The original transforming event as witnessed by heavy chain re-arrangement, happens in the lymphnode. This area of transformation would favor a viral etiology. A retro virus explains a lot of the phenomena seen in MM. After the original infection, which has to be spesific to a particular gene on a spesific chromosome, the KSHV would activate the expression of IL-2 gene by the tax (or generic) gene. It is one of the cytokines responsible for B-cell differentiation and proliferation. It also acts with IL-6 to aid transcription of c-myc from the P0 transcript regulator.
With TNF it acts as a 'osteoclast stimulating' factor. In other words the virus has the gene to start the process. On differentiation the pre-B cell moves to the BM to become a plasma cell. It is important to remember that the malignant plasma cell is a normal plasma cell which has a few genetic mutations. In other words in many respects it acts like a normal plasma cell.The MM plasma cell interacts with the bone marrow stromal cells (BMSC). The plasmacytosis induces a normal feedback system, whereby TGF-B1 is produced by BMSC. TGF- B1 acts on the Rb gene to stimulate cell differentiation and proliferation and ultimately programmed cell death (PCD) after terminal differentiation. 80% of MM patients have a monoallelic deletion of the Rb gene, but Juge-Morineau et al (1996) found no decrease in the Rb gene or gene product expression. It would be very unlikely that a deletion of high penetration does not have any affect on the disease process. This is the first of the mutations giving rise to MM. A possible explanation for the Rb gene not functioning properly is the E2F molecule which binds pRb. Various viruses make a antagonist for this molecule called E1A in DNA virusses like Karposi sarcoma Herpes virus. It would interfere with normal function of pRb and no differentiation would take place. The increase of TGF- B1 would continue because the BMSC want to decrease the amount of plasma cells in the marrow. TGF- 1 has a powerful down regulation on the whole immune system and gives a negative feedback signal to the pre-B cells in order to reduces the amount of plasma cells produced. It also has a direct depressive effect on the cellular immunity and this explains part of the immune deficiency seen in MM. It is also possible that the retrovirus will infect T cells with the CD4+ receptor, and cause decreased functioning of these cells.
In an effort to induce differentiation via a third pathway TGF- B1 induces IL-6 secretion by BMSC. IL-6/IL-6R bind with gp130 to induce cell differentiation, but once again we have found various mutations in the cytoplasmic domain of gp130. Futher on in this pathway p21 ras has also been shown to have point mutations. The amount of IL-6 in the bone marrow environment is now at high levels and this gives rise to various pathological processes:

1. IL-6 acts as a proliferation and not a differentiation cytokine on MM plasmacells. The plasma cells increase and the vicious circle repeats its self.
2. IL-6 and IL-2 transcribe c-myc from the P0 promoter. The normal regulatory function c-myc has on p53 is lost. Various mutations have also been reported affecting p53.
3. IL-6 acts with various other cytokines to activate osteoclasts and give bone resorption.

It is obvious that MM develops as a consequence of various mutational abnormalities in various crucial pathways. Every cell has a built in program to facilitate programmed cell death. There are various backup pathways to facilitate PCD and until all these pathways have been neutralized, MM will lie dormant as MGUS. Dr Mathew Rettig et al. has show a virus that infects dendritic cells and is closely associated to MGUS transforming to Multiple Myeloma. The increase cell survival is important in this respect to give enough time for the multiple genetic events to occur. The best explanation for the multiple mutations seen in MM is a transforming retrovirus. This means a retrovirus with the ability to incorporate in the host DNA lifelong. This virus acts different to HIV and is not cytopathic. It can only spread by direct cell to cell contact. The various adhesion molecules in MM make this task much easier. Over years there is a continuous bombardment of the plasma cells genetic structure with viral genetic insults, and as soon as the critical pathways to PCD have been destroyed, multiple myeloma develops. This explains the long dormancy period from the development of MGUS to MM.

In order to cure MM or at least revert back to MGUS it is only necessary to activate one of these pathways:

1. Functional Rb gene replacement - this can be done with a retroviral vector.
2. IL-6 superantagonist - a decrease of IL-6 in vitro causes cell apoptosis, most likely by reducing the amount of abnormal c-myc production and the tumor suppressor signal via p53.
3. B7- cells can be transfected with a retroviral vector. Expression of B7 should give T-cell mediated cytolysis, in a normal functioning immune system. (Early disease). MM is an immunogenic tumor.
4. Anti-retroviral therapy will give reduction of IL-2 gene expression, which will give a normal c-myc transcript and cell apoptosis. (This seems to be the most feasable option and the one which will now be vigorously investigated)
5. A superantagonist for TGF- 1 and IL-2 will help our cause a lot.
6. Upregulation of hetrodimer BAX associated with downregulation of BCL-2 and BCL-Xl.
7. BAD and ICE molecules are there to be used when necessary.
8. Fas antigen stimulation.

The Multiple myeloma cells are mostly still intact enough to realize that they have to undergo cell death. This is evident by the expression of high levels of activation markers, but the pathways effecting PCD are not functioning. Lets help them.