Part 4. Thalidomide for Multiple Myeloma

Introduction

Policy Context of the Current Technology Assessment

Section 641 of the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) calls for a demonstration that would pay for drugs and biologicals that are prescribed as replacements for drugs currently covered under Medicare Part B. The demonstration project will be national in scope and will be limited to 50,000 beneficiaries or $500,000,000 in funding, whichever comes first. Forty percent of the funding for this demonstration will be reserved for oral anti-neoplastic drugs.

CMS has requested an assessment of the efficacy of selected oral cancer therapies included in the demonstration relative to drugs currently covered under Medicare Part B. This assessment will provide information that will be used to evaluate the likely effects of the demonstration on patient outcomes and may also provide underlying information to be used for cost-effectiveness analyses that will be completed by CMS.

The scope of the assessment will be limited to the following demonstration drugs and conditions:

• Imatinib for treatment of chronic myeloid leukemia.
• Imatinib for treatment of gastrointestinal stromal cancer.
• Gefitinib for treatment of non-small cell lung cancer.
• Thalidomide for treatment of multiple myeloma.

This report is responsive to the fourth item: an assessment of thalidomide for the treatment of multiple myeloma.

Clinical Context of the Current Technology Assessment

Multiple myeloma is a debilitating malignancy that is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. First described in 1848, multiple myeloma is characterized by the proliferation and accumulation of cancerous plasma cells and the overabundance of monoclonal paraprotein.²

Plasma cells are terminally differentiated B-lymphocytes that have the ability to produce immunoglobulin (Ig, a.k.a. antibodies). The cancerous myeloma plasma cells are clonal and therefore produce an abundance of a single immunoglobulin known as a monoclonal protein (a.k.a., M-protein, myeloma paraprotein; Figure 1). Each monoclonal protein consists of two heavy polypeptide chains of the same class and subclass and two light polypeptide chains of the same type.³ The heavy polypeptide chains are IgG, IgA, IgM, IgD and IgE while the light chain types are kappa and lambda.

This malignant proliferation of plasma cells often results in extensive skeletal destruction; osteolytic lesions, osteopenia, and/or pathologic fractures are common. Other common clinical findings in multiple myeloma include anemia, high serum calcium levels, and kidney dysfunction. Recurrent bacterial infections and bleeding (nose, gums, easy bruising) can also occur.

Incidence and Prevalence

In the United States, multiple myeloma is uncommon, accounting for 1 percent of all cancers and 10 percent of hematologic cancers.⁴ It occurs in about 4 out of 100,000 individuals each year (about 15,980 total new cases and 11,300 deaths). Multiple myeloma accounts for approximately 2 percent of all cancer deaths and close to 20 percent of the deaths caused by hematologic malignancies. Slightly more men than women develop multiple myeloma and almost twice the number of blacks as compared to whites. The predominant risk factor is age.⁵ Multiple myeloma occurs most frequently in older adults; the average age at diagnosis is 65 years with less than 2 percent under age 40.

Other risk factors for the increased likelihood of multiple myeloma include genetic factors and prior diagnosis of a plasma cell proliferative process.⁶ First-degree relatives with multiple myeloma related to familial clustering occurs in about 3 familial cases per 1000 patients.⁵ The cause of multiple myeloma is unknown, but increased risk of myeloma has been linked to chemicals, asbestos, laxatives, and radiation.⁷

Pathogenesis

A series of steps leads to the development of multiple myeloma, as described by Kyle and Rajkumar in the New England Journal of Medicine in 2004 (Figure 2).⁸ Not all of these are fully understood. A limited number of clonal plasma cells initially develop. Genetic translocations involving the immunoglobulin genes occur in at least half of instances. These first steps lead to the production of some monoclonal plasma cells more representative of a "monoclonal gammopathy of uncertain significance" (MGUS) rather than true multiple myeloma. Additional complex changes then occur including further genetic alterations and changes in the bone marrow microenvironment. Specifically, the bone marrow microenvironment evolves with production of new supportive blood cells (angiogenesis), suppression of cell-mediated immunity, and the development of paracrine signaling cascades involving cytokines such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). This creates a supportive environment where the malignant plasma cells replicate. The disease progresses until it is a clinically significant multiple myeloma. Interactions between the myeloma cells, bone marrow stromal cells, and microvessels contribute to expansion of the tumor and its resistance to drugs.

