Management by Stage
Smoldering or Asymptomatic Stage I Disease: Patients often have an indolent course that progress slowly over months to years. The median time to progression to symptomatic disease is two to three years after diagnosis.9 Therapy may not be necessary at this time. Observation, consisting of evaluations every three to six months, is performed until the disease progresses.4 Treatment may become necessary if the patient develops clinical problems such as renal dysfunction, hypercalcemia, bone damage, nerve damage, or reduced blood counts.
Active or Symptomatic Disease:
The initial goal of
therapy for patients with active disease is to induce a complete remission.
The European Group for Bone and Marrow Transplant response criteria are the
most commonly employed.10 Responses are classified as complete,
partial, minimal, stable, plateau, relapsed, and progressive disease. A newer
set of response criteria, developed by an international working group, is
under evaluation.11 The most common drug dosing regimens are
presented in TABLE 3.
Once the extent and stage of disease have been established, patients are evaluated to determine if they are candidates for a stem cell transplant. Stem cell transplantation is the standard of care in patients up to age 65 who are transplant candidates. Patients may be found ineligible for transplantation because of age, physical condition, comorbidities, or the inability to harvest adequate cells.
Induction Therapy for Transplant
Thalidomide: Thalidomide (Thalomid) is one of several new agents approved for patients with multiple myeloma. Although the exact mechanism of action is unknown, it has immunomodulating and antiangiogenesis properties. Major adverse effects associated with thalidomide include somnolence, fatigue, peripheral neuropathy, deep venous thrombosis (DVT), constipation, and rash. The incidence of DVT can be reduced by prophylactic anticoagulant administration or aspirin. Because of its teratogenic potential, patients must enroll in the STEPS (System for Thalidomide Education and Prescribing Safety) program before they can receive the drug. Thalidomide is FDA-approved for use with dexamethasone in patients with newly diagnosed multiple myeloma.12
In a pivotal trial, Rajkumar et al randomized 207 patients to dexamethasone or dexamethasone plus thalidomide.13 Thalidomide was administered at a dose of 200 mg po daily for four weeks and dexamethasone was administered at a dose of 40 mg po days 1 to 4, 9 to 12, and 17 to 20 in both arms. Treatment cycles were repeated every four weeks. There was a significantly higher response in the thalidomide/dexamethasone arm (63%) compared to dexamethasone alone (41%, P =.0017). However, the thalidomide arm was associated with significantly more toxicity including grade 3 DVT or above, neuropathy, rash, and bradycardia. The incidence of DVT was 17% in the thalidomide arm versus 3% with dexamethasone alone (P <.001).
Lenalidomide: Lenalidomide (Revlimid) is an analog of thalidomide.14 The major adverse effects seen with lenalidomide include marrow suppression, thromboembolism, rash, and a potential for teratogenesis during pregnancy. Because of this, patients must be registered and meet all of the conditions of RevASSIST, a restricted distribution program, before receiving the drug. 14
Although lenalidomide is currently approved for patients with relapsed/refractory myeloma, it has been studied as first-line treatment. In one small trial, 34 patients received lenalidomide 25 mg po daily for 21 days of a 28-day cycle plus dexamethasone 40 mg po days 1 to 4, 9 to 12, and 17 to 20.15 Thirty-one patients (91%) achieved an objective response, described as a partial response or better.
A major Phase III trial randomly assigned patients to lenalidomide 25 mg po daily for 21 days of a 28-day cycle plus high-dose dexamethasone, 40 mg days 1 to 4, 9 to 12, and 17 to 20 (n = 223), or to lenalidomide plus low-dose dexamethasone, 40 mg days 1, 8, 15, 22 (n = 222).16 Lenalidomide plus low-dose dexamethasone produced a significantly higher one-year overall survival (96.5%) compared to the high-dose dexamethasone regimen (86%, P <.001). The survival results were so impressive that an independent monitoring committee recommended early release of the data and switching all patients to the low-dose dexamethasone regimen. The low-dose regimen was also associated with less grade 3 and 4 toxicity including less infection/pneumonia, thromboembolism, and hyperglycemia. Like thalidomide, patients receiving lenalidomide should receive anticoagulant prophylaxis.
