Studies Suggest Role For KS Herpesvirus in Myeloma Pathogenesis

SAN DIEGO—Reports at the American Society of Hematology (ASH) meeting suggest that a recently discovered virus may play an important role in the pathogenesis of multiple myeloma.

Kaposi’s sarcoma-associated herpesvirus (KSHV), first identified in patients with Ka- posi’s sarcoma and also known as human herpesvirus 8 (HHV8), has been detected in dendritic cells from both cultured and fresh bone marrow samples, and in enriched peripheral blood mononuclear cells (PBMCs), of multiple myeloma patients but not in samples from normal controls or from patients with other malignancies, researchers from the UCLA School of Medicine reported.

Further, preliminary data suggest that the presence of KSHV may correlate with clinical outcome in these patients.

After failing to detect significant KSHV levels in unselected PBMCs of multiple myeloma patients, the UCLA researchers, under the direction of James R. Berenson, MD, undertook a similar experiment with PBMCs enriched for dendritic cells. An immunomagnetic bead technique was used to select dendritic cells using the dendritic antibody markers CD68 and CD83, Matthew Rettig, MD, said in his presentation of the data.

Results showed that 51 of 74 multiple myeloma patients (70%) had detectable KSHV in their enriched PBMC samples, compared with fewer than 10% of normal subjects (1 of 13), none of the patients with other malignancies, and approximately one quarter (5 of 19) of patients with MGUS (monoclonal gammopathy of undetermined sig-nificance).

To evaluate the correlation between the detection of KSHV and the patients’ clinical status, Dr. Berenson’s team subdivided the myeloma cohort into three groups: untreated patients, patients who had undergone or were undergoing conventional treatment, and patients who had undergone high-dose chemotherapy with autologous peripheral blood progenitor cell transplantation.

Preliminary findings in this small group of patients showed that the majority of the untreated patients had detectable virus, in particular about 80% of the stage II/III patients. Among those conventionally treated, the detection of virus correlated with response: Only 2 of 7 patients in remission had detectable virus, whereas the majority of those with stable or relapsed disease were KSHV positive.

Dr. Rettig said that the transplanted patients provided “the most intriguing data.” None of the transplanted patients who achieved a complete or partial remission were positive for the virus, whereas all of the patients who relapsed after transplantation had detectable virus. “Interestingly enough, one of these relapsed patients was induced into a second remission with conventional treatment and was subsequently negative for the virus,” Dr. Rettig said.

A Possible Clinical Application

In another study, presented by Robert Vescio, MD, the researchers in Dr. Berenson’s lab showed that mobilization chemotherapy increases the number of circulating dendritic cells and leads to increased detection of KSHV in PBMCs in multiple myeloma patients undergoing autologous PBMC transplant.

Using CD34 selection, they were able to reduce the number of dendritic cells in the PBMC autografts, which led to a decrease in the detection of KSHV in the autografts. KSHV was identified in the autografts of 15 of 31 patients before CD34 selection and in only 3 patients after selection. Thus, fewer KSHV-infected cells were reintroduced via autograft after high-dose chemotherapy.

Dr. Rettig hypothesizes that KSHV-infected dendritic cells in PBMCs in myeloma patients may be a source of lytic virus capable of disseminating and maintaining the KSHV infection. If that is the case, elimination of dendritic cells in PBMC autografts could reduce KSHV load and possibly lead to improved clinical outcomes.

The question remains, Dr. Rettig said, as to whether KSHV “is a bystander or is playing a cause-and-effect role in mye-loma,” and if it does have an etiological role, he asked, what is the mechanism?

A possible factor may be the presence of IL-6 in the KSHV genome, he said. This cytokine has been shown to stimulate tumor cell growth and inhibit apoptosis of tumor cells in human malignant plasma cells.