Commentary on Abstracts #28, #27, #99, and #111

These four studies further establish the remarkable antitumor activity of thalidomide (Thalomid) in a variety of hematologic disorders. This drug was initially used as a nonbarbiturate sedative/hypnotic and antiemetic during pregnancy in the 1950s. It was learned shortly after its introduction that this drug caused birth defects in the form of severe infant limb defects (phocomelia). This discovery led to its withdrawal from the market in the early 1960s. Interestingly, it was this teratogenic effect that suggested that this drug might possess antiangiogenic properties, which was demonstrated shortly thereafter in a number of animal models.

Angiogenesis in Hematologic Malignancies

Over the past few years, it has become clear that a number of hematologic malignancies are associated with enhanced angiogenesis. Specifically, myeloma patients show increased numbers of blood vessels in their bone marrow, and the extent of bone marrow angiogenesis is correlated with overall outcome. Elevated levels of cytokines such as basic fibroblastic growth factor (bFGF) and vascular endothelial growth factor (VEGF) are found in myeloma patients. VEGF has recently been shown to be produced by malignant plasma cells and capable of enhancing interleukin-6 secretion by bone marrow stromal cells in myeloma patients. Interleukin-6 has been shown to stimulate growth and prevent apoptosis of malignant plasma cells. Recent studies show that VEGF is an important cytokine in early osteoclast activation; this protein may also be involved in the pathogenesis of myeloma bone disease. In addition, human herpesvirus 8-which is found in the bone marrow of most myeloma patients-expresses viral proteins such as an interleukin-8–receptor homolog and chemokines, which are potent inducers of angiogenesis. Similar increases in angiogenesis have been observed in the bone marrow of patients with other hematologic disorders, including non-Hodgkin’s lymphoma, acute lymphoblastic leukemia, myelodysplasia, and acute myelogenous leukemia. These findings have provided the rationale for the use of antiangiogenesis drugs such as thalidomide in the treatment of hematologic malignancies.

Antitumor Mechanisms of Action of Thalidomide

Thalidomide has been shown to inhibit angiogenesis in a variety of ways. It reduced corneal neovascularization induced by bFGF in a rabbit model and by VEGF in a murine model. Recent studies suggest that the antiangiogenic effects may be mediated by the generation of hydroxyl radicals by this drug. In addition, it is clear that this agent has a number of other potential antitumor mechanisms of action. The drug reduces tumor necrosis factor–alpha (TNF-alpha) production by monocytes and macrophages. Its efficacy in erythema nodosum leprosum is associated with a drop in serum levels of this cytokine. This protein is thought to play a critical role in the development of myeloma and its most important clinical manifestation-bone disease.

Thalidomide has also been shown to alter the expression of adhesion molecules, especially members of the integrin-receptor family. Moreover, it has been shown to have effects on T-cell function. In vitro, the drug is a potent costimulator of T-cell responses, particularly in the CD8-expressing subset. However, the exact antitumor mechanisms of action of thalidomide remain an enigma. This is an important area for further studies, because elucidating the drug’s mechanisms may lead to the development of other agents with enhanced antitumor activity and reduced toxicity.

Multiple Myeloma

The majority of myeloma patients respond to chemotherapy and/or glucocorticosteroid therapy, and complete responses can be achieved in 20% to 40% of patients following high-dose chemotherapy. However, all of these patients will ultimately relapse, with a paucity of therapeutic options available. Even in responding patients, antitumor effects are only of short duration. Thus, it is imperative that new agents be evaluated in these patients.

The recent pivotal report from the University of Arkansas demonstrating the antitumor activity of thalidomide in relapsing multiple myeloma patients has led to a dramatic change in the treatment of patients with relapsing disease. Most of the 84 patients in the initial report had relapsed following autologous peripheral blood stem-cell transplantation. The doses of thalidomide varied from 200 to 800 mg daily, with most (56%) of the patients receiving the maximum dose. Responses (³ 25% reduction in paraprotein) were observed in nearly one-third of patients, within 2 months of initiation of therapy in most cases. However, side effects were observed in the majority of patients in a dose-related fashion and included somnolence, weakness, constipation, neuropathies, edema, and skin rash.

An update including an additional 85 previously treated patients continues to show a ³ 25% paraprotein reduction in one-third of cases, many of whom had poor prognostic features (abstract #28). Consistent with other data evaluating prognostic factors among patients undergoing high-dose therapy at the University of Arkansas, loss of chromosome 13 was associated with a worse outcome. It is clear from many other reports that this agent has marked antimyeloma activity alone, even for patients with plasma-cell leukemia and extramedullary disease. Some of these reports show similar antimyeloma activity with lower doses that are better tolerated.