Bortezomib: Bortezomib (Velcade) is a proteasome inhibitor that is administered intravenously. Cancer cells are dependent on proteasome regulatory activities for proliferation and survival. Inhibition of proteasomes can lead to disruption of normal cellular homeostasis, which can lead to cell death. 17
Bortezomib was evaluated as first-line therapy in two small trials. In the first, bortezomib was administered to 49 patients for up to six cycles. Dexamethasone was added in cycle 2 or 4, respectively, if a partial or complete response was not achieved. The overall response rate was 90%. Stem cell transplantation was performed in 23 patients. The one-year overall survival among transplanted patients was 90% versus 80% for those not transplanted.18 Therapy with bortezomib and dexamethasone was well tolerated. The most common grade 2 or higher adverse effects were sensory neuropathy or neuropathic pain (37%), fatigue (20%), constipation (16%), neutropenia (12%), and nausea (12%). One patient each developed grade 4 neutropenia and thrombocytopenia.
In the second trial, 48 patients received four cycles of bortezomib plus dexamethasone prior to stem cell transplantation and achieved a response rate (partial response or higher) of 66%.19 Adverse effects were reported in 88% of patients (n = 44), 14% of which were reported as serious (n = 7) and required hospitalization. Most other toxicities were grade 1 or 2 gastrointestinal (GI) effects. Grade 3 effects included pneumonia, herpes zoster infections, peripheral neuropathy, GI toxicity, fatigue, infection, rash, and elevation of alkaline phosphatase and transaminases. One patient experienced a grade 4 reaction consisting of transient intestinal obstruction.
Bortezomib has also been studied in combination with pegylated doxorubicin and achieved a response of 79% (28% complete response [CR]) in 29 patients who completed therapy; with thalidomide there was an 82% response (31% CR) reported among 27 patients. 20,21
Induction Therapy for Nontransplant Candidates
Any induction regimen available for transplant candidates can also be used in patients who are not transplant candidates. There are some regimens that can be administered to nontransplant candidates, but they should not be used in transplant candidates due to their effects on stem cell reserve. One of these is melphalan and prednisone (MP).
A meta-analysis of 27 randomized trials involving 6,633 patients that compared MP to other chemotherapy regimens reported an average response rate of 53% (range 33%-83%) with MP and a median overall survival of 29 months.22 An advantage of MP is that it can be administered on an outpatient basis and it is usually well tolerated. A major disadvantage is that it can decrease the ability to mobilize stem cells for transplantation. Long-term melphalan use can also lead to myelodysplasia or leukemia.
Palumbo et al randomly assigned 255 patients to MP versus melphalan, prednisone, and thalidomide (MPT). Overall response rates were 76% for MPT and 47.6% with MP. The respective two-year, event-free survivals were 54% and 27% for MPT and MP (P =.0006), with three-year overall survivals of 80% and 64% (P =.19), respectively. Grade 3 and 4 toxicities were significantly more common with MPT (48% vs. 25%, P =.0002).23 Administration of enoxaparin reduced the incidence of DVT in the thalidomide arm to 3%.
MPT and MP were also compared in a three-arm study that randomly assigned 436 patients to MP (191), MPT (124), or a VAD-based regimen (vincristine, doxorubicin, and dexamethasone) followed by tandem autologous stem cell transplants (121).24 Median progression-free survivals (PFSs) were 17.2, 29.5, and 19.0 months in the MP, MPT, and transplant arms, respectively. PFS was significantly longer with MPT than MP and with MPT versus the transplant arm (P <.0001), but not with MP versus the transplant arm. Median overall survivals were 30.3 months with MP, 38.6 months with the transplant regimen, and were not yet achieved at 56 months with MPT. Median survivals were significantly longer with MPT versus MP and versus the VAD-based regimen, but not with MP versus the transplant regimen. Enrollment in the trial was stopped at this interim analysis due to the superior results with MPT.
