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Myeloma

Velcade: A New Strategy Treating Multiple Myeloma 
  Submitted By: Judah Friedman, M.D.

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Velcade: A New Strategy for Treating Multiple Myeloma

Authored by: Judah Friedman, M.D. and Andrzej J. Jakubowiak M.D., Ph.D.
Division of Hematology/Oncology, Department of Internal Medicine
University of Michigan, Ann Arbor, MI 48109-0848


Abstract: Velcade is a new drug that acts in a different way from typical chemotherapy drugs. It is rapidly becoming a standard treatment for patients with multiple myeloma who have relapsed after other treatments, and is now being explored in clinical trials in newly diagnosed patients. This article describes how this new drug works, its side effects, and its effectiveness. It also discusses new areas of research with Velcade in patients with multiple myeloma.

Article: Velcade (bortezomib is the generic name) was approved by the Food and Drug Administration (FDA) in May 2003 for patients with multiple myeloma who had recurrence of disease after other treatments. It is the first proteasome inhibitor to be tested in humans and in early clinical trials Velcade showed impressive anticancer activity in patients with multiple myeloma. The proteasome is a multi-enzyme complex present in all cells that normally degrades proteins that regulate cell growth and proliferation. Such degradation is important for normal cellular function since it allows the cell to remove defective proteins that are no longer useful; proteasomes, therefore, ‘clean-up’ the cell. The ability of Velcade to inhibit the proteasome in myeloma cells results in the accumulation of excessive levels of these defective proteins. This forces the cell to undergo a specific type of cell death called apoptosis. Inhibition of the proteasome has also been shown to interfere with growth signals from other cells in the bone marrow which can stimulate myeloma cells. Thus, Velcade is a unique drug that does not work like typical chemotherapy agents that directly damage the DNA of rapidly dividing cells.

Velcade’s dosing and administration schedule have been well established. It is administered intravenously (through a vein) over three to five seconds twice per week for 2 weeks followed by a 10 day rest period (or in terms of a 21-day cycle: days 1,4, 8 and 11). It is usually given for a maximum of 8 cycles, but if a patient has a good anti-cancer response and minimal side effects, then additional maintenance dosing may be given for a longer period of time. It is also common practice, for oral dexamethasone, a drug commonly used for multiple myeloma, to be given along with Velcade to improve the chance for response if little benefit is noted after the initial two cycles of Velcade alone.

Velcade’s anti-cancer activity has also been well established in Phase I, II and III clinical trials. Phase I studies are done to determine the safety of a drug by treating patients with progressively higher doses and observing them closely for side effects (toxicity). A dose that causes an acceptable level of side effects is then chosen for future studies. In a Phase II trial the chosen drug dose is given to patients with a specific type of cancer to determine if the drug has anti-cancer activity, meaning can the drug shrink the tumor or improve the patient’s symptoms. In a Phase III trial, patients with a specific cancer are randomly assigned to receive either the new drug (or treatment) or standard treatment. The response rate and survival of each group of patients can be compared to determine if the new treatment is better than the pre-existing standard therapy. Many times a Phase III trial is required for a drug to receive approval from the FDA.

In a large, multi-center, Phase II trial (called the SUMMIT trial), 193 patients with relapsed multiple myeloma were treated with Velcade. Thirty-five percent of patients showed a significant fall in their myeloma protein (1). Such a fall in the myeloma protein is called either a partial response (declines by >50 %) or a complete response or near complete response (complete or almost complete normalization of the myeloma protein). The overall response rate is defined as the percentage of patients who achieve either a partial, complete or near complete response. In the SUMMIT trial, 10% of patients experienced a complete or near complete response and 18% had a partial response. Importantly, over 90% of the patients in this trial had previously received three or more types of treatment for their disease and had not responded to their most recent treatment. The median duration of response to Velcade was 12 months, and patients with a response had improvement in quality of life, kidney function, and blood counts.

In a recent large, randomized, multi-center trial (the APEX trial), the effectiveness of Velcade was compared to dexamethasone in 669 patients with relapsed multiple myeloma (2). The overall response rate was 38% in patients treated with Velcade and 18% in patients treated with dexamethasone. Thirteen percent of patients who received Velcade achieved either a complete or near complete response and 32% had a partial response. In contrast, only 2% who received dexamethasone achieved a complete or near complete reduction in the myeloma protein. Importantly, one-year survival was 80% in patients treated with Velcade versus 66% in those treated with dexamethasone. Response to Velcade is rapid, usually occurring within one or two cycles of the therapy. Based on the effictiveness demonstrated in these trials, Velcade has become a standard treatment for patients with myeloma who have relapsed following initial treatment.. Additionally, Velcade, unlike other anti-myeloma drugs such as melphalan, does not damage the blood stem cells and can therefore be given prior to a bone marrow transplant. Also, Velcade remains effective in patients whose myeloma cells exhibit a genetic deletion of DNA on chromosome 13q, an abnormality that confers resistance to several other anti-myeloma drugs (3).

