Efficacy of the M-2 protocol in previously untreated patients with advanced multiple myeloma

37 consecutive, previously untreated patients with advanced multiple myeloma (16 patients Stage II, 21 patients Stage III) were treated with a five drug regimen consisting of carmustine, melphalan, vincristine, cyclophosphamide and prednisolone (M-2-protocol) in a prospective manner. Remission was achieved in 24 patients (65%). The median time to remission was 10 weeks, the median duration of remission 15,3 months. Median survival time from the onset of treatment was 24 months for all patients. Responding patients have a projected 65% three year survival. Median survival in non-responders was 10 months. 8 patients died during the first year of treatment. These results do not confirm the favourable results with this drug combination obtained in a previous trial. The discrepancy may be explained by a higher proportion of poor risk patients in the present study.     

T-cell subsets in multiple myeloma. Impact of cytostatic treatment

Blood leukocyte and lymphocyte counts, absolute and relative numbers of T-lymphocytes and T-cell subsets were studied in 45 patients with multiple myeloma and 18 healthy controls. No differences were found between untreated patients and controls. In the group of untreated patients similar results were obtained in patients with low-intermediate tumour cell mass as in patients with large tumour cell mass. In patients with large tumour cell mass studied during cytostatic therapy, leukocyte and lymphocyte counts, T-cells, OKT4+ cells and OKT4/OKT8 ratios were significantly lower than in untreated patients. Patients studied at varying intervals (2-28 mo.) after cessation of therapy still exhibited abnormal leukocyte and lymphocyte counts, numbers of T-cells, OKT4+ cells and OKT4/OKT8 ratios.     

Management of multiple myeloma

There has been no improvement in the treatment of multiple myeloma (MM) during the last decades and two meta-analyses of randomized trials recorded no significant survival benefit for combination chemotherapy compared to the classic melphalan-prednisone combination. However the past 15 years has seen several innovative strategies which have dramatically modified the management of MM. In younger patients, high-dose therapy with autologous stem cell transplantation is considered to be superior to conventional chemotherapy and is used as part of front-line therapy. A number of issues have been addressed in recent trials in order to improve the results of autologous transplantation (source of stem cells, conditioning regimen, impact of double transplants, maintenance therapy). Bisphosphonates reduce the incidence of skeletal-related events and improve the quality of life. Recombinant erythropoietin reduces red blood cell transfusion need and improves the quality of life. Thalidomide has been introduced more recently. Phase II studies with thalidomide alone or combined with dexamethasone have shown impressive response rates and this drug is currently being evaluated as part of front-line therapy. Finally, analysis of prognostic factors such as beta 2 microglobulin and cytogenetics define subgroups of patients with a completely different outcome and help the process of selecting therapeutics strategies.     

Management of multiple myeloma

There has been little progress in the treatment of patients with multiple myeloma, and the average survival time is still only about 3 years. Although there have been significant therapeutic advances in recent years, clinical trials have only just begun. The major concern is, of course, the achievement of major disease control (which can be equated with a cure). The data available to date indicate that this is possible only with the use of allogeneic bone marrow transplantation, with which a survival plateau of around 30% can be attained. The trials should perhaps include the sequential use of all regimens with established efficacy in refractory myeloma. Immunoconjugate therapy with either radioisotopes or cytotoxic agents could also be envisioned, and expansion with suitable biological agents such as interleukin-2 could be considered. There is a plethora of promising treatment possibilities and novel concepts that may improve the dismal outlook for patients with multiple myeloma.     

