Multiple myeloma treatment: Imunotherapy

At present, the high-dose chemotherapy with autologous stem-cell support is considered to be the optimal therapeutical option for eligible patients with multiple myeloma. Complete medical response is achieved after the autologous transplantation in 30-50 % patients, which is a very satisfactiory result as well as a significant extension of the time to progression and of the overall survival, compared with the standard medical procedures. After 20 years of stagnation, the progress in treatment of multiple myeloma is nowadays unquestionable, however, the high-dose chemotherapy is not able to prevent relapse of the disease.

The relapse of the disease originate from surviving tumor cells disseminated in the organism (minimal residual disease). Procedures undertaken to eradicate the residual disease are believed to be the key approaches leading to a prolonged survival of the patients with myeloma and with a cancerous disease in general.

Clinical trials (phase I/II) are conducted to test new immunotherapeutical methods, such as the use of monoclonal antibodies, interleukines, immunotoxins, vaccines and induction of graft-versus-host disease effect. Current strategies and new trends in multiple myeloma treatment - insights and advances - are presented here below.

Role of interferon alfa

Maintenance treatment with interferon alfa (IFN) is considered to be the standard option in patient with relapsed myeloma. The results of the overall analysis of the patients´data (the patients were treated with IFN - 1518 patients in induction and 924 in maintenance therapy) reported the benefit of IFN use as a maintenance therapy but not as a part of induction therapy. Randomised clinical trials, testing the maintenance therapy with IFN, following standard therapy, report the potential of IFN to prolong survival and the time to progression - however only by months.  This gives rise to the need for finding a more effective maintenance therapy able to improve the prognosis of the patients with multiple myeloma.

Other cytokines

Currently, many preclinical trials are underway studying the effects of other cytokines in multiple myeloma treatment.  The most tested are: Interferon gama (IFN-g), Interleukine 4 (IL-4), Granulocyte-macrophage colony stimulating factor (GM-CSF), Interleukine 2 (IL-2) and anti-IL-6 monoclonal antibodies (MoAbs).

Other antibodies used in immunotherapy 

Clinical experimentsare studying other antibodies (MoAbs), for example anti-HM1,24, anti-CD54 (ICAM-1) and anti-CD38-blocked ricin as an immunotoxin. These clinical trials didn´t report any positive effect of any of the mentioned antibodies in multiple myeloma treatment.  The trials evaluating the effect of anti-CD19 of immunotoxin IgG-HD37-SMPT-dgA in patients with minimal residual disease achieved with intensive chemotherapy are underway. Furtermore, the new perspective antibody  anti-CD20 is going to be under evaluation for its impact on myeloma treatment.

Adoptive cellular immunotherapy

The procedure titled adoptive cellular immunotherapy involves stimulation of specific immune cells, ex vivo (outside the body), followed by transfer of expanded numbers of these activated immune cells back into patients. The clinical use of cytokines, such as interferons, interleukines and monoclonal antibodies is limited by the toxicity factor. A promising field of immunotherapy research is the stimulation and expansion of effector cells along with cytokines in a high concentration "ex vivo". This procedure limits significantly the toxicity compared to a simple parenteral administration of cytokines and very probably leads to an improved biological impact of cytokines. In the eightees, clinical trials were conducted to evaluate LAK cells, nowadays, a trial tests the activation of various types of immunocompetent cells.

Activation of natural killers (NK = "natural killer")
NK-cells are examinated for their big potential consisting in nonspecific lysis of tumor cultures in vitro and in vivo.

Activation of T-cells
The topic of phenotypic and functional alteration of T-cells is recently established in multiple myeloma research. The identification of the intrinsic impulse influencing the T-cells immunity would be valuable as an improved therapeutic strategy.

Myeloma cell vaccine
Specific myeloma vaccines offer another possibility of immunotherapy that is being evaluated in clinical trials. Idiotype (Id) of myeloma immunoglobulin can be used as a tumor specific antigen. This rises the question, whether activated T-cells, recognising the specific antigen, have the specific cytotoxic potential for killing myeloma cells and whether this impact is valuable enough to have a clear clinical outcome. The specific propperties of dendritic cells to present antigen may be exploited in cytotoxic T-cell activation. 

Activation of dendritic cells

Dendritic cells, antigen-presenting cells - APCs, are able to intensely activate T-lymfocytes. The clinical use of dendritic cells was started after the recent discovery having determined how to obtain the optimal dendritic cells expansion in a sufficient quantity and in a clear form. Effective combination of dendritic cells administration and chemotherapy becomes a  very perspective issue of immunotherapy. Nonetheless, teh T-cell tolerance could represent a major obstacle to the achievement of adequate immune function.

Graft-versus- myeloma effect
Despite the proven therapeutical efficacy of allogenic transplantation, only a limited number of patients are eligible for this procedure.  The reason is usually a high age of myeloma patients or difficulty to find a compatible donor. The allogenic approach is associated with a high incidence of morbidity and mortality (30-50 %), especially because of the graft-versus-host disease (GVHD). These facts rationalise less frequent use of this procedure in myeloma patients.

Allogenic graft-versus-myeloma effect 
The possibility of allogenic graft-versus-myeloma effect (GVM) without myeloablative chemotherapy but with DLI - donor lymphocyte infusion was reported. The potential for modification of the GVMD effect can dicrease the mortality and morbidity associated with this approach. Thus, more patients could have access to the GVM method. The mechanism that underlies the response to DLI remains unexplained. This phenomenon could activate specific cytotoxic tumor-targeted effectors  (CD4+T, CD8+T, NK-cells, antigen-presenting cells) but this can represent only a secondary effect of cytokines reaction to GVHD. This therapeutical strategy should be studied in myeloma patients with inevitable relapse. Administrating of donor´s lymfocytes exhibit antitumor effects. Well-considered use of this method may provide GVT effects, optimally, without inducing GVHD. Involving this procedure in therapeutical strategy could improve patients´outcome.

Autologous graft-versus-myeloma effect 
Rarely, a spontaneus autologous GVHD after transplantation with GVM effect was reported. Various immunotherapeutic approaches targeted at GVT effects after autologous BMT are being evaluated. The endpoint of these approaches is to demonstrate GVHD associated with GVT effect. The issue of impact on a long-term and relapse-free survival remains uncleared. At present, a hypothesis has been formulated on induction of autologous GVT effect with a tolerable toxicity that could be achieved thanks to the combination with dendritic cells because the tumor antigen presentation is believed to play the key role in immunocompetent cells efficacy. 

Detailed information on the topic is available in the chapter 19 of the publication titled  Immunotherapy in the Ttreatment of Multiple Myeloma; monograph: Multiple Myeloma and Monoclonal gammopathy by  Z. Adam, R. Hájek, J. Mayer, V. Ščudla, J. Vorlíček et al.