Lenalidomide was combined with MP as induction therapy followed by lenalidomide maintenance therapy in a trial of 53 newly diagnosed patients.25 The overall response rate was 85.4%. All patients received aspirin prophylaxis, and thromboembolic events were seen in three patients, two of whom experienced thromboembolic events after they discontinued aspirin.
A three-drug combination of bortezomib, melphalan, and prednisone (VMP) was employed in a Phase I and II study involving 60 newly diagnosed elderly patients, all of whom were 65 years or older and almost half of whom were over 75 years of age. Fifty-three patients completed at least one cycle and achieved an overall response rate of 89%. At a median follow-up of 16 months, the PFS was 91% and the projected two-year survival was 86%.26
High-Dose Chemotherapy and Stem Cell Transplantation
After induction, transplant candidates are reevaluated for response. Responders have their stem cells harvested in a quantity sufficient to allow for a second transplant, if needed. The most common transplant is an autologous transplant in which patients serve as their own donors. The advantages are that there is no risk of graft versus host disease and the assurance that a suitable donor will be available.
The results from chemotherapy induction followed by autologous stem cell transplant studies have been mixed. Three randomized studies compared conventional-dose chemotherapy to intermediate- or high-dose chemotherapy plus autologous stem cell transplantation.27-29 A total of 399 patients received conventional chemotherapy and 396 received intermediate to high-dose chemotherapy plus transplantation. All three studies reported significantly higher response rates, either event-free or PFS, and median overall survival in the transplant groups. However, two randomized trials failed to demonstrate an improved response, event-free survival, or overall survival advantage to high-dose chemotherapy plus autologous stem cell transplantation.30,31
Koreth et al performed a meta-analysis of nine randomized controlled trials involving 2,411 patients that compared high-dose therapy and single autologous stem cell transplantation to standard-dose chemotherapy without transplantation.32 The authors reported that high-dose therapy and autologous transplantation were associated with a benefit in PFS but not in overall survival.
Although thalidomide is not FDA-approved for this indication, it has been well studied in patients with relapsed/refractory disease. Glasmacher et al published a review of 42 Phase II trials of thalidomide alone in 1,629 patients with relapsed/refractory disease.33 The overall response rate was 29.4% with a median overall survival of 14 months. Dimopoulos et al evaluated the activity of thalidomide plus dexamethasone in a population of 44 patients. The response rate was 55% on an intent-to-treat basis, with a median PFS of 20.3 months and a median overall survival of 12.6 months.34 Palumbo et al reported a median survival of 55.5 months among 43 patients who received thalidomide and dexamethasone as a first salvage treatment after autologous stem cell transplantation.35 In another trial, 62 patients with relapsed/refractory disease after one chemotherapy regimen achieved a PFS of 17 months and a probability of a three-year survival of 60% with thalidomide and dexamethasone.36 PFS was 11 months in those who had received two or more prior chemotherapy regimens.
Bortezomib is FDA-approved for patients with relapsed/refractory disease.17 In a pivotal study, 669 patients were randomly assigned to bortezomib or high-dose dexamethasone. 37 There was a significantly higher response and one-year survival in the bortezomib group. Respective response rates were 38% and 18% with bortezomib versus dexamethasone and respective one-year survivals of 80% and 66% (P =.003). Thirty-seven percent of bortezomib patients had to stop therapy early due to adverse effects. The most common effects necessitating discontinuation of therapy were peripheral neuropathy (8%), followed by thrombocytopenia, nonspecified GI disorders, fatigue, hypercalcemia, and spinal cord compression (2% each). Adverse effects seen more commonly with bortezomib in general were GI disorders such as nausea, vomiting, diarrhea, and constipation, as well as thrombocytopenia and peripheral neuropathy.