Allogeneic stem cell transplantation for multiple myeloma

The sensitivity of myeloma cells to high dose chemotherapy has led to the use of allogeneic hematopoietic stem cell transplantation (HSCT) as a therapeutic modality in this disease. In addition to providing more effective chemotherapy, the transplantation of allogeneic stem cells also initiates the development of an allogeneic immune response directed against residual myeloma cells. Direct evidence for a graft vs. myeloma (GVM) effect is provided by the ability of donor lymphocyte infusion (DLI) to induce significant responses in 30-50% of patients with myeloma who have relapsed after allogeneic HSCT. Nevertheless, allogeneic stem cell transplantation is also associated with a high incidence of transplant related toxicities, including regimen-related toxicities, graft vs. host disease (GVHD) and opportunistic infections. DLI has been shown to enhance immune reconstitution after allogeneic HSCT in addition to inducing a GVM response. Current efforts are directed at reducing the toxicities associated with allogeneic HSCT, identification of the target antigens of GVM and the development of new strategies to selectively enhance the immune response to myeloma cells.     

DC in multiple myeloma immunotherapy

Therapy for patients with multiple myeloma (MM) is currently unsatisfactory and most patients eventually succumb to relapsed disease. DCs are a subset of leukocytes with the capacity to initiate and control the adaptive immune response against many cancers, including MM. In MM patients, in vivo DC function is often abnormal, however, it appears that it can be restored by in vitro manipulation. This has led to the development of DC immunotherapy for MM patients. We review the background research leading to the recognition of an anti-MM immune response, and discuss abnormalities in DC function, potential tumor-associated Ags, and the results of clinical trials of DC immunotherapy in MM patients.     

The HGF/MET pathway as target for the treatment of multiple myeloma and B-cell lymphomas

Hepatocyte growth factor (HGF) and its receptor MET are essential during embryonic development and throughout postnatal life. However, aberrant MET activation, due to overexpression, mutations, or autocrine ligand production, contributes to the development and progression of a variety of human cancers, often being associated with poor clinical outcome and drug resistance. B cell malignancies arise from B cells that are clonally expanded at different stages of differentiation. Despite major therapeutic advances, most mature B cell malignancies remain incurable and biologically-oriented therapeutic strategies are urgently needed. This review addresses the role of the HGF/MET pathway during B cell development and discusses how its aberrant activation contributes to the development of B cell lymphoproliferative disorders, with particular emphasis on multiple myeloma and diffuse large B cell lymphoma. These insights, combined with the recent development of clinical-grade agents targeting the MET pathway, provide the rationale to envision the HGF/MET pathway as a new promising target for the treatment of B cell malignancies.     

Intracytoplasmic immunofluorescence in multiple myeloma

A new intracytoplasmic immunofluorescence staining procedure has been investigated to detect and quantify myeloma cells by means of flow cytometry. Freshly harvested bone marrow aspirations from 12 patients with multiple myeloma were treated with collagenase and Triton X-100, and incubated with different specimens of fluoro-isothiocyanate-marked antihuman immunoglobulins. DNA-staining was then done with propidium iodide. Biparametric evaluation in a cytofluorograph 6300A/FC 200 showed a characteristic cluster distribution of normal and pathological immunoglobulin-producing cells. This intracytoplasmic fluorochromic staining procedure may be significant for the specific identification of nonsecretive immunocytomas, which cannot be detected by serodiagnostic methods.     

Molecular genetics of human multiple myeloma

Molecular methods of defining gene rearrangements and DNA alterations that effect gene expression offer additional insights into malignant transformation of lymphoid cells. The highly clonal nature of myeloma is revealed by characterization of the unique Ig and TcR rearrangements. Whereas detection by DNA blot hybridization requires 2–5% clonality, more recent methods of DNA analysis, such as the polymerase chain reaction (PCR), can now increase the sensitivity of detection by several orders of magnitude. With improvement in therapies to treat myeloma, the issue of detection of minimal residual disease may be an important consideration in clinical management of the disease. The unique combinations of immunoglobulin gene segments and additional nucleotide alterations at junctional regions can be determined, and DNA probes can be synthesized that are clone-specific (Figure 1). By combining PCR amplification with detection methods employing clone-specific probes, significant improvements in disease detection are possible. As we begin to understand the functional consequences of genetic alterations associated with growth promoting genes such as the oncogenes myc and ras, and their role in myeloma, more promising therapies may be devised.