Single-Agent Thalidomide vs Combination Therapy

However, only a minority of patients respond to single-agent thalidomide. Moreover, the duration of response varies greatly and may last only a few months for some patients. Thus, it is clear that there is a need for improvement. Combining thalidomide with other drugs with known activity in myeloma is one possibility. The University of Arkansas has initiated a number of trials evaluating thalidomide with steroids alone or combination chemotherapy (abstract #28). Importantly, a number of studies suggest that the addition of thalidomide to other agents potentiates their antitumor effects. This has been demonstrated in animal models with combinations involving chemotherapeutic agents and nonsteroidal anti-inflammatory drugs. Previous in vitro studies suggested the synergistic antitumor effects of the combination of steroids with thalidomide on tumor cells from multiple myeloma patients. The M. D. Anderson group showed that in relapsing myeloma patients failing to respond to single-agent thalidomide, the addition of oral dexamethasone at 40 mg for 4 days three times monthly led to responses in nearly an additional third of patients. In addition, a number of reports suggest that those patients unresponsive to both glucocorticosteroids and thalidomide as single agents may nonetheless have dramatic responses to the combination.

Durie previously presented findings suggesting that the macrolide antibiotic clarithromycin (Biaxin) may possess antimyeloma activity in a small study of previously relapsing patients. This led to the combination evaluated by Coleman and colleagues in patients with multiple myeloma and Waldenstrom’s macroglobulinemia (abstract #27). Patients received oral clarithromycin at 500 mg twice daily; oral thalidomide at 50 mg/d, initially escalated by 50 mg/d biweekly to a maximum oral dose of 200 mg/d; and oral dexamethasone at 40 mg/wk. An update of the data presented at the 2000 American Society of Clinical Oncology meeting showed that 29 patients, most of whom had relapsed previously, were evaluated. All 21 evaluable patients responded to the combination, with complete remissions observed in three cases and most patients showing a ³ 75% reduction in paraprotein levels. Moreover, the remissions were durable with no relapses observed to date in any of the 21 patients. Among the eight other patients considered not evaluable, five were too early in treatment and three died suddenly. These three latter patients had a history of prior cardiopulmonary disease.

Key Points

• Dose: The Coleman study demonstrates several key points regarding the use of thalidomide among patients with monoclonal gammopathies. First, it suggests that lower doses of thalidomide may be highly effective, especially when combined with other antimyeloma agents. The relatively low dose of dexamethasone was also shown to be effective in this combination. Thus, the addition of thalidomide to dexamethasone may allow lower doses of glucocorticosteroids to be administered to these patients, and may result in a reduction in the side effects from steroids without compromising antimyeloma activity. The contribution of clarithromycin to the antimyeloma activity of this combination is somewhat unclear, because other reports from the Mayo Clinic and the French group showed no antitumor activity of this agent alone in multiple myeloma. However, it is certainly possible that this antibiotic potentiates the antimyeloma effects of one or both of the other two agents.

• Patient Monitoring: Second, the study supports the in vitro studies and previous small clinical trial from M. D. Anderson showing that the antimyeloma activity of thalidomide is enhanced by the addition of steroids. Third, the occurrence of three sudden deaths in the Coleman study indicates the importance of closely monitoring patients on this drug combination. It is clear from recent case reports that this drug can cause bradyarrhythmias, which may have contributed to the three patients’ demise. However, it is possible that these patients’ deaths were unrelated to the combination, or that the addition of clarithromycin may have specifically had some untoward effect on these three patients.

• Risks: Recent reports also suggest an increased risk of bleeding, as well as clotting problems among patients treated with thalidomide. Specifically, gastrointestinal bleeding, deep venous thromboses, and pulmonary emboli have been reported in some patients receiving thalidomide alone or with steroids. Whether this results from an inability to “neovascularize” (repair) local blood vessel damage or from other effects of this drug on the clotting system remains unknown. It is important that patients on the combination receive appropriate acid-lowering drugs, as was done in the Coleman study (omeprazole [Prilosec]), and that they be aware of the signs of deep venous thrombosis and pulmonary embolism. It is also important to recognize that patients experiencing deep venous thrombosis or pulmonary embolism respond to anticoagulation, and may be continued on thalidomide without additional clotting problems.

Activity in Waldenstrom's Macroglobulinemia

Fourth, the study suggests the activity of thalidomide in Waldenstrom’s macroglobulinemia-another malignancy associated with monoclonal gammopathies. This is further supported by the study of Dimopoulos (abstract #99). In the latter study, use of single-agent thalidomide resulted in a ³ 50% reduction in both the IgM paraprotein and organomegaly in three of seven patients with this B-cell malignancy. Similarly, our group has recently reported improvement in five of six patients with primary amyloidosis who received thalidomide alone (n = 1) or with glucocorticosteroids (n = 5). Most of these patients had previously received steroids and not responded to this drug as a single agent. These patients showed improvement in macroglossia, renal function, gastrointestinal symptoms, and neuropathic symptoms.

Questions Remaining

Many questions remain regarding the use of thalidomide for patients with myeloma, macroglobulinemia, and amyloidosis.

