Partial or complete deletion of chromosome 13 (del13) is considered one of the most important prognostic factors for multiple myeloma (MM).1-4 The impact of del13 on the outcome of allogeneic stem cell transplantation is unknown. We describe 2 patients with unfavorable MM who benefited from a graft-versus-myeloma effect, resulting in sustained molecular remissions.5Retrospectively a del13 was found in the diagnostic bone marrow (BM) aspirates of both patients.
The first patient progressed from monoclonal gammopathy of undetermined significance (MGUS; diagnosed in 1982) to MM (1991, IgA λ, stage IIIA). She was refractory to melphalan+prednisone, and in March 1992 at age 48 she received a partial T-cell–depleted (1 × 105 T cells/kg) BM transplant from her HLA-identical sister after conditioning with cyclophosphamide (120 mg/kg) and total body irradiation (12 Gy). This was complicated by transient acute graft-versus-host disease (GVHD), grade I. At the time of transplantation, her BM contained 55% myeloma cells. After achieving a partial remission (PR; disappearance of M protein, 8% residual BM cells), she relapsed 8 months after transplantation: reappearance of M protein, increasing 10 months later to 20g/L, 30% BM infiltration. She then received donor lymphocyte infusions (DLIs), 3.3 × 108 T cells/kg. DLIs were complicated by severe extensive chronic GVHD of skin and joints. Since May 1994 she is in complete clinical and molecular remission as demonstrated by absence of M protein, normalization of BM, and quantitative allele-specific oligonucleotide (ASO)–PCR6 (sensitivity to detect 1 tumor of 1 × 105 normal cells). Molecular remission was demonstrated in 8 subsequent BM aspirates.
The second patient (stage IIIA, IgG κ) presented with bone pain and diplopia. His BM showed a 99% infiltration, labeling index 3%, and β2-microglobulin level of 5 mg/mL. The liquor was infiltrated with plasmablastic cells. He achieved a PR after induction with intermediate-dose melphalan7 but relapsed just before allogeneic (allo)–BMT. In the liquor a persistent M protein of 1 g/L was found after treatment with methotrexate and cytarabine intrathecally. Evaluation 6 months after transplantation showed a complete clinical remission. Residual myeloma cells however could be detected by quantitative ASO-PCR until 36 months after transplantation (Figure1). Double-color FISH was performed on thawed cytocentrifuged BM cells, which had been prepared from diagnostic samples and had been stored at −20°C. A del13 was found in 99 of 100 myeloma cells of patient 1 and in 35 of 100 myeloma cells of patient 2.
The 2 patient histories demonstrate that alloreactivity may overcome the prognostic unfavorable impact of del13 in myeloma. The first patient is in molecular remission more than 10 years after allo-BMT and 8 years after DLIs. The second patient presented with a combination of adverse prognostic factors including a high β2-microglobulin level, high labeling index, and meningeal infiltration. He received a transplant in relapse after a very short period of remission. Remarkable, quantitative PCR became negative not until 3 years after transplantation.
Our results suggest that in patients with del13 a search for an HLA-identical family or unrelated donor is justified. The promising results of nonmyeloablative allo-SCT in MM8,9 justify inclusion of patients in such protocols as soon as unfavorable factors are identified after diagnosis.