Targeted therapy of multiple myeloma

Abstract

The diagnosis of multiple myeloma requires the presence of monoclonal bone marrow plasma cells, a monoclonal (M) protein in serum and/or urine and evidence of end-organ damage from the plasma cell proliferative disorder. Initial therapy for transplant-eligible patients includes thalidomide, bortezomib or lenalidomide, all with dexamethasone. Stem cells for a possible autologous stem cell transplant (ASCT) should be collected if the patient is considered eligible for an ASCT. Initial therapy for patients ineligible for an autologous stem cell transplant includes melphalan and prednisone as well as thalidomide, bortezomib or lenalidomide. More than 100 agents are in phase I, II or III clinical trials. The most promising are carfilzomib and pomalidomide.

Keywords:

• Therapy
• Multiple myeloma

Introduction

Multiple Myeloma (MM) is a plasma cell malignancy that accounts for about 1% of all types of cancer. Its incidence is 4–5 per 100 000 in the United States; but the incidence has not changed in Olmsted County, Minnesota, for more than five decades.

The diagnosis of MM requires the presence of monoclonal bone marrow plasma cells, a monoclonal (M) protein in serum and/or urine and evidence of end-organ damage from the plasma cell proliferative disorder (CRAB). End-organ damage consists of hypercalcemia, renal insufficiency, anemia or bone lesions (CRAB). Smoldering multiple myeloma (asymptomatic) must be excluded. Smoldering multiple myeloma is characterized by an M protein ⩾3 g/dl and/or ⩾10% bone marrow plasma cells but no evidence of end-organ damage. The risk of progression to symptomatic MM occurs at a rate of approximately 10% per year for the first 5 years and then decreases.1

An Approach to Therapy

Patients with MM may be classified as high risk based upon fluorescence in situ hybridization. High-risk disease is characterized by del(17p), t(14;16) or t(14;20) or a high risk signature with gene expression profiling and constitutes about 25% of MM patients. Clinical trials are strongly recommended, but if they are not available, the physician must first decide whether the patient is eligible for an autologous stem cell transplant (ASCT). In most situations patients aged >70 years (physiologically), poor performance status (ECOG 3 or 4), New York Heart Association functional status (class III or IV) or other concomitant medical disorders are ineligible for an ASCT.

Initial Therapy for Transplantation-Eligible Patients

Alkylating agents have been associated with damage to the hematopoietic stem cells so they must be avoided because they may prevent mobilization of sufficient stem cells for a successful transplant. Most use granulocyte colony-stimulating factor with or without cyclophosphamide for stem cell collection. If this is not effective, Plerixafor is often helpful for the mobilization of hematopoietic stem cells.2 Sufficient stem cells for two transplants should be collected.

Thalidomide plus dexamethasone is a viable option for induction therapy. In a randomized study, 470 patients with symptomatic previously untreated MM were randomized to receive thalidomide in a dose of 50 mg daily with escalation to 200 mg daily if tolerated plus dexamethasone 40 mg (days 1–4, 9–12 and 17–20) vs placebo plus dexamethasone in the same dose and schedule. Sixty-three per cent of patients receiving thalidomide/dexamethasone obtained a response (CR/PR) compared to 40% for those receiving placebo plus dexamethasone. The time to progression was 22·6 months versus 6·5 months favoring the thalidomide/dexamethasone regimen. Deep vein thrombosis was more common in those receiving thalidomide/dexamethasone compared to dexamethasone alone (12 vs 2% respectively). Prophylactic prevention of thromboembolic phenomena is necessary. The System for Thalidomide Education and Prescribing Safety (STEPS) program must be followed when thalidomide is given.

Lenalidomide plus low-dose dexamethasone is another option. In a randomized trial of 445 previously untreated symptomatic MM, patients were assigned to lenalidomide (25 mg daily on days 1–21) plus high-dose dexamethasone (40 mg daily on days 1–4, 9–12, and 17–20) or to lenalidomide in the same dose and schedule plus dexamethasone 40 mg given weekly for each 28-day cycle.3 The 2-year survival was 87% for the weekly dexamethasone compared to 75% for the standard dose dexamethasone.

Bortezomib plus dexamethasone is another option for induction therapy. Forty-eight previously untreated symptomatic MM patients who received bortezomib 1·3 mg/m² twice weekly for 2 weeks every 3 weeks plus dexamethasone 40 mg on the day of and the day after bortezomib had a 90% response rate. The adverse effect of unfavorable cytogenetic abnormalities appears to be overcome by a bortezomib regimen. In addition, bortezomib plus dexamethasone is recommended for patients with renal failure. Bortezomib given weekly is not inferior to the previously standard twice weekly regimen.4 The addition of clarithromycin to lenalidomide and weekly dexamethasone has been reported to produce an objective response in 90% of patients.

