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Multiple myeloma is an incurable plasma cell malignancy that accounts for 10% of all hematologic cancers. For decades the mainstay of therapy has been the use of melphalan and prednisone; with this regimen, the median survival is approximately 3 years. Recently, important advances were made that have substantially altered the manner in which patients with myeloma are treated. Newly diagnosed patients with good performance status are now treated with autologous stem cell transplantation, resulting in improved survival. Because of the increasing use of transplantation as initial therapy, several therapeutic issues have emerged: the role of tandem transplantation, early vs delayed transplantation, and the role of allogeneic transplantation. The pronounced activity of thalidomide in patients with refractory myeloma represents another important advance. This has prompted the study of several novel agents in the treatment of myeloma, at least 2 of which appear promising. Supportive care measures also have improved, including the use of bisphosphonates to prevent osteolytic lesions. The purpose of this review is to summarize recent advances and provide an evidence-based approach to the treatment of multiple myeloma.
Multiple myeloma is a clonal plasma cell disorder characterized by the presence of a monoclonal protein in the serum or urine, osteolytic lesions, increased plasma cells in the bone marrow, anemia, and hypercalcemia.
The annual incidence is approximately 4 per 100,000 population. The incidence rates in Europe are slightly lower: approximately 3 per 100,000 in the United Kingdom, Sweden, and the Netherlands and 2.5 per 100,000 in Denmark, France, and Spain.
The incidence in black persons is almost twice that of white persons.
At present, there is no cure for myeloma, and median survival with standard therapy is approximately 3 years. A state-of-the-art, evidence-based approach to the treatment of symptomatic, newly diagnosed multiple myeloma is presented in this review.
MANAGEMENT OF SYMPTOMATIC MULTIPLE MYELOMA
Symptomatic multiple myeloma is defined by the presence of increased monoclonal plasma cells in the bone marrow, presence of a serum or urinary monoclonal protein, and symptoms related to 1 or more of the following features: osteolytic lesions, anemia, hypercalcemia, or renal failure. Other causes of anemia, renal failure, and hypercalcemia must be considered and excluded.
A schematic approach to the management of patients with newly diagnosed, symptomatic multiple myeloma is shown in Figure 1. Of importance, a subset of patients may have mild anemia or small osteolytic lesions on skeletal survey, with minimal or no symptoms. These patients can be observed without therapy until definite evidence of progression, based on the results of 2 randomized trials that showed no significant improvement in overall survival in patients who received immediate treatment with melphalan plus prednisone compared with those who received treatment at progression.
It is also based on the toxic effects of therapy and the fact that some patients may not experience disease progression for many months with no therapy.
Figure 1Approach to the treatment of newly diagnosed, symptomatic myeloma. *Induction therapy is given for 3 to 4 cycles. MP = melphalan plus prednisone; VAD = vincristine, doxorubicin (Adriamycin), dexamethasone; VBMCP = vincristine, carmustine (BCNU), melphalan, cyclophosphamide, prednisone.
Once a decision is made that therapy is indicated, the next issue is to determine whether the patient is a candidate for autologous stem cell transplantation because survival is superior with this strategy.
Patients who are not candidates for autologous stem cell transplantation because of advanced age, poor performance status, pronounced renal failure, or comorbidity should receive standard-dose alkylator-based therapy with melphalan (an alkylating agent) and prednisone or a suitable alternative therapeutic regimen. The rest of the patients are treated with early or delayed autologous stem cell transplantation.
Conventional-Dose Chemotherapy
For decades, the simple oral regimen of melphalan plus prednisone has remained the cornerstone of therapy for myeloma. The overall response rate with this regimen is about 50%.
Myeloma Trialists' Collaborative Group Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials.
Melphalan is administered orally at a dose of 0.15 mg/kg daily for 7 days. Prednisone is administered orally at a dose of 60 mg/d during the same 7 days. The treatment is repeated every 6 weeks. An alternative schedule is to administer melphalan, 9 mg/m2 per day, for 4 days in combination with prednisone, 100 mg/d, on the same 4 days, with the treatment repeated every 4 weeks. The white blood cell count and platelet count must be obtained 2 to 3 weeks after initiation of therapy and before re-treatment. Based on these counts, the dose of melphalan for subsequent cycles is adjusted to produce mild cytopenia at mid cycle. Patients are treated in this manner for 1 year or up to 6 months after a plateau phase has been achieved. The complete response (CR) rate with this strategy is less than 10%, and the median survival is about 3 years.
