anomalous serum immunoglobulins was evident on immunoelectrophoresis in Figure 1 (left row). These represent G-myeloma protein and lambda-Bence Jones protein. The D-mye- loma protein is seen in Figure 1 (center row). By means of Sephadex G200 chromatography (Fig. 3) it was possible to separate the G- and D-myeloma proteins. Both had light chains of lambda type. The clinical features of this case (Case 3, Table I and III) were not remarkable.

Major features of the disease were bone pain, osteolytic bone lesions, anemia, infection, Bence Jones proteinuria and renal insufficiency. On admission, nine of the fourteen patients had a performance status [6] of 2 or less which in- dicated that patients were symptomatic enough to spend part of the day in bed. Four of the fourteen patients were bedridden at the time of diagnosis.

Four patients had normal hemoglobin levels (>12 gm. per cent) and four of the patients had hemoglobin levels of 9 gm. per cent or less at the time of diagnosis (Table I). Platelet counts were usually normal. Only one patient had thrombo- cytopenia. The leukocyte count ranged from 2,900 to 10,100 per cu. mm.

Bone marrow examination revealed increased numbers of plasma cells in all but two patients. Slides of six bone marrow aspirates or biopsy material were available for review by Dr. George Brecker who noted a wide range of malignant plasma cell forms in several cases; there was no cell type or pattern of marrow cell distribution that seemed to be characteristic of patients with D-myeloma protein.

Numerous small osteolytic lesions were fre- quently seen on roentgenographic examination of the bones. Osteoporosis without osteolytic lesions was noted in two patients. Serum calcium values were normal except in one patient who had two episodes of clinically evident hyper- calcemia.

Bence Jones proteinuria was noted in all fourteen patients tested. Blood urea was greater than 30 mg. per cent in six patients.

Serious bacterial infection occurred in four patients. Herpes zoster infections were noted in two additional patients.

Therapy with phenylalanine mustard, cyclo- phosphamide, urethane, prednisone or x-ray was given to ten patients. Objective responses were recorded in nine patients, most frequently with the use of either phenylalanine mustard or cyclophosphamide. The median survival from the time of diagnosis to death was twenty-four months (range three to fifty-one months). Ten of the fifteen patients have died. The most com-

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IgD Myeloma-Fahey et al. 377

TABLE III CLINICAL DATA ON PATENTS WITH D-MYELOMA PROTEIN

Case Skeletal No. X-Ray Reports

Perform- ance

Status Therapy

1 Osteoporosis 2

2 Osteoporosis, small areas 1 of lytic lesion

3 Multiple small lytic areas, 4 spinal fracture, multiple rib fractures

4 Skull normal, vertebral 4 compression fracture

5 Widespread osteolytic 3 lesions, vertebral collapse

6

8

9

10

11

12

13 14

15

Multiple rib fractures, _ compression spine, small skull lesions

Multiple osteolytic small lesions, compression fracture

Small osteolytic lesions- skull ; compression fracture of spine, fracture of ribs

Osteoporosis, no osteolytic lesions

Pathologic fracture of ribs, smalI osteolytic lesions of skull, no spine lesions

Small osteolytic lesions of skull, ribs, femur

Osteolytic lesions of skull, ribs, peIvis

No data No abnormalities, old

fracture of spine

Osteolytic lesions of skull, ribs, vertebrae

1

X-ray,* L-phenylalanine mustard, prednisone, cyclophosphamide

L-phenylalanine mustard, x-ray

L-phenylalanine mustard, prednisone

4

1

Urethane, x-ray, cyclophosphamide,* L-phenylalanine mustard

L-phenylalanine mustard*

2 L-phenylanine mustard

1 Testosterone, cyclophosphamide*

4

2-3

Cyclophosphamide* None Alive

2

1

X-ray, phenylalanine mustard, (back pain relief)

No data X-ray, chlorambucil, *

prednisone, proteinuria decreased

PAM-no response

L-phenylalanine mustard,* corticosteroids

Urethane,* x-ray,* prednisone

Corticosteroids

Bacterial Infections

During Clinical Course Cause of Death

Multiple myeloma, extensive extramedullary plasmacytosis

Pneumonitis, Two hypercalcemic episodes, moniliasis mild azotemia, multiple

myeloma, steroid induced infection

. Multiple myeloma, renal insufficiency, cerebral vascular accident

Herpes zoster Multiple myeloma, terminal bronchopneumonia

Herpes zoster Alive

Acute bacteremia, amyloidosis, retrobulbar tumor

Broncho- Multiple myeloma pneumonia

None

Urinary tract Multiple myeloma, uremia, infection hemorrhage, plasma cells

in lymph nodes Paronychia Renal failure, anemia,

multiple myeloma

None Alive; hypercalcemia, responded to steroids

. Urinary tract Died, renal failure

infections

Acute Alive pharyngitis

* Implies that patient had a beneficial clinical effect as ju edged by patient’s physician

mon causes of death in these patients were in- fection or renal insufficiency. All had extensive myelomatosis and one had amyloidosis.

