Case History

A 54-years-old female, with known history of hypertension, presented with low back pain. She was incidentally found to have anaemia with haemoglobin of 6.6 g/dL. She also complained of tiredness and palpitations.

Physical examination revealed pallor only and was otherwise unremarkable.

Complete blood picture showed: haemoglobin 6.6 g/dL, white cell count 7.3 x 10⁹/L and platelets 86 x 10⁹/L. ESR was raised to 121 mm/hr. The albumin to globulin ratio was reversed at 38 to 41 g/L. Immune marker study included RF and ANF was negative. Upper endoscopy was normal. Ultrasound abdomen revealed a slightly prominent liver but otherwise unremarkable.

Bone marrow aspirate was dry tap but trephine biopsy showed markedly hypercellular marrow which was diffusely replaced by sheets of discohesive mildly pleomorphic tumour cells containing eccentrically situated, vesicular nuclei and granular, amphophilic cytoplasm. Immunohistochemical stains showed the tumour cells were negative for CD45 (leucocyte common antigen), myeloperoxidase, cytokeratin, neuroendocrine markers (chromo-granin and synaptophysin) and S100 protein. They were also negative for choroacetate esterase histochemically. The overall features were consistent with haematolymphoid malignancy, and myeloma had to be excluded in view of the morphology and the negativity towards CD45.

Another bone marrow examination was performed. The peripheral blood smear showed leucoerythroblastic blood picture with occasional plasmacytoid lymphocytes seen (Figure 1). Bone marrow aspirate was again a dry tap. Imprints showed a few poorly-spread yet markedly hypercellualr particles. The background showed predominantly small to medium-sized lymphoid cells with significant plasmacytoid differentiation (Figure 2). There was no obvious increase in blasts. Trephine biopsy revealed markedly hypercellular marrow with diffuse replacement by small to medium-sized abnormal lymphoid cells (Figures 3 & 4).

Figure 1. Peripheral blood film	Figure 2. Imprint

Figures 3 & 4. Trephine biopsy sections

Further immunophenotyping on ficoll preparation of marrow blood using APAAP technique revealed a monocytic population of lymphoplasmacytoid cells with expression of CD38, IgD and lambda light chains. (Figures 6, 7, 8 & 9)

Figure 6. Ficoll preparation of bone marrow showing lymphoplasmacytoid cells	Figure 7. CD38 staining
Figure 8. IgD staining	Figure 9. Lambda light chain staining

Immunology results

Figure 10: Serum protein electrophoresis of the patient (lane 8), showing M-band that was located slightly anodal to that found in another myeloma patient (lane 4).

(A)	(B)
Figure 11: Immunofixation test. A) Negative staining for IgG, IgA and IgM. B) The paraprotein is documented as IgD/l.

Diagnosis

IgD lambda multiple myeloma.

Clinical course

Chemotherapy (VAD regimen) was started. She achieved complete remission and interferon maintenance was given.

Trephine biopsy after treatment revealed findings that were consistent with multiple myeloma with good control after chemotherapy. The marrow was normocellular and granulopoiesis was active with full maturation noted. Erythropoiesis was also active and megakaryocytes were reduced in number. No obvious increase in plasma cells was noted. (Figure 12)

Figure 12. Trephine biopsy section (post chemotherapy)

The patient presented with low back pain again after a remission of 2 years.

Bone marrow biopsy at this juncture revealed markedly hypercellular marrow that was diffusely infiltrated by sheets of abnormal small to medium-sized mononuclear cells (Figure 13), consistent with frank relapse of her disease. Normal haemopoiesis was markedly reduced.

Figure 13. Trephine biopsy section (relapse)

MRI spine thus performed showed focal myeloma deposits in left T11. Bone scan performed revealed increased uptake over L1, patchy uptake over skull, left 4th rib and thoracolumbar spine, most probably due to myelomatosis involvement.

Palliative radiotherapy covering T9-12 (3Gy x 8) was given. Since two HLA matched sisters were found, a mini-allograft was planned.

Before BMT, a reassessment bone marrow examination was performed. The aspirate was aparticulate while the trephine biopsy sections showed a normocellular marrow with a fibrotic background. Apart from normal haemopoiesis, abnormal plasma cells in clusters were noted. They are morphologically immature showing large cell size, fairly open chromatin, multiple small nucleoli and scanty basophilic cytoplasm. Some showed eccentric nuclei and an occasional Dutcher body was noted (Figures 14 & 15). Further immunophenotyping of these abnormal plasma cells showed IgD expression and lambda light chain restriction (Figure 16). Overall, the findings were consistent with myeloma not in remission but with morphological evidence of disease progression.

Figures 14 & 15. Trephine biopsy sections (Pre-BMT)

Figure 16. Lambda light chain staining on trephine biopsy

Discussion

Immunoglobulin D (IgD) multiple myeloma (MM) is a rare disorder, usually with an aggressive course and a poor prognosis. It occurs in fewer than 2% of patients with MM. There is a predisposition of males and the mean age at presentation is younger than average for the disease. The main presenting features are bone pain, gastrointestinal discomfort, weight loss and general malaise. A high frequency of renal function impairment and hypercalcaemia is observed in patients. The common finding for IgD MM is small or no monoclonal spike seen on serum electrophoresis together with heavy light-chain proteinuria. Thus IgD MM may mimic Bence Jones (light chain) myeloma, since the IgD M-protein is inconspicuous and light chain, commonly lambda light chain, predominates. Our patient, however, showed a readily detectable M-protein on serum protein electrophoresis, thus rendering diagnosis more straightforward.

The response to therapy is similar to that observed in other myeloma types. Response to combination chemotherapy appears to be better than the response to a single alkylating agent plus prednisone. The median survival of around 2 years in patients with IgD MM is shorter than that currently achieved in patients with MM as a whole, with one third of them surviving for more than 3 years and one fifth of them surviving for more than 5 years.

References

1. Tan LK, Suri R, Lim HL, Ong SK. Deaprtment of Laboratory Medicine, National University Hospital, Singapore. Immunoglobulin D multiple myeloma in our hospital -a rare occurrence. Singapore Med J 2000 Oct:41(10):500-3
2. Lin TL, Shih LY, Dunn P, Wang PN, Wu JH, Kao MC. Department of Internal Medicine, Chang Gung mMemorial Hospital, Taipei, Taiwan, R.O.C. Immunoglobulin D multiple myeloma. Changgeng Yi Xue Za Xhi 2000 Aug;23(8):451-7
3. Blade J, Kyle RA. Hematology Department, Hospital Clinic, Institut d'Investigations Biomediques August Pi i Sunyer, Barcelona, spain. Nonsecretory myeloma, immunoglobulin D myeloma, and plasma cell leukemia. Hematol Oncol Clin North Am 1999 Dec;13(6):1259-72
4. Blade J, Lust JA, Kyle RA. Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN 55905. Immunoglobulin D multiple myeloma: presenting features, response to therapy, and survival in a series of 53 cases. J Clin Oncol 1994 Nov;12(11):2398-404
5. Jancelewicz Z, takatsuki K, Sugai S, Pruzanski W. IgD multiple myeloma. Review of 133 cases. Arch Intern Med 1975 Jan;135(1):87-93