Click here to view next page of this article


New Treatments for Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy after non-Hodgkin’s lymphoma. As you can see, the incidence of new cases are about 13,800 annually in the United States according to the data from 2006. Again, the incidence is in the older age group. The median age could vary. If you are looking at multiple myloma.

Now one more thing that I wanted to point out is that this isotype switching from IgM producing B-cell to IgG or IgA production, the signaling has to happen between the B lymphocyte which activated B lymphocytes would have the CD40 receptor and then the activated T lymphocyte would have the CD40 ligand. These is a genetic disorder where there is a mutation in CD40.

Why do the plasma cells home into the bone marrow instead of developing lymphadenopathy and splenomegaly like in every other case of lymphoma? That has to do with the homing technique or expression of cell surface markers. If you want to identify plasma cells routinely by flow cytometry, people usually use CD38 expression or CD138 expression. It also expresses CD56. Only CD56 expression is unusual in normal plasma cells. Otherwise the mature plasma cells in the normal person and in myeloma plasma cells, almost have similar surface antigen.

The cell adhesion results in the production of a bunch of factors from the myeloma cells, which have been characterized so far. Transforming growth factor B that is produced by the tumor cells is responsible for immunophoresis in these patients. So these patients will usually have their monoclonal paraprotein elevated but the other isotypes, such as in an IgG myeloma.

The other one that I’ve shown you is IL-1 beta. As a matter of fact, John Lutz from the Mayo Clinic has shown that expression of IL-1 beta by the tumor cells is responsible for progression to multiple myeloma from an earlier precursor stage such as monoclonal gammopathy.

Recently there is a lot of activity - I’ll talk to you later - about angiogenesis in the bone marrow of multiple myeloma patients and they do elaborate vascular endothelia growth factor and matrix metalloproteinase is 2 and matrix metalloproteinase is 9 which are gelatinases, which are responsible for breakdown of the bone in patients with multiple myeloma.

So what is the role of IL-6 in multiple myeloma? It could be broadly divided into two categories. One, to induce proliferation and the other one is to inhibit apoptosis. In the proliferation pathway people have shown that the __ pathway is activated and that’s the specific pathway which gives the signaling for proliferation. Even though the STAB-3 and STAB-1 signaling is also there, they are not the ones which are responsible for proliferative signal in multiple myeloma.

Now cytogenetics is being applied in multiple myeloma more frequently, but if you just order a routine cytogenetics in a patient with multiple myeloma and a bone marrow sample, the bone marrow aspirates will come back abnormal in only 40% of the cases. But if you have extramedullary blastocytoma and you do a fine needle aspiration and send it for cytogenetics the yield will be much much higher. People have done other kinds of maneuvers.

So if you look at that, what kind of cytogenetic abnormality do we encounter in multiple myeloma? It could be broadly classified into numeric and structural. The numeric typical, if you want to close your eyes and rattle out all the odd chromosomes you can see - trisomy of 3, 5, 7, 9, 11 - skip 13 because typically you will encounter monosomy 13 and then having again 15 and 19. In terms of structural abnormality you will find again there will be translocation involving the heavy chain gene region 14Q32. And especially in multiple myeloma Leifberg-Sagal and others have shown that it is the switch region which is involved. So you could have 11-14 translocation where you could have the B-cell 1 or an up-regulation of cyclin D1. And you will typically think of mantle cell lymphoma. But a similar translocation could also happen and you could end up with a multiple myeloma.

One more thing which is coming along now. This is a hematologic malignancy where we now start talking about new angiogenesis. Now in order to stain for angiogenesis you want to stain for the endothelial cells and you could stain the endothelial cells using two kinds of stain. One is either use anti CD34 monoclonal antibody and do an immunoperoxidase staining technique. Or use anti factor VIII monoclonal antibody and use the immunoperoxidase technique. This is using anti factor VIII monoclonal antibody. What do we expect typically that you will have large sinusoids lined by the endothelial cells and there are several cell diameters because the mature hematopoietic cells will go into the sinusoids and they go into the circulation. But you wouldn’t drugs that are being employed successfully in the management of recurrent multiple myeloma.

Moving on to bone diseases. Multiple myeloma leads to lytic bone disease and it is purely lytic. There is no new bone formation, so this is very classic. If you do just an x-ray of the skull, the radiologist will tell you that this patient has multiple myeloma, because he could see a lot of punched out lytic lesions in the skull. There will be no osteoblastic reaction. And this is shown on this biopsy of the bone marrow, of a patient with multiple myeloma. So you could see all these plasma cells. They are activating the osteoclasts and here is the Howship’s lacuna where the plasma cells are eating into the bone osteoid seam there. And there is no osteoblastic activity. This is important for us because when you do bone scan the bone scan technician.

This is just to show you that skeletal survey is very important in every newly diagnosed multiple myeloma because you could find that skeletal involvement in quite common in the newly diagnosed myeloma in two-thirds of the patients. Now in every newly-diagnosed multiple myeloma it is very important that you order an MRI of the spine and you have to specifically request a T1 rate of sequence and short time inversion recovery sequence, or STIR sequence. This is also important for a newly diagnosed solitary plasmacytoma patients because you could have a solitary plasmacytoma, you could do a skeletal survey.

Now, a little bit about treatment of lytic bone disease in multiple myeloma. Evidence-based medicine published in the New England Journal of Medicine showing that pamidronate is a bisphosphonate which increases the bone density and reduces skeletal-related events. This was a randomized trial; chemotherapy alone versus chemotherapy plus pamidronate. And this is the time to develop the first skeletal-related events. You’ve got to realize that usually in a normal person 90% of the bone turnover will be in the cancellous bone, typically in the spine and the pelvis and the ribs and like that. The cortical bone turnover is only 10%. So when you use agents like pamidronate the bone density will increase in the spine.

Treatment of hypercalcemia; I just want to show this but not to elaborate on it except for two points. You’ve got to remove, in a newly diagnosed patient with multiple myeloma who presents to you with a very high paraprotein and a lot of Bence Jones proteinuria and renal impairment. These patients could also have light chain deposition and have a restrictive cardiomyopathy. So in my opinion, in multiple myeloma it is more important to just correct the dehydration due to hypercalcemia and not rely on loop diuretics to actually improve the cause of calciuria. These days it is better to give calcitonin and pamidronate to these patients to control the hypercalcemia rather than rely on this extensive, forced diuresis as we were taught earlier .