Myeloma Trialists' Collaborative Group Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials.
Many investigators have sought to improve the results obtained with melphalan plus prednisone by using more complex multiagent chemotherapy. Unfortunately, these more aggressive combination chemotherapeutic regimens such as vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone (VBMCP) result in superior response rates (60%-70%) but no substantial survival benefit.
Myeloma Trialists' Collaborative Group Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials.
Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and pred-nisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479.
Similarly, the addition of interferon to initial therapy produces slightly better response rates with no clinically meaningful improvement in survival.
Myeloma Trialists' Collaborative Group Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients.
As a result, melphalan and prednisone remain the best choice for initial therapy for patients who are not candidates for stem cell transplantation.
Alternatives to melphalan and prednisone are useful when a more rapid reduction of tumor burden is needed or when melphalan and prednisone are ineffective. A good alternative is VBMCP, as is the regimen of vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD).
It is thought that highdose dexamethasone accounts for most of the activity of the VAD regimen, with much less toxicity. Dexamethasone is administered at a dose of 40 mg/d orally on days 1 through 4, 9 through 12, and 17 through 20 every 5 weeks. Dexamethasone has the advantage over melphalan of not causing alky lator-mediated stem cell damage. However, toxicity may be higher, including severe proximal muscle weakness and increased risk of opportunistic infections.
Autologous Stem Cell Transplantation
High-dose therapy followed by autologous stem cell transplantation improves response rate and survival in patients with myeloma, but the strategy is not curative.
A French randomized trial in 200 previously untreated patients with myeloma showed improved survival with autologous bone marrow transplantation compared with conventional chemotherapy, with 5-year survival rates of 52% and 12%, respectively.
Thus, the current standard of care is autologous stem cell transplantation for eligible patients younger than 65 years with good performance status and adequate renal function. Preliminary data from a recent randomized trial by the Spanish Cooperative Group have not yet confirmed a similar difference in overall survival.
High-dose therapy autotransplantation/intensification vs continued conventional chemotherapy in multiple myeloma patients responding to initial treatment chemotherapy: results of a prospective randomized trial from the Spanish Cooperative Group PETHEMA [abstract].
Based on this study and others, there are concerns regarding the true efficacy of stem cell transplantation, especially with the emergence of novel active agents such as thalidomide and the proteasome inhibitor PS-341.
Age older than 65 years alone is not a contraindication for transplantation.
Such patients are candidates for transplantation if they have good functional status and limited comorbidity.
The process of transplantation involves 3 to 4 cycles of induction therapy to minimize tumor burden, then peripheral blood stem cell collection using apheresis techniques (harvest), followed by high-dose myeloablative therapy (conditioning regimen), and finally reinfusion of stem cells (rescue). Peripheral blood stem cells are preferred over bone marrow because they result in more rapid engraftment and minimize discomfort to the patient compared with that from bone marrow collection. The standard conditioning regimen is melphalan, 200 mg/m2. Total body irradiation is not used, based on the results of a French randomized trial showing increased toxicity with no significant survival benefit.
Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial.
Similarly, stem cells are not purged of contaminating myeloma cells or enriched for CD34+ cells, based on the results of a large randomized trial that showed no clinical benefit.
Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized controlled trial.
Controversial issues in the treatment of myeloma with stem cell transplantation are discussed subsequently.
Optimum Pretransplantation Induction Regimen.—Although infusional VAD is considered the standard pretransplantation induction therapy, it is cumbersome to administer and is associated with substantial toxicity. Lack of response to initial VAD (primary refractory disease) does not portend poor survival after transplantation, and patients are treated with transplantation regardless of response status to VAD.
The best strategy for managing patients who have progressive disease with induction therapy is unclear. Alternative induction regimens with new agents may be an option and need to be studied. It is clear that dexamethasone accounts for a significant proportion of the activity of VAD, and although the response rate may be lower, there is no effect on overall survival.
Autologous stem cell transplantation (ASCT) after nonmyelosuppressive induction therapy with dexamethasone alone is safe and effective for newly diagnosed multiple myeloma (MM) pts who receive high dose chemotherapy (HDC) [abstract].
Therefore, dexamethasone is an appropriate alternative to VAD as pretransplantation induction therapy.
Recently, there was interest in thalidomide as induction therapy. A Mayo Clinic study of 50 patients with previously untreated myeloma showed a response rate of 64% with use of the combination of low-dose thalidomide (200 mg/d) and pulsed dexamethasone.