Velcade does have side effects such as nausea, vomiting, diarrhea, constipation, thrombocytopenia (low platelet count), fatigue, numbness or pain in the hands and feet, anemia (low red blood cell count), fever, and low blood pressure. Although a significant decrease in the platelet count (platelets circulate in the blood and prevent bleeding) occurs in about 30% of patients, the platelet count usually rebounds quickly before the next cycle of treatment (4). Numbness or pain in the hands and feet develops in 30-40% of patients. The condition is more frequent in those who have preexisting nerve injury (as can occur in patients with diabetes) or who have previously received certain types of chemotherapy (such as vincristine) that can cause nerve damage. In the initial phase II studies, 18% of patients discontinued Velcade therapy due to drug-related side effects (1). In the large APEX trial, 37% of patients discontinued Velcade early due to side effects (2). Reductions in the dose of Velcade can be made to improve or lessen certain side effects.

Given the impressive response rates seen in patients with relapsed myeloma, Velcade is now undergoing testing in patients with symptomatic, newly diagnosed multiple myeloma. In two small trials, the combination of Velcade and dexamethasone as initial therapy resulted in an overall response rate greater than 65%, with over 20% of patients achieving a complete or near complete response (5,6). This high level of complete response is usually seen only after high-dose chemotherapy and stem cell transplantation. Most patients on these trials were able to complete Velcade therapy, and all were subsequently able to undergo successful stem cell harvest for stem cell transplantation.

Studies in the laboratory or in animals have shown a potential benefit of combining Velcade with traditional chemotherapeutic agents. Research in myeloma cell lines demonstrated that Velcade made the cells more susceptible to traditional chemotherapeutic drugs, such as doxorubicin and melphalan (7). However, this was not the case for dexamethasone. Importantly, myeloma cell lines that were resistant to doxorubicin, became sensitive to doxorubicin in the presence of Velcade. For example, treatment of myeloma cells from a patient with refractory multiple myeloma with doxorubacin or Velcade alone did not result in cell death. However, the combination of the two drugs resulted in significant cell death.

Early clinical testing of Velcade and doxil (a different formulation of doxorubicin) in patients with relapsed malignancies, showed that 16 of 22 patients with multiple myeloma had a significant response (8). Another study of Velcade and melphalan showed a response rate of 50%, with minimal toxicity (9). The combination of Velcade and thalidomide appears equally promising with an overall response rate of 60% and a near complete response rate of 20% in patients with relapsed myeloma (10). Many of these combinations with Velcade and other drugs are currently being further evaluated in large phase III randomized trials (11).

Because of the high level of anti-myeloma activity seen with Velcade alone, and the high response rates noted when Velcade is used with doxil or dexamethasone we are testing the combination of all three agents in patients with both relapsed and newly diagnosed, symptomatic multiple myeloma. In the setting of relapsed disease, we have treated over 20 patients and noted that over 80% have demonstrated either a complete or partial response. While these results using combinations of Velcade and traditional chemotherapy are encouraging, they are early, and will need to be confirmed by larger trials in more patients.

In summary, Velcade is showing impressive results in patients with relapsed multiple myeloma and is being tested in clinical trials in newly diagnosed patients. The role of Velcade combined with traditional chemotherapy and its role in relation to traditional bone marrow transplant remains to be determined from future clinical trials.  


 


Additional Authors:  

Works Cited:  
  1. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609-2617.
2. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-2498.
3.Richardson PG, Barlogie B, Berenson J, et al. Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma. Blood. 2005; 106:2977-81.
4. Lonial S, Waller EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005; 106:3777-3784.
5. Jagannath S, Durie B, Wolf JL, et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol. 2005; 129:776-83.
6. Harousseau J-L, Attal M, Leleu X, et al. Bortezomib (Velcade) plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: preliminary results of an IFM phase II study. Blood. 2004;104. Abstract 1490.
7. Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood. 2003;101:2377-2380.
8. Orlowski RZ, Voorhees PM, Garcia RA, et al. Phase I trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood. 2005;105:3058-3065.
9. Yang HH, Vesico R, Schenkein D, Berenson JR. A prospective, open-label safety and efficacy study of combination treatment with bortezomib (PS-341, Velcade) and melphalan in patients with relapsed or refractory multiple myeloma. Clin Lymphoma. 2003;4:119-22.
10. Zangari M, Barlogie B, Hollmig K, et al. Marked activity of Velcade plus thalidomide (V+T) in advanced refractory multiple myeloma (MM). Blood. 2004;104. Abstract 1480.
11. Jagannath S. Commentary: treating multiple myeloma with proteasome inhibitors. Clin Adv Hematol Oncol. 2005; 3(suppl 9):19-22.
 
 


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