Autologous Stem Cell Transplantation

Following 3–4 months of induction therapy with thalidomide, bortezomib or lenalidomide, all with dexamethasone, one must collect the stem cells. Induction therapy associated with a greater depth of response [Very Good Partial Response (VGPR) or Complete Response (CR)] before transplantation translates into superior progression-free survival (PFS) following transplantation.

The initial ASCT may be given ‘early’ when the patient recovers from hematopoietic stem cell collection or delayed until first relapse. In general, there is no difference in overall survival whether the ASCT is given early or late. Early ASCT allows for a shorter duration of chemotherapy, a longer event-free survival and a superior quality of life. Thus, we prefer an early ASCT.

The performance of a single or a double (tandem) ASCT is controversial. In general, it is felt that those patients who obtain a CR or a VGPR with the first ASCT do not benefit from a second transplantation. The advantages of an ASCT are that the mortality is approximately 1% and the procedure is available for up to one-half of patients with MM. Almost one-half of our patients who undergo an ASCT do so as an outpatient. Unfortunately, ASCT is not curative and patients must be told that they will likely relapse. The median duration of response is approximately 2 years.

The role of maintenance therapy following ASCT is controversial. Two large studies reported longer progression-free survival in patients undergoing an ASCT when randomized to lenalidomide maintenance compared to placebo. The PFS from the time of randomization was approximately 3·5 years with lenalidomide maintenance therapy versus 2 years when randomized to placebo. However, no meaningful survival data has been published. Although lenalidomide is well tolerated, cytopenias, fatigue and possibly serious side effects may occur in the future. The quality of life may be reduced with maintenance therapy because it entails office visits and repeated blood cell counts. The possibility of more second cancers is unlikely but has not been excluded. Patients who have undergone ASCT do not need to be followed up so frequently. In addition, the cost of maintenance therapy with lenalidomide approaches $100 000 dollars annually. However, patients with MM who have adverse prognostic features such as unfavorable cytogenetic abnormalities or a high-risk gene expression profile may benefit from maintenance therapy. More data are needed before deciding about maintenance therapy following ASCT. We do not use maintenance therapy following ASCT unless patients fall into the high-risk category. At present we recommend that patients who have obtained a response from an ASCT be followed without maintenance therapy unless they are part of a clinical trial.

Allogeneic Transplantation

The advantage of allogeneic transplantation is that there is no contamination of hematopoietic stem cells by tumor cells. Unfortunately, more than 90% of patients with MM are ineligible because of their age or lack of an HLA-matched donor. Although the mortality has been reduced from 40% to approximately 25%, we do not recommend conventional allogeneic transplantation in MM.

A nonmyeloablative stem cell transplantation has been recommended for MM. It is probably better to perform an ASCT prior to the nonmyeloablative allogeneic stem cell transplant. The mortality rate has been reduced but relapse of the myeloma and the graft-versus-host reaction are major problems.

Initial Therapy for Patients Ineligible for an Autologous Stem Cell Transplant

The first active agent for the treatment of MM was melphalan which was introduced in 1958. Prednisone was subsequently added to melphalan and this became the standard therapy for almost four decades. However, melphalan and prednisone result in a response rate of only 50–60%. Therefore, for decades investigators developed various combinations of chemotherapeutic agents. In a large meta-analysis of nearly 5000 symptomatic myeloma patients in 20 prospective trials, the response rate was 60% for a variety of chemotherapy combination regimens compared with 53% for melphalan and prednisone (P<0·00001). However, there was no difference in overall survival and no subsets benefited from either single or multiple combinations of chemotherapeutic agents.

In a randomized study, melphalan, prednisone and thalidomide were compared with melphalan and prednisone. The response rate of 76% was superior to the melphalan plus prednisone regimen (48%). The 3-year overall survival favored the melphalan, prednisone and thalidomide regimen (80 vs 64%). In another study, 447 previously untreated patients ineligible for an ASCT were randomized to melphalan, prednisone and thalidomide or melphalan plus prednisone (MP) or melphalan 100 mg/m² IV × 2 followed by stem cell rescue. The overall survival was 52, 33 and 38 months, respectively for the three approaches.