This regimen may be a suitable oral alternative to infusional chemotherapy with VAD as initial treatment of myeloma in preparation for stem cell transplantation. An Eastern Cooperative Oncology Group randomized phase 3 trial of thalidomide plus dexamethasone vs dexamethasone alone as induction therapy for newly diagnosed myeloma is ongoing in the United States (P.R.G., oral communication, June 2002).
Prolonged alkylator therapy before transplantation results in poor engraftment. Hence, alkylating agents should be avoided in patients who are candidates for stem cell transplantation.
Factors influencing collection of peripheral blood progenitor cells following high-dose cyclophosphamide and granulocyte colony-stimulating factor in patients with multiple myeloma.
Early vs Delayed Transplantation.—Autologous stem cell transplantation for myeloma is often performed early in the course of the disease, after 3 to 4 cycles of induction chemotherapy. However, it is possible to delay transplantation until relapse without compromising survival, provided hematopoietic stem cells are harvested and cryopreserved early in the course of disease before alkylator therapy. Data from 2 French randomized trials that compared early vs delayed transplantation indicate no significant difference in outcome between the 2 strategies.
High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? results of a multicenter sequential randomized clinical trial.
Front-line or rescue autologous bone marrow transplantation (ABMT) following a first course of high dose melphalan (HDM) in multiple myeloma (MM): preliminary results of a prospective randomized trial (CIAM protocol) [abstract].
The results of another large US multicenter randomized trial addressing this issue were recently obtained, analysis of which is awaited (P.R.G., oral communication, June 2002). The choice between the 2 options currently is based on patient preference and other clinical conditions and risk factors.
Single vs Tandem Transplantation.—At present the role of tandem (double) transplantation in myeloma is unclear. With tandem transplantation, patients receive a second planned transplant after recovery from the first procedure. Barlogie et al
Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities.
at the University of Arkansas advocate tandem autologous stem cell transplantation to improve CR rates and survival. In a study of 231 patients with newly diagnosed myeloma, they showed that more than 70% of patients are able to go through induction therapy and both transplantations successfully.
The mortality rates were 3% during induction, 1% with the first transplant, and 4% with the second transplant. With use of an intent-to-treat analysis, the CR rate was 26% with the first transplant and 41% after the second transplantation. Overall survival with this approach was 68 months. These results have prompted several studies of tandem stem cell transplantation in myeloma.
Preliminary data from 4 different randomized trials on this treatment strategy were presented recently.
These trials indicate a slight increase in response rates and possibly event-free survival with tandem transplantation. However, only 1 of the 4 trials has thus far shown any improvement in overall survival with tandem transplantation.
The final results of these trials will clarify this important issue. Because the role of tandem transplantation is not settled, it is wise to harvest enough stem cells for 2 transplantations. At Mayo Clinic, Rochester, Minn, a single transplantation is done with half of the stem cells collected, and the other half are cryopreserved for transplantation at relapse. A recent study by Sirohi et al
suggests that this strategy produces results equivalent to those reported with tandem transplantation.
Role of Allogeneic Transplantation.—Autologous stem cell transplantation has 2 drawbacks. First, the harvested stem cells are inevitably contaminated by tumor cells. Second, there is no possibility of an immunologically mediated graft-vs-myeloma effect. Allogeneic transplantation eliminates the problem of tumor cell contamination of the stem cells. Furthermore, using donor lymphocyte infusions, several investigators found a graft-vs-myeloma effect in myeloma with allografting.
High-dose busulfan and cyclophosphamide are an effective conditioning regimen for allogeneic bone marrow transplantation in chemosensitive multiple myeloma.
However, the high treatment-related mortality rate (approximately 30%) and significant toxicity from graft-vs-host disease (GVHD) have limited the role of this procedure in the treatment of myeloma. As a result, we rarely recommend conventional allogeneic bone marrow transplantation for the treatment of myeloma.