Geograjhic Distribution and Frequency of D-Mye- loma Protein. Patients with D-myeloma protein come from many parts of the world. Patients from North America, Europe, Israel, Japan, Hong Kong and New Guinea are included in

VOL. 45, SEPTEMBER 1968

this and in other reports [g-12] of D-myeloma. At present there is no evidence for geographic or racial restriction of this type of plasma cell myeloma and cases have been identified in Caucasian and mongoloid (Chinese and Japa- nese) subjects.

D-myeloma protein occurs relatively in- frequently among patients with plasma cell

Page 6: Plasma cell myeloma with D-myeloma protein (IgD myeloma)

378 IgD Myeloma-Fahey et al.

TABLE IV

COMPARISON OF CLINICAL AND LABORATORY FEATURES OF PATIENTS WITH PLASMACYTIC MYBLOMA

BY TYPE OF PROTEIN PRODUCED

Protein Abnormality

(No. of Patients)

IgG IgA

No Serum All Patients Bence Jones Protein Ig”

Data (63) (18) (9) (14) (15)

(NCI,ll;;-1964) *

Median (yr.) age 60 60 57 51 51 59 Range 41-78 38-71 SO-67 37-58 40-66 38-78

Male/female 27/36 13/5 5/4 4/l 0 1 o/5 53/59 Median survival (mo.) diagnosis ten death

Performance status 2 2.0 $63 (44%) $18 (65%) $9 (44%) $14 (64%) :414 (64%) z/112* (51%)

Initial hemoglobin <9.0 pm.%

Initial blood urea &ogen

20/63 (32%) 7/18 (39%) 6/9 (67%) 3/14 (21%) 4/14 (28%) 40/112* (21%)

> 30 mg.% 9/63 (14%) 6/18 (33%) 7/9 (78%) 4/14 (29%) 5/14 (35%) Initial serum calcium 2 12x mg.%

28/112* (25%) 5/63 (8%) 8/18 (47%) 3/9 (33%) 4/14 (29%) l/14 (7%) 22/l 12* (20%)

Bence Jones excretion, no. of patients/total 21/62 (34%) 3/16 (19%) 9/9 (lOO%‘o) 5/13 (38.5%) 14/14 (100%) 38/100 (38%)

* Includes eight patients who had no serum available for testing.

myeloma. Of 104 patients with plasma cell myeloma seen at the National Cancer Institute [6], D-myeloma protein was found in three (2.9 per cent). In a series of 625 serums obtained from patients with myeloma referred to the NCI-Immunoglobulin Reference Center, ten contained D-myeloma protein (1.5 per cent); but if serums specifically referred because of a suspicion of D-myeloma protein are excluded, the frequency is 0.2 per cent. In a series of 1,408 serums tested in Sweden at the MalmG Hos- pital [8] the frequency of D-myeloma protein was 0.6 per cent.

COMMENTS

Recognition of D-Myeloma Proteins. Factors that contribute to the difficulties of recognizing D-myeloma proteins are (1) relatively low serum levels, (2) their relatively fast electrophoretic mobility which often means they are included in the normal beta globulin peaks with con- sequent difficulty in detecting a characteristic discrete myeloma protein peak, and (3) the re- quirement for specific antiserums for immuno- globulin D (IgD) .

The serum D-myeloma protein levels typically are lower than the anomalous protein level in serums with G- or A-myeloma proteins or Waldenstrbm’s macroglobulins. The serum levels of D-myeloma protein varied from 0.8 to 33 mg. per ml. (Table II).

The relatively low serum D-myeloma protein levels appear to be a direct result of the rapid rate of IgD catabolism. IgD molecules in the body are catabolized at the fractional rate of about 26 per cent per day [73]. This catabolic

rate is faster than that of the other 7S immuno- globulins. IgG and IgA molecules of the body are removed at rates of 3 to 6 per cent and 10 to 15 per cent per day, respectively. To achieve serum levels which can be detected as discrete components on electrophoresis, relatively large amounts of D-myeloma protein must be synthe- sized each day because of the rapid rate of IgD catabolism. For example, D-myeloma protein must be synthesized at rates approximately three times greater than that required for G-myeloma protein for each myeloma protein to reach the same serum concentration [ 731.

Immunoelectrophoresis with specific anti- IgD serum permits identification of D-myeloma protein (Fig. 1 and 2). Polyvalent antiserum prepared against whole human serum usually fails to disclose the presence of IgD. Antiserum reacting specifically with immunoglobulin G, A or M does not detect D-myeloma protein. Polyvalent antiserum reacting with immuno- globulins G, A and M and with kappa and lambda light chains frequently but not always indicates the presence of an anomalous immuno- globulin. Specific anti-IgD serum, however, is required to identify the D-myeloma protein. D-myeloma protein characteristically is eluted from Sephadex G200 columns prior to IgG molecules. This is shown clearly in Figure 3 which is representative of our experience with IgD in normal serum [Z] and in six serums from patients with D-myeloma protein.

Comparison of Disease Associated with D-, G- and A-Myeloma Proteins. The clincial and labora- tory features of the patients with D-myeloma protein were compared (Table IV) with the

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IgD Myeloma-FahPy et. al.

characteristics of 112 patients with myeloma admitted to the Clinical Center between 1953 and 1964 [6]. Bence Jones proteinuria, noted in all our patients, was the most striking finding. Hobbs et al. [9] also reported this in six patients, two of whom are included here. The frequency of Bence Jones proteinuria is lower in patients with G-myeloma (35 per cent) and A-myeloma (20 per cent) proteins [6]. Not all patients with D-myeloma protein have Bence Jones pro- teinuria, as was convincingly demonstrated in one patient by Dr. C. A. Alper [74].

The median age for patients with D-myeloma protein was fifty-one years; the only other group in which the median age was as low consisted of the patients with plasma cell myeloma who had no serum protein abnormalities. The male to female ratios were higher in the patients with D-myeloma (ten of fifteen being male) and A-myeloma proteins (thirteen of eighteen being male) than in the others (Table IV). Survival from the time of diagnosis was longest for the patients with D-myeloma protein, being twenty- four months. The median survival for all myeloma patients was eighteen months. Sixty- four per cent of the patients with D-myeloma protein had performance status equal to or greater than 2. Patients with A-myeloma protein were similarly incapacitated but patients with G-myeloma or Bence Jones proteins tended to have better performance. The initial hemoglobin values and blood urea nitrogen levels in the pa- tients with D-myeloma protein were similar to those in the other groups, except that the pa- tients whose only serum abnormality was a Bence Jones protein had significantly more anemia and higher blood urea nitrogen levels than the others. There was a relatively low in- cidence of hypercalcemia in patients with D-myeloma protein.

Bence Jones Protein and Lambda Light Chain

Associations. Malignant plasma cells are the source of the Bence Jones proteins occurring in multiple myeloma [ 75,761 and the high fre- quency of Bence Jones proteinuria in patients with D-myeloma protein reflects a feature com- mon to most of the plasma cell tumors producing D-myeloma protein. Askonas and Williamson [77] have indicated that the malignant plasma cells of a mouse tumor producing G-myeloma protein contain a pool of free light chains and that these light chains combine with gamma heavy chains to facilitate separation of heavy chain from the ribosome preparatory to release

var.. 45, SEPTEMBER 1968

of the G-myeloma protein molecule. If a similar mechanism operates in plasma cell tmnors with D-myeloma protein, it may be that light chains are formed in great excess of delta hcitvy chain or in excess of the capacity of the cell to com- bine light chain with delta chain in these tumors. Further study of this interesting phenomenon is warranted.

The high frequency (83 per cent) of lambda- type light chains in D-myeloma protein is in in- teresting contrast to their lower frequency in other myeloma proteins. In a large series of myeloma and macroglobulinemic serums [ 78,791 lambda light chains (type L) were found in only 20 per cent of Waldenstrom’s macroglobulins, 35 per cent of G-myeloma protein, 53 per cent of A-myeloma protein and 43 per cent of Bence Jones protein. Thus the high frequency of myeloma proteins with lambda light chains (type L) sets the D-myeloma protein apart from the other anomalous immunoglobulins. This observation may be related to the genetic regulation of the type of light chains produced by immunoglob- ulin-D synthesizing cells or to features of im- munoglobulin structure; for example, delta chains may have configurations which pref- erentially combine with lambda chains, or the light chains (lambda or kappa) which combine with delta chains may have distinctive features.

Acknowledgment: We are grateful to the fol- lowing physicians who generously made avail- able clinical information and serum: Prof. Jan Waldenstrom, Malmo, Dr. C.-B. Laurel& Malmo, Dr. Hans Krook, Vanersborg and Dr. Sven Nilson, Kristianstad, Sweden; Dr. G. P. Clein, Cambridge and Dr. J. R. Hobbs, London, England ; and Dr. William J. Hammock, Birmingham, Dr. G. E. Cartwright, Salt Lake City and Dr. Paul K. Hamilton, Denver, United States and Dr. David Todd, Hong Kong; and Prof. M. Murakami and Dr. F. Teramura, Kanazawa, Japan.

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