This is the newest and most exciting addition to this homepage.

After 2 years of research, we believe this to be the direction future myeloma research should head in. The ethical committee approved the trial with minor alterations on the 9 of February 1998. It was approved by the Pharmaceutical committee as well. But due to a lack of funding it was never submitted to the Medical control council. The Pharmaceutical company decided that it was not in their interest to sponsor the trial. We are now looking for another sponsor and are collecting funds for this purpose. If you could print this page and spread it to all the persons you know of doing reseach we would be very thankful.
We have to stress that this trial is at present only a theoretic possibility and until trials have been done we do not condone unauthorised use of these drugs outside a clinical setting.

Treating Multiple Myeloma by inhibiting viral RNA production: Viviers J, Mendelow B, Patel M.
We propose treating Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) (HHV-8) in patients with Multiple Myeloma (MM) with therapies already available. This virus seems to be intricately involved in the pathogenesis of MM.

Background:
The aetiology of MM has eluded scientists for many years. Many factors have been proposed but none showed reproducible results.1,2 Dr. Rettig and colleagues at UCLA published an article in Science June 1997 which showed HHV-8 DNA in dendritic bone marrow cells in all MM patients examined.3 Furthermore, 25% of Monoclonal gammopathies of undetermined significance (MGUS) were infected with the same virus. This is the same proportion as patients developing MM. Dr. Rettig showed that the virus expresses viral IL-6 (vIL-6) which we know is a strong growth factor for MM. Other researchers showed this expression as well. The virus DNA has the ability to produce MIP-1 (macrophage inflammatory protein-1), Bcl-2 and various other cytokines as well.4-10 The exact role of HHV-8 in MM has not been defined. Our study will do a great deal in elucidating this fact.

Evaluation of patients with an M-protein (Monoclonal protein)

1. Measure the M-protein:
   a. Serum: Identify H-(heavy) and L-(light) chain by immunoelectrophoresis or immunofixation. Measure M-peak in g/L by electrophoresis or immunofixation.
   b. Urine: Measure total urine protein, grams per 24 hours. Determine the proportion of M-protein in the urine by electrophoresis or immunofixation.
2. Evaluate the bone marrow: Percent plasma (myeloma) cells.
3. Evaluate the skeleton: Is there osteoporosis , vertebral collapse , a solitary bone lesion, how many lytic (destructive) lesions .
4. Biochemistry: Calcium, urea, creatinine, ß2-microglobulin, CRP (c-reactive protein).
5. Haematology: Hemoglobin, leukocytes, neutrophils, platelets.
6. Virology: Detecting the HHV-8 in peripheral blood mononuclear cells. Antibody titers to CMV, EBV, HSV, HIV done on protocol entry.

These are the most important tests we do in the initial evaluation of a patient. First, we identify the heavy- and light- chain in the M-protein, and measure its concentration in the serum and urine. The bone marrow is sampled to determine the percentage of marrow plasma cells.

Radiographs are made of the skeleton to determine the extent of the bony disease, and the need for radiation therapy. The levels of serum calcium, creatinine and ß2-m have an important influence on the decision to treat. An elevated serum calcium indicates that the myeloma is progressing rapidly, and destroying bone. These patients need treatment urgently. An elevated serum creatinine indicates renal failure which could be secondary to the dehydration associated with an elevated serum calcium, or, more ominously, to the deposition of light chains in the kidney. ß2-m is released from the cell membranes of dying cells, and is excreted in the urine. In the absence of renal failure, an elevated ß2-m in myeloma patients indicates increased cell turnover, and correlates well with an increased myeloma growth fraction. Anemia, neutropenia or thrombocytopenia indicate probable marrow failure secondary to myeloma, and suggest that the patient may require treatment. Patients with no symptoms, a normal serum calcium, creatinine, ß2-m, and no anemia, neutropenia or thrombocytopenia, do not require immediate standard treatment but are excellent candidates for our protocol. The serum and urinary M-protein should be followed at 1 to 2 monthly intervals. Treatment should not be started until there are definite signs or symptoms of disease progression. A retrospective study of 402 myeloma patients entered on a trial of interferon maintenance therapy by the National Cancer Institute of Canada revealed that 14% of this group had stable disease.16

Proposed therapy: The ideal treatment for myeloma patients would be the following: Salmon Durie stage I and II or <50 years: high dose chemotherapy supported by a peripheral stem cell transplant. Salmon Durie Stage III or>50 years old: standard or high dose therapy. Patients who will be treated will be defined fully in the international protocol format. They will receive: Clarithromycin 250mg bd and Ritonavir 600mg bd for the 6 months duration of the trial. The reasoning behind using Clarithromycin is the observation by Durie et al.15 that Clarithromycin has been shown to induce a response in MM patients. The reasoning behind adding a Protease inhibitor is the observation by Rizzieri et al and Murphy et al.11,12 They described clearance of KSHV from the peripheral blood mononuclear cells with a protease inhibitor. It would thus make sense to add a protease inhibitor for its known effects on KSHV. MM is characterized by the accumulation of "malignant" plasma cells in the bone marrow of patients. These plasma cells produce a monoclonal immunoglobulin in the serum and/or urine. Normal immunoglobulin levels are profoundly suppressed. Morbidity and mortality are primary related to haematological, skeletal, and renal complications of the disease. Despite some advances in chemotherapy regimes, median survival of MM patients has remained at about 30 months for the past several decades.13 A meta-analysis done showed no improved survival on standard chemotherapy.14 At present, a large randomized trial is being conducted comparing standard to high-dose chemotherapy. But even high-dose chemotherapy is not providing a cure for this disease and to date only a few patients who received allogeneic transplants have stayed in long term remission. This does not seem to be the case with autologous transplants with peripheral stem cell support, either done as a single therapy or in tandem. There is thus a wonderful scope to look for alternate treatments in this disease. We believe our protocol would go far toward inhibiting the growth of the "malignant" plasma cell clone because we are specifically targeting the virus known to be present in all MM patients. This virus has all the genetic programming to support plasma cell growth. The proposed treatment is non invasive, relatively non toxic and has few side effects.

Monitoring patients: After initial evaluation has been made it would be simple and cost effective to monitor the response to treatment of these patients.

At follow up visits the following would be done:

1. M-protein evaluation.
2. FBC, U+E, Ca2+ and limited LFT.
3. Bone marrow aspiration on initiation of treatment and at 6 months.

Response will be judged by decrease of M-protein in the serum and/or disappearance of Bence Jones Protein from the urine, improvement of anemia, return to normocalcaemia, and decrease of bone marrow plasmacytosis. (SWOG). U+E is done to monitor kidney function. Limited LFT is done to monitor possible hepatitis induced by anti-biotic therapy.

I put myself onto this protocol in October 1997. At this stage I am in complete remission with no trace of Myeloma.

Patient information
20th January 1998.

If you have anything to add please e-mail me at: viviers@icon.co.za