There is interest in studying nonmyeloablative (“mini”) allogeneic transplantation for selected patients with myeloma, either immediately after autologous stem cell transplantation
recently reported results in 32 patients treated with autologous stem cell transplantation followed by a nonmyeloablative allogeneic transplantation. They used melphalan, 200 mg/m2, as the conditioning regimen for autologous transplantation and mycophenolate, cyclosporine, and total body irradiation (200 cGy) as conditioning agents for the nonmyeloablative allogeneic transplantation. All allografts were from HLA-identical sibling donors. The response rate to therapy was 84%, with a relatively low day-100 treatment-related mortality rate of 6%. However, the high incidences of acute (45%) and chronic (55%) GVHD tempered enthusiasm for this approach. A recent study by Badros et al
also confirmed the high incidence of GVHD with this approach, with rates of 58% for acute GVHD and 29% for chronic GVHD. Treatment-related mortality was 29%. Until further refinements are made and additional confirmatory studies are completed, the role of allogeneic stem cell transplantation as initial therapy for myeloma must be considered investigational.
Maintenance Therapy
The role of maintenance therapy after either conventional-dose melphalan plus prednisone therapy or stem cell transplantation is investigational. Several studies show that interferon alfa as maintenance therapy prolongs the plateau phase in patients with myeloma.
A comparison of poly-chemotherapy and melphalan/prednisone for primary remission induction, and interferon-alpha for maintenance treatment, in multiple myeloma: a prospective trial of the German Myeloma Treatment Group.
A large randomized trial in the United States evaluating the role of interferon alfa as maintenance therapy for myeloma is awaiting analysis (P.R.G., oral communication, June 2002). The Myeloma Trialists’ Collaborative Group recently completed a meta-analysis of interferon alfa therapy for myeloma.
Myeloma Trialists' Collaborative Group Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients.
The analysis included 12 maintenance trials with 1543 patients. Maintenance therapy with interferon alfa was associated with a slight increase in overall survival by about 4 months with the benefit restricted to the smaller trials. Given the cost, adverse effects, and minimal benefits, interferon alfa is not routinely used as maintenance therapy.
Prednisone at low doses has been studied as maintenance therapy and is promising.
In a recently published randomized trial, progression-free survival after initiation of maintenance therapy was significantly longer in patients receiving 50 mg of prednisone orally every other day compared with those receiving a lower dose of 10 mg every other day, with median progression-free survival times of 14 vs 5 months, respectively.
A similar difference was seen in overall survival, with median times of 37 vs 26 months, respectively.
Clinical trials currently are being designed for further study of the role of low-dose prednisone, as well as thalidomide, dendritic cell vaccination, and other novel approaches as maintenance therapy after stem cell transplantation or conventional chemotherapy.
Supportive Care Strategies
Myeloma is characterized by osteolytic lesions, fractures, and osteoporosis that cause pronounced pain. Anemia, infections, hypercalcemia, and renal failure are other common complications. As a result, supportive care measures are important in management.
Bisphosphonates to Prevent Myeloma Bone Disease.—Recent studies
show that bisphosphonates (such as pamidronate or zoledronic acid) can delay or prevent osteolytic lesions, osteoporosis, and vertebral compression fractures. The goal is to prevent or delay skeletal events.
Randomized trials show that pamidronate at a dose of 90 mg intravenously over 4 hours every month reduces skeletal complications and improves the quality of life of patients with myeloma.
Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.
Based on these studies, we now recommend that all patients with myeloma-related bone disease receive bisphosphonate therapy monthly as supportive care, for an indefinite period. The role of bisphosphonates in patients who have no evidence of bone disease is unclear and needs further investigation.
Treatment of Anemia.—Anemia is a source of distress for patients, resulting in fatigue and poor performance status. Reversible causes of anemia such as iron, folate, or vitamin B12 deficiency must be identified and treated. Anemia is often secondary to bone marrow involvement and renal dysfunction. Treatment of the underlying disease and improvement in renal function often lead to improvement in hemoglobin concentration. Erythropoietin therapy can improve the anemia associated with myeloma and is well tolerated.
Clinical results of recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokines and monitoring of erythropoiesis.
Erythropoietin therapy should be considered for myeloma patients with symptomatic anemia who are receiving myelosuppressive chemotherapy or have severe renal dysfunction. Blood transfusions are indicated for patients with severe anemia who do not receive substantial benefit from other therapies.
Management of Infections.—Patients with myeloma are prone to infectious complications due to suppressed humoral and cell-mediated immunity from the disease and the added effects of therapy. The principal organisms involved are Streptococcus pneumoniae and Haemophilus influenzae.
Herpes zoster activation is also common and requires antiviral therapy to prevent dissemination. Patients with severe hypogammaglobulinemia and recurrent infections may benefit from monthly intravenous immunoglobulin infusions.
