Multiple myeloma in two HIV-infected patients

Although non-Hodgkin‚s lymphomas are common in HIV-infected patients, plasma cell tumours are more rare. Here, we report two new cases of multiple myeloma in HIV-seropositive patients.

Patient 1

A 57-year-old man has been followed for HIV infection Centers for Disease Control and Prevention (CDC) classification A1, for 7 years, for which he has received stavudine and didanosine. His HIV-RNA level was less than 500 copies/ml and CD4 cell count was 310/mm3. In December 1997, he complained of lumbago and lower limb weakness. Laboratory studies detected a monoclonal IgG kappa paraprotein (14g/l). Skeletal radiography revealed a lytic lesion of L5 (Fig. 1). The bone marrow plasma cell infiltrate was moderate (10%), but vertebral biopsy led to the diagnosis of plasmocytoma. Treatment consisted of radiation therapy to the L5 region, and chemotherapy (melphalan, prednisone). The patient remains asymptomatic 12 months later.

Fig. 1

Patient 2

A 45-year-old man was hospitalized in November 1991 with lumbago. Physical examination was unremarkable. Laboratory studies detected an IgG kappa monoclonal paraprotein (32g/l). Radiographs showed collapse of vertebral bodies L1, L2, L3 and L4 (Fig. 2). Bone marrow biopsy was hypercellular with an infiltrate of malignant plasma cells (30%). HIV seropositivity was discovered during systematic testing, CD4 lymphocyte count was 220/mm3. He received radiation therapy to the lumbar region, chemotherapy (vincristine, adriamycin and decadron) for a 12 month period, which led to clinical improvement and a reduction of the monoclonal paraprotein level (13g/l). He also received zidovudine and didanosine, then stavudine, lamivudine and nevirapine. In November 1998, the myeloma relapsed with skeletal pain, multiple generalized lytic bone lesions and increased monoclonal paraprotein level (40g/l). Chemotherapy (vincristine, methotrexate, cyclophosphamide and prednisone) was reinstated. The HIV infection was asymptomatic. The HIV-RNA level was less than 500 copies/ml and CD4 cell count was 200/mm3.

Fig. 2

HIV-positive patients are at risk of the development of aggressive, disseminated and extranodal B cell lymphoma[^1,2]. Plasma cell tumours are seen less frequently, with only approximately 20 cases reported in the literature[³]. Several observations suggest that HIV infection plays a major role in the evolution of malignant plasma cell tumours. As in B cell lymphomas, HIV-positive patients with plasma cell tumours are distinguishable from non-infected patients both by the higher number of patients and their younger age at presentation compared with the general population, in which there is an overall incidence of monoclonal gammopathy of 0.5%[⁴], whereas in HIV-positive patients the incidence ranges between 2.5 and 56%.

Multiple myeloma is an age-related disease whose incidence peaks between 60 and 70 years; it is extremely uncommon in persons under 40 years of age[⁵]. The mean age of AIDS patients who developed multiple myeloma is 33 years.

Studies have demonstrated marked abnormalities of B cell activation and immunoregulation in AIDS patients. Polyclonal B cell activation is commonly observed[⁶], and may represent a signal of B lineage tumorigenesis. Elevated IL-6 plasma levels have been detected in HIV-infected patients[⁷]; this apparent overproduction of IL-6 promotes B cell proliferation, Ig secretion, myeloma cell growth, and a central role for it in the pathophysiology of myeloma has been suggested[^8,9].

IL-6 is a multifunctional cytokine induced by a variety of stimuli, including bacteria, viruses and other cytokines. Many viruses can stimulate IL-6 production, in particular HIV[¹⁰], human herpes virus 8 [^11,12] and Epstein-Barr virus[¹³]. Finally, it appears that HIV-1 antigen can induce clonal selection that plays a part in the pathogenesis of plasmacytic disorders. Indeed, Konrad et al. [¹⁴] reported an HIV-1-positive patient with myeloma whose IgG kappa paraprotein specifically recognized the HIV-1 p24 antigen.

In addition, the observation that T cells were able to induce terminal differentiation of transformed B cells into mature plasma cell tumours [¹⁵] might explain the high frequency of lymphoma compared with myeloma in AIDS patients depleted of T cells. In the future, highly active antiretroviral therapy and immune restoration might favour the emergence of plasma cell malignancies rather than lymphomas.

Finally, as in B cell lymphoma, myeloma patients, especially young patients, should be systematically screened for HIV, and HIV-positive patients should be monitored for the occurrence of monoclonal gammopathy.

Acknowledgement

The authors wish to thank Janet Jacobson for her help with English translation.