• What is the appropriate dose? Clearly, several recent groups, including our own, report success with lower doses as was reported by Coleman and colleagues (abstract #27). Should responding patients remain on the same dose of the drug indefinitely, or can it be reduced or discontinued altogether after some time period? Although most myeloma investigators are continuing the drug at the same dose until signs of progression occur, there are no clinical data to guide the physician on when to reduce or discontinue the drug. However, studies evaluating other antiangiogenesis agents suggest that withdrawal of these drugs for prolonged periods is not accompanied by the development of drug resistance as is commonplace with conventional chemotherapeutic agents. This is important given the cost and side effects associated with thalidomide.

On the other hand, several recent reports show that progressive disease may not be an indication to discontinue treatment with thalidomide. In fact, patients relapsing while on thalidomide alone may respond dramatically to the addition of steroids or other chemotherapeutic agents that were previously ineffective. Support for this approach comes from studies showing the synergistic antitumor effect of chemotherapy and antiangiogenesis treatment in a number of animal models. Should the drug be used as maintenance therapy? Recent studies show the efficacy of low-dose prednisone as maintenance therapy for myeloma patients responding to conventional (vincristine/Adriamycin [doxorubicin]/dexamethasone [VAD]) chemotherapy. The Coleman study certainly suggests the marked antimyeloma activity of the combination of steroids and thalidomide consistent with the results from the M. D. Anderson group and our own experience. The use of thalidomide in maintenance therapy certainly is an area ripe for clinical investigation.

 • What is the role of this drug as part of up-front therapy for myeloma patients? Because of its marked activity at better tolerated lower doses, even for patients with relapsing disease, thalidomide should be evaluated earlier in the course of the disease. It is clear that as most patients with myeloma are not candidates for high-dose therapy, other options should be explored. Although steroids, alkylating agents such as melphalan (Alkeran) or cyclophosphamide (Cytoxan, Neosar), or infusional VAD have activity in this disease, there certainly is a need to improve upon these results. It is already clear that thalidomide alone has activity in these diseases; the more interesting questions involve its use with these other active agents in newly diagnosed patients.

• Does thalidomide help reduce bone loss in myeloma patients? As mentioned earlier, it is becoming clear that VEGF plays a role in early osteoclast activation. Thus, it is possible that the use of antiangiogenesis agents may reduce bone resorption among myeloma patients. In fact, recent studies show that nitrogen-containing bisphosphonates such as pamidronate (Aredia) and zoledronic acid are markedly antiangiogenic. This may help explain in part the antitumor effects of these agents, and the survival advantage observed in some studies evaluating these drugs in myeloma patients. It is also possible that thalidomide may potentiate the anti–bone-resorptive effects of bisphosphonates in myeloma patients.

• Should thalidomide be given to patients requiring radiation therapy? Several recent studies show that other antiangiogenesis agents can potentiate the antitumor effects of radiotherapy. It is possible that thalidomide may provide additional benefit to myeloma patients requiring radiation therapy or improve the long-term survival among patients with solitary plasmacytoma who receive radiotherapy with curative intent. Importantly, the positive results with thalidomide have led to the initiation of clinical trials evaluating a number of other novel antiangiogenesis agents in these patients. Defining the optimal ways to use thalidomide among patients with myeloma, amyloidosis, and Waldenstrom’s macroglobulinemia will help guide the development of these other antiangiogenesis agents that are currently in early development.

Thalidomide in Myelodysplasia

Although a number of treatment options are available to patients with myelodysplasia, the results have been rather disappointing. Thus, there is a need for new approaches to this disorder. Similar to patients with myeloma, individuals with myelodysplasia also show increased amounts of TNF-alpha and blood vessels in their bone marrow. Thus, Raza and colleagues treated 61 patients with this disorder with doses of oral thalidomide ranging from 100 to 400 mg at bedtime for 12 weeks (abstract #111). Responses were observed in 17 of 25 evaluable patients and were accompanied by a reduction in transfusion dependence in many cases. Improvement was monolineage in most cases (n = 10) but some patients experienced bilineage (n = 4) or trilineage (n = 3) responses. The responses occurred more slowly than previously reported for myeloma patients. Among patients receiving 200 mg, the drug was well tolerated. The groups at the University of Arizona and M. D. Anderson have achieved similar results in patients with this disorder. It will be interesting to determine if long-term treatment with thalidomide leads to a reduction in the transformation to acute leukemia. In addition, the addition of thalidomide to other active agents in myelodysplasia should be evaluated. Other early reports suggest the activity of thalidomide among patients with myelofibrosis with improvement in organomegaly and cytopenias. The optimal dose remains to be determined for these patients as well as patients with myelodysplasia.

Summary

These four studies have provided additional support for the activity of thalidomide in a wide range of hematologic disorders. This nonchemotherapeutic treatment offers a novel approach to a variety of hematologic disorders that remain incurable. It adds a new active agent to the therapeutic armamentarium available to the treating physician that is likely to improve the overall outcome of patients with these diseases. It is important to note that this drug also provides further rationale for the evaluation of other novel antiangiogenesis agents for patients with hematologic disorders.