For patients receiving high-dose corticosteroid regimens, prophylactic therapy against Pneumocystis carinii with trimethoprim-sulfamethoxazole must be considered.
Fungal infections can occur with high-dose corticosteroid therapy, but no data are available on the role of antifungal prophylaxis. A large randomized trial is ongoing in the United States to determine the role of prophylactic antibiotics in myeloma patients undergoing chemotherapy (P.R.G., oral communication, June 2002).
Management of Hypercalcemia.—The current treatment of hypercalcemia in myeloma is aggressive hydration and corticosteroid therapy. Bisphosphonates are given if no response occurs or if the hypercalcemia is severe. A single dose of pamidronate, 60 to 90 mg intravenously over 2 to 4 hours, will normalize the calcium levels within 24 to 72 hours in most patients.
Treatment of cancer-associated hypercalcemia: double-blind comparison of rapid and slow intravenous infusion regimens of pamidronate disodium and saline alone.
Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials.
With the advent of bisphosphonates, true refractory hypercalcemia is rare. Occasionally, salmon calcitonin, 4 IU/kg every 12 hours, is used if a rapid reduction in serum calcium is needed. A skin test (0.1 mL of a 10 IU/mL dilution, intracutaneous) to rule out hypersensitivity is performed before salmon calcitonin is administered.
Management of Renal Failure.—Patients with myeloma are prone to renal failure from various causes. Prompt treatment of myeloma with chemotherapy is critical for the control of renal failure and prognosis.
The most common reversible causes of renal failure in patients with myeloma are hypercalcemia and dehydration. Light chain cast nephropathy (myeloma kidney) is an important cause of renal failure that requires treatment with hydration and institution of chemotherapy to control the light chain production. Alkaline diuresis may be helpful. Selected patients with excess light chain excretion in the urine and evolving acute renal failure due to cast nephropathy may benefit from plasmapheresis. Data from a small randomized trial showed that plasmapheresis can lead to recovery of renal function.
Pain Control Measures and Orthopedic Interventions.—Narcotic analgesics may be needed to control bone pain from osteolytic lesions or fractures. Splinting or other orthopedic interventions such as vertebroplasty can also reduce pain. Physical therapy and activity should be encouraged because there is a high risk of deep venous thrombosis (DVT) in the first 6 months after myeloma diagnosis, likely a result of immobilization. Mild degrees of pain can be controlled with acetaminophen-codeine, acetaminophen-oxycodone, or similar preparations. Nonsteroidal anti-inflammatory agents can precipitate renal failure or exaggerate corticosteroid-induced gastritis in patients with myeloma and should generally be avoided.
For severe pain, oral morphine sulfate administered as a sustained-release preparation with an immediate release form available for breakthrough pain is effective. Alternatives to morphine include hydromorphone or transdermal fentanyl. Radiation therapy to limited areas is indicated to control pain that is refractory to narcotics and to prevent or treat spinal cord compression. Orthopedic interventions and/or radiation may also be needed to prevent or treat pathologic fracture in susceptible long bones with large lytic lesions. In general, it is wise to limit the amount of radiation that is administered because radiation to large areas of bone can limit the amount of systemic chemotherapy that can be administered. The dose of radiation must be individualized, and some patients may require doses lower than the traditional 30 Gy administered in 10 fractions.
Therapy for relapsed myeloma is inadequate. Typically, patients who have relapse are treated with chemotherapeutic regimens such as VAD, VBMCP, pulsed methylprednisolone, or dexamethasone. Remissions with such therapy are usually short-lived. In selected patients with refractory disease, stem cell transplantation may be beneficial.
The choice of therapy depends on several factors, including the nature of the relapse, response to initial therapy, number of prior treatment regimens, age, performance status, and patient preference.
In general, patients who have relapse several months after remission induced by alkylator-based therapy should receive the same regimen. However, high-dose corticosteroids may be a reasonable option if the response duration after alkylator-based therapy is brief or for patients who have relapse shortly after stem cell transplantation. A second transplant is probably futile in patients who have relapse very early after the initial procedure. The choice of therapy for relapsed myeloma is based on weighing the risks and benefits of each option, and the final decision should consider the patient's wishes. No standard therapy exists for relapsed myeloma, and depending on the clinical situation any or all of the approaches mentioned in Table 1 can be considered. Patients refractory to 1 regimen may respond to another. At each step, based on the clinical situation, palliative and supportive care must also be considered.