Bortezomib alone has been compared with bortezomib plus pegylated doxorubicin in a randomized Phase III study involving 646 patients. The overall response rates were 41% for bortezomib alone and 44% for the combination, an insignificant difference (P =.43). There was a significant difference in respective median time to progression (9.3 vs. 6.5 months, P =.000004), median duration of response (10.2 vs. 7.0 months, P =.0008), and 15-month survival (76% vs. 65%, P =.03) with the combination compared with bortezomib alone. 38
Lenalidomide is indicated for use with dexamethasone in patients who have experienced at least one prior therapy. Two pivotal Phase III randomized trials compared lenalidomide plus dexamethasone (LD) to dexamethasone alone in patients with refractory/relapsed disease.39 LD was administered to 345 patients, while 346 received dexamethasone alone. The overall response rates with LD (58% and 61%) were significantly higher than with dexamethasone alone (22% and 23%, P <.001). The median time to progression was also significantly longer with LD (13.3 and 15 months) versus 5.1 months in both trials with dexamethasone alone (P <.000001). Adverse effects were more common in the LD arm, most notably grades 3 and 4 anemia, neutropenia, and thrombocytopenia. Thromboembolic complications were more common in the LD arm in one study, underscoring the need for prophylactic anticoagulation during lenalidomide therapy.
Mihelic et al recently reviewed the literature on maintenance therapy in patients with myeloma.40 Most of the available data involved the use of interferon, corticosteroids, or thalidomide. They concluded that the literature does not support the use of interferon due to lack of improvement in overall survival and the toxicity associated with interferon administration, and that there is insufficient data available to recommend corticosteroids as maintenance therapy. The data on thalidomide maintenance therapy was not as clear.
There are few major studies that employed maintenance thalidomide. Those that did had methodological problems such as small sample sizes, lack of controls, and use of thalidomide in combination with other treatments, making the contribution of thalidomide to the outcomes uncertain. Attal et al randomized 597 patients who had undergone high-dose induction therapy to one of three arms: 1) no maintenance, 2) pamidronate 90 mg/month, or 3) pamidronate 90 mg/month plus thalidomide 100 mg/day.41 The probability of event-free survival three years after randomization was 36%, 37%, and 52% for arms 1, 2, and 3, respectively; this was significantly better for those in arm 3 than in either or in other arms of the study (P <.009). The four-year postdiagnosis probability of survival was significantly higher for patients in arm 3 (87%) versus no treatment (77%) or pamidronate alone (74%, P <.04). Subgroup analysis indicated that patients who did not achieve a partial response and those with cytogenic abnormality deletion 13 did not benefit from maintenance thalidomide.
Brinker et al performed a retrospective review of 112 patients treated with thalidomide and interferon or observation alone.42 Half of the thalidomide patients received the drug as maintenance and half after relapse. The overall survival for patients who received thalidomide at any time after transplantation was 65.6 months versus 44.5 months for those who did not (P =.09). Overall survival was also significantly better in those who received thalidomide maintenance therapy (65 months) versus those who received it after relapse (54 months, P =.05). Maintenance thalidomide appears to offer benefit in select populations; however, it needs further evaluation in controlled clinical trials.
Data collected by the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program from 1973 to 2003 evaluated the survival outcomes in 40,538 patients with multiple myeloma. The average age at diagnosis was 68 years. The average survival for the entire group was 41 months with a median survival of 24 months. Women experienced a significantly better overall survival than men. Overall survival was better for younger patients.43
The initial goal of therapy for a patient with symptomatic multiple myeloma is to induce a complete remission with drug therapy. Then, if possible, perform an autologous stem cell transplant. Several induction regimens have been employed, many of which involved IV therapy. However, with the advent of two new oral drugs, oral induction therapy is becoming more common. Oral therapy has also demonstrated favorable activity in patients with relapsed/refractory disease.
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