In another study from France, 229 patients aged >75 years who were previously untreated were randomized to melphalan, prednisone and thalidomide or melphalan and prednisone. The overall survival was 45·3 months for the combination with thalidomide compared to 27·7 months for melphalan and prednisone alone. In another report 511 patients with untreated MM >65 years of age were randomized to bortezomib, melphalan, prednisone and thalidomide with bortezomib and thalidomide maintenance or to bortezomib, melphalan and prednisone. The response rate, 89 vs 81% and the three-year PFS were superior with the combination and maintenance (56 vs 41%) but the three-year overall survival was not statistically different (89 vs 87%). On the other hand, a total of 289 elderly patients was randomized to thalidomide and dexamethasone or to melphalan and prednisone; overall survival was 41·5 vs 49·4 months respectively. As expected, toxicity was greater with thalidomide and dexamethasone, especially in patients with poor performance who were >75 years of age.

Another option is bortezomib for patients ineligible for an ASCT. A total of of 668 patients considered ineligible for an ASCT were randomized to bortezomib, melphalan and prednisone or melphalan and prednisone in the same dose and schedule. CR plus VGPR was reported in 45% of the patients receiving the three agents compared to 10% for those given melphalan and prednisone only. A partial response or better was found in 71% of those randomized to melphalan, prednisone and bortezomib compared to 35% for those given only melphalan and prednisone. The median duration of response was 19·9 vs 13·1months, favoring the combination. However, peripheral neuropathy occurred in 44% of those receiving bortezomib, melphalan and prednisone compared to 5% of patients receiving only melphalan and prednisone. In addition, neutropenia, thrombocytopenia, anemia, gastrointestinal symptoms, fatigue and herpes zoster were more common in patients receiving bortezomib.5

In our practice, we continue the chemotherapy regimen until the patient reaches a plateau state. There is no convincing evidence that continued chemotherapy is of benefit after obtaining a plateau and there is a potential risk of untoward side effects as well as inconvenience and cost.

Treatment of Relapsed/Refractory MM

Management of patients with relapsed MM is important because almost all patients will eventually develop resistant or refractory disease. The median OS in 578 patients with symptomatic MM at Mayo Clinic was 28·4 months. The OS at 1, 2, and 5 years was 72, 55 and 22%, respectively. The median survival of patients who relapsed after initial therapy (first relapse) was 17·1 months from the beginning of the second therapy, but duration of response decreased with each successive relapse. The median duration was 7·3, 6·0, 4·5, 4·0, and 3·2 months, respectively for the second, third, fourth, fifth, and sixth relapses.6

If relapse occurs more than six months after therapy has been discontinued, the initial regimen should be reinstituted in most instances. Thalidomide produces a response in about one-third of patients with relapsed refractory myeloma with a median duration of response of approximately a year. The response rate is enhanced when corticosteroids are added to thalidomide. Sedation, fatigue, constipation, rash, peripheral neuropathy and deep vein thrombosis are the most problematic side effects. The STEPS program must be followed carefully.

Bortezomib, a proteasome inhibitor, produces an objective response in about one-third of patients with relapsed/refractory myeloma with a response duration of approximately 1 year. In a randomized study, 669 patients were assigned to bortezomib or dexamethasone.7 The time to progression was 6·2 vs 3·5 months, while the OS was almost 30 vs 24 months respectively, favoring bortezomib. Bortezomib usually produces a response within 1 or 2 cycles of therapy. As previously mentioned, it should be used in the presence of renal failure and it appears to overcome the adverse chromosomal features. It should be given at weekly intervals because efficacy is not inferior and toxicity is less. Bortezomib can also be given subcutaneously rather than intravenously.

The third novel agent is lenalidomide which produces an objective response in approximately 30% of patients with relapsed/refractory MM. In a large international randomized trial of more than 700 patients, 60% obtained a PR or better with lenalidomide and dexamethasone compared to 22% for dexamethasone alone.8,9 The time to progression was 11·2 vs 4·7 months, favoring the combination. Thrombocytopenia, neutropenia and anemia are the major side effects of lenalidomide, but neuropathy is uncommon.

More than 100 agents are in phase I, II or III clinical trials. The most promising include pomalidomide, which is a third-generation immunomodulatory drug. In a recent report, almost half of patients who had myeloma refractory to both lenalidomide and bortezomib showed some response. Another new proteasome inhibitor, carfilzomib, is in a phase III clinical trial. It does not produce peripheral neuropathy.

Evidence of Progress

The survival of MM was less than 1 year prior to the introduction of melphalan. Over the next several decades, many combinations of alkylating agents were introduced, but overall survival was not prolonged when compared with melphalan and prednisone only. The introduction of ASCT and the novel agents, thalidomide, bortezomib and lenalidomide have improved survival. The median survival was 29·9 months for MM patients seen at Mayo Clinic between 1971 and 1996, while those diagnosed after 1996 had a median survival of 44·8 months.10 The availability of ASCT and the novel agents account for the improved survival after 1996. Although progress has been made especially in the last decade, much remains to be done concerning the treatment of MM.