Table 1Therapeutic Options for Patients With Relapsed Myeloma
Modality
Comment
Autologous stem cell transplantation
For eligible patients in whom cryopreserved stem cells are available or for patients who have received minimal alkylator therapy in whom stem cells can be collected
Alkylator-based therapy
Melphalan plus prednisone or combination chemotherapeutic regimens such as VBMCP (vincristine, carmustine [BCNU], melphalan, cyclophosphamide, prednisone)
Corticosteroids
High-dose corticosteroid-based therapy such as dexamethasone alone, VAD (vincristine, doxorubicin [Adriamycin], dexamethasone), or methylprednisolone
Thalidomide
As single agent or in combination with corticosteroids or chemotherapy
Investigational therapy
In approved clinical trials including miniallogeneic transplantation and novel agents such as PS-341 and CC-5013
at the University of Arkansas conducted the first trial investigating the activity of thalidomide in relapsed myeloma. In most patients, stem cell transplantation had failed. The overall response rate defined as a decrease in monoclonal protein levels by 25% or more was 32%. Paraprotein responses were accompanied by improvements in anemia and other symptoms. The median duration of response was not achieved after 14.5 months of follow-up. An update to this study confirms the activity of thalidomide in 169 patients with relapsed myeloma.
Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients.
The usual initial dose is 200 mg/d, increased after 2 weeks to 400 mg/d. Most patients will respond to these dose levels, and further dose escalation usually is not needed. However, some patients will require a higher dose (up to 800 mg/d) to achieve or sustain a response.
The return of thalidomide to clinical practice as an effective agent in the treatment of myeloma represents a major comeback by a drug with a notorious past.
Thalidomide was first marketed in the late 1950s as a sedative in more than 40 countries. In the United States, the Food and Drug Administration was concerned about peripheral neuropathy, and the drug was not approved for clinical use. In 1961, the severe teratogenic potential of the drug was recognized, and thalidomide was taken off the market. However, thalidomide never really disappeared. The drug was soon found to be effective in the treatment of erythema nodosum leprosum. Over the past 10 years, other uses emerged, such as the treatment of acquired immunodeficiency syndrome-related cachexia and oral ulcers, aphthous ulcers in Behcet disease, and chronic GVHD. In 1998, the Food and Drug Administration approved the drug for use in erythema nodusum leprosum, with substantial precautions.
The study of thalidomide in myeloma was prompted by 2 factors: the understanding that angiogenesis (new vessel formation) is critical for the proliferation and metastases of most malignant neoplasms, including myeloma,
Because of its severe teratogenicity, the use of thalidomide in pregnant women is absolutely contraindicated. Women of childbearing age must undergo pregnancy testing before therapy is initiated and every 2 to 4 weeks during treatment. They must abstain from sexual intercourse or use 2 highly effective contraceptive methods during treatment. Men must abstain from sexual intercourse or use a condom while receiving treatment even if they have had a successful vasectomy. All patients must continue these measures for at least 1 month after the last dose of the drug. Breast-feeding is contraindicated. In the United States, all patients, physicians, and pharmacists must participate in the System for Thalidomide Education and Prescribing Safety program that explains these risks and precautions before therapy is initiated.
The most common adverse effects of thalidomide are sedation, fatigue, constipation, and rash. Because severe constipation is a common problem, laxatives are recommended prophylactically. If a rash occurs, the drug should be discontinued and reinstituted at a lower dose after the rash clears. Thalidomide also causes peripheral neuropathy, generally after chronic use over a period of several months. There is also increasing concern about the relationship between thalidomide therapy and DVT. The incidence of DVT is approximately 1% to 2% in patients receiving thalidomide alone, 10% in patients receiving thalidomide in combination with dexamethasone, and about 25% in patients receiving the agent in combination with other cytotoxic chemotherapeutic agents, particularly doxorubicin.
Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients.
The role of prophylactic low-dose warfarin or low-molecular-weight heparin for high-risk patients receiving thalidomide in combination with other regimens remains unclear. Also, because some myeloma patients are predisposed to DVT due to their malignancy and reduced mobility from osteolytic lesions, the precise contribution of thalidomide to the incidence of DVT remains to be determined.
Other less common but important adverse effects of thalidomide include edema, bradycardia, neutropenia, increased liver enzymes, menstrual irregularities, impotence, hyperglycemia or hypoglycemia, and hypothyroidism.
Novel Agents
Given the activity of thalidomide in myeloma, investigations are under way to identify safer and more active analogues. Immunomodulatory drugs represent a class of thalidomide analogues that show promise in laboratory studies. Two recently completed phase 1 trials with an immunomodulatory drug (CC-5013) have shown significant activity in heavily pretreated patients with refractory disease.
A phase 1 study of oral CC5013, an immunomodulatory thalidomide (Thal) derivative, in patients with relapsed and refractory multiple myeloma (MM) [abstract].
Confirmatory phase 2 trials with this agent are ongoing.
The proteasome inhibitor PS-341 is another active agent in refractory myeloma. A recent multicenter trial with PS-341 in patients with refractory myeloma showed a response rate of 50%.
Phase II study of PS-341, a novel proteasome inhibitor, alone or in combination with dexamethasone in patients with multiple myeloma who have relapsed following front-line therapy and are refractory to their most recent therapy [abstract].
A confirmatory phase 3 trial comparing PS-341 with high-dose dexamethasone in the treatment of refractory myeloma is ongoing (M. Q. Lacy, MD, oral communication, June 2002).
Other active areas of investigation include dendritic cell vaccination, 2-methoxyestradiol, farnesyl transferase inhibitors, flavopiridol, and inhibitors of angiogenic cytokines.
FUTURE DIRECTIONS
After 3 decades of alkylator- and corticosteroid-based therapy, major strides are being made in the treatment of myeloma, and several novel agents have emerged. Future studies will seek to define the role of these novel agents, improve transplantation-conditioning regimens, and develop effective maintenance therapy. Nonmyeloablative allogeneic transplantation is promising. These advances are still short of the eventual goal of a cure. However, the momentum clearly is in favor of dramatic strides in the next decade.
Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and pred-nisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479.
High-dose therapy autotransplantation/intensification vs continued conventional chemotherapy in multiple myeloma patients responding to initial treatment chemotherapy: results of a prospective randomized trial from the Spanish Cooperative Group PETHEMA [abstract].
Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial.
Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized controlled trial.
Autologous stem cell transplantation (ASCT) after nonmyelosuppressive induction therapy with dexamethasone alone is safe and effective for newly diagnosed multiple myeloma (MM) pts who receive high dose chemotherapy (HDC) [abstract].
Factors influencing collection of peripheral blood progenitor cells following high-dose cyclophosphamide and granulocyte colony-stimulating factor in patients with multiple myeloma.
High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? results of a multicenter sequential randomized clinical trial.
Front-line or rescue autologous bone marrow transplantation (ABMT) following a first course of high dose melphalan (HDM) in multiple myeloma (MM): preliminary results of a prospective randomized trial (CIAM protocol) [abstract].
Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities.
High-dose busulfan and cyclophosphamide are an effective conditioning regimen for allogeneic bone marrow transplantation in chemosensitive multiple myeloma.
A comparison of poly-chemotherapy and melphalan/prednisone for primary remission induction, and interferon-alpha for maintenance treatment, in multiple myeloma: a prospective trial of the German Myeloma Treatment Group.
Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.
Clinical results of recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokines and monitoring of erythropoiesis.
Treatment of cancer-associated hypercalcemia: double-blind comparison of rapid and slow intravenous infusion regimens of pamidronate disodium and saline alone.
Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials.
Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients.
A phase 1 study of oral CC5013, an immunomodulatory thalidomide (Thal) derivative, in patients with relapsed and refractory multiple myeloma (MM) [abstract].
Phase II study of PS-341, a novel proteasome inhibitor, alone or in combination with dexamethasone in patients with multiple myeloma who have relapsed following front-line therapy and are refractory to their most recent therapy [abstract].
This study was supported in part by grants CA93842, CA85818, and CA62242 from the National Cancer Institute, Bethesda, Md. Dr Rajkumar is a Leukemia and Lymphoma Society of America Translational Research Awardee and is also supported by the Judith and George Goldman Foundation Fighting Catastrophic Diseases and by the Multiple Myeloma Research Foundation.
Additional members of the Mayo Clinic Myeloma, Amyloid, and Dysproteinemia Group are listed at the end of this article
Additional members of the Mayo Clinic Myeloma, Amyloid, and Dysproteinemia Group are: Drs Rafael Fonseca, Angela Dispenzieri, Martha Q. Lacy, John A. Lust, Thomas E. Witzig, and Stephen J. Russell.
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