Diagnosis

The diagnosis of multiple myeloma is often suspected because of one (or more) of the following clinical presentations:²

• Bone pain related to lytic lesions discovered on routine skeletal films (two-thirds of cases; usually back or chest, but occasionally in arms and legs).
• An increased total serum protein concentration and/or the presence of a monoclonal protein in the urine (Bence Jones protein) or serum (M protein, usually >3 g/dL).
• Systemic signs or symptoms suggestive of malignancy, such as unexplained anemia with weakness and fatigue (two-thirds).
• Hypercalcemia (20 percent).
• Impaired renal function (creatinine >2.0 mg/dL; 25 percent).

The initial approach to the patient is to establish the diagnosis, which traditionally requires the detection of >10 percent plasma cells on a bone marrow examination or a plasmacytoma plus one of the following:^9,10

• Serum M-protein of >3 g/dL (IgG or IgA isotype most common) by immunoelectrophoresis or immunofixation (IFE). Over 80 percent of patients have serum M-protein.
• Bence Jones protein, denoting evidence of monoclonal light chain (kappa or lambda) proteins identified in a 24 hour urine collection.
• Detection of lytic bone lesions or generalized osteoporosis in skeletal x-rays. Usually a skeletal survey is conducted.

Multiple myeloma is only one disease within a category of illnesses called monoclonal gammopathies (paraproteinemias). These disorders are characterized by the monoclonal expansion of plasma cells. It can be difficult to distinguish the different gammopathies from one another, but it is important to do so as they have different prognoses and standard treatments. In response, the International Myeloma Working Group has developed the following simplified criteria for the diagnosis of MGUS, asymptomatic (smoldering) myeloma, symptomatic multiple myeloma and other gammopathies (Figure 3).³ No specific percent of plasma cells in the bone marrow is specified for symptomatic myeloma, since 5 percent of patients may have fewer than 10 percent bone marrow plasma cells and marrow involvement may be focal, rather than diffuse. The majority do have >10 percent, however, and if flow cytometry is performed, most plasma cells (>90 percent) will show a 'neoplastic' phenotype. Evidence of related organ or tissue impairment figures prominently in this classification system.

Approximately 5-15 percent of multiple myeloma patients meet diagnostic criteria for myeloma but are asymptomatic.¹¹ A confusing distinction is indolent vs. smoldering myeloma. Few resources offer a distinction between the two, and most consider them together as asymptomatic multiple myeloma. Others describe indolent myeloma as a subset of smoldering myeloma with <30 percent plasma cells in the bone marrow.⁷

Staging

The staging of multiple myeloma is based on the myeloma tumor cell mass (monoclonal protein, M-protein) in the serum and/or urine, along with other clinical parameters, such as the hemoglobin and serum calcium levels, and the presence of lytic bone lesions or renal failure.¹² There are two main staging systems used—the Durie/Salmon criteria and the International Myeloma Staging System (Figure 4). The Durie/Salmon system is oldest, first published in 1975.¹³ Since impaired renal function worsens prognosis regardless of stage, different staging levels are subdivided into A and B based upon creatinine.

The great majority of symptomatic myeloma patients are classified as stage III by the Durie/Salmon criteria, making it difficult to identify patients with intermediate and poor prognosis.¹² Other problems with the Durie-Salmon system, such as inter-observer variability in assessment of staging, also limit its usefulness. In response, the International Myeloma Working Group derived the International Staging System,¹⁴ and this staging system is now referred to most commonly.¹² This system was derived using multifactorial prognostic models mixed with practicality. Beta-2 microglobulin (B2M) has been shown to be a reliable marker for prognosis; ¹⁵ similarly, albumin and other clinical factors have important prognostic value in multiple myeloma. A combination of B2M and serum albumin provided the simplest, most powerful and reproducible three-stage classification when developing the model supporting the ISS. The three stages of the ISS are predictive of survival.¹⁴ Since the ISS was only derived in the past several years and the main publication was recently released in 2005, many studies were still published with the older system.

Patients with newly diagnosed disease are staged according to these systems and then the treatment is matched to their degree of illness. This is typically described as the "newly diagnosed" or "untreated" multiple myeloma setting. Since patients with asymptomatic myeloma are often closely monitored without specific interventions as their initial treatment plan, these patients are also grouped into the "untreated" category. When the disease recurs or fails to respond to the initial therapy, the myeloma is called "refractory" or "resistant". "Advanced" myeloma can imply advanced stage disease (Stage III) or progressive disease, depending upon the author. For the purposes of this review, these categories are divided between "newly diagnosed/untreated" and "advanced/refractory/resistant". Note that some newly diagnosed advanced Stage III study participants are included in the "advanced/refractory/resistant" category based upon categorization by the study authors, although the majority of participants reported in this review in the "advanced/refractory/resistant" category have disease that has progressed after initial therapy (i.e., refractory or resistant to initial therapy).

Prognosis

Outcome for patients with multiple myeloma is highly variable.¹⁴ The median overall survival time is 3-4 years, but ranges from less than 6 months to greater than 10 years. This is due to substantial individual variation in myeloma cell biology and clinical characteristics.

The American Cancer Society quotes 5-year survival rates for multiple myeloma, but does not designate which staging system was used to generate these data (Figure 5).¹⁶

Survival analyses for 10,750 patients with multiple myeloma were conducted as part of the development and validation phases for the ISS (published in 2005).¹⁴ Clear relationships between stage and survival were identified (Figures 6 and 7). Of the total, 7,920 patients were treated with standard-dose therapy as the primary modality, whereas 2,807 patients received high dose therapy with autologous stem cell transplantation (SCT). The ISS system discriminated similarly for the two groups.

The median survival prior to the advent of any chemotherapy era was less than a year.¹⁷

A number of patient clinical factors and laboratory tests are indicative of poorer prognosis in multiple myeloma. In a series of 1,027 patients with multiple myeloma seen at a single institution between 1985 and 1998, adverse prognostic risk factors affecting survival included the following:¹⁸

• Performance status 3 or 4 (Relative risk (RR) 1.9).
• Serum albumin <3 g/dL (RR 1.7).
• Serum creatinine 2 mg/dL (RR 1.5).
• Platelet count <150,000/microL (RR 1.5).
• Age 70 years (RR 1.5).
• Beta-2-microglobulin >4 mg/L (RR 1.5).
• Plasma cell labeling index 1 percent (RR 1.5).
• Serum calcium 11 mg/dL (RR 1.3).
• Hemoglobin <10 g/dL (RR 1.3).
• Bone marrow plasma cell percentage 50 percent (RR 1.2)

Cytogenetic findings are also associated with survival in multiple myeloma and complement established clinical prognostic factors.⁸ In a study of 351 patients treated with conventional chemotherapy in an Eastern Cooperative Oncology Group (ECOG) clinical trial, the following correlation was identified:¹⁹

• t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 all had poor prognosis with median survival 25 months.
• -13q14 had intermediate prognosis with median survival 42 months.
• All other cytogenetic abnormalities had good prognosis with median survival 50 months.

Cytogenetic abnormalities of chromosome 13 including deletion 13 occur in about one-third of patients and are associated with poorer prognosis

All of these prognostic variables were evaluated for their association with ISS stage (and therefore survival) within the ISS validation study with 10,750 myeloma patients.¹⁴ The following factors were associated with advanced stage:

• Age >65 years (p<0.001).
• Beta-2-microglobulin 3.5 mg/L (p<0.001).
• Albumin <3.5 g/dL (p<0.001).
• Hemoglobin <10 g/dL (p<0.001).
• Creatinine 2 mg/dL (p<0.001).
• Platelets <130,000/microL (p<0.001).
• Calcium 10 mg/dL (p<0.001).
• >3 lytic bone lesions (p<0.001).
• C Reactive Protein (CRP) 0.8 mg/dL (p<0.001).
• Lactose dehydrogenase (LDH) above normal (p<0.001).
• Bone marrow plasma cells 33% (p<0.001).
• Performance status 2 (p<0.001).
• Durie-Salmon Stage III (A or B) (p<0.001).
• Any clonal cytogenetic abnormality (p=0.093).
• Complex karyotype (p=0.162).
• Deletion of chromosome 13 by cytogenetics (p=0.112).
• Deletion of chromosome 13 by fluorescence in situ hybridization (FISH; p=0.075).
• t(11;14) (p=0.921).
• t(4;14) (p=0.035)

Other predictors have been considered. Overexpression of cyclin D1 has variably predicted increased and decreased survival.¹⁰ Measures of angiogenesis such as bone marrow microvessel density predicted survival in a study of 36 patients with multiple myeloma such that median survivals for patients with low-, intermediate-, or high-grade bone marrow angiogenesis were 77, 30, and 14 months, respectively.²⁰

Treatment

Approach to Treatment

The stage of the disease at presentation is a strong determinant of survival, but it has little influence on the choice of therapy since almost all patients have generalized disease except for rare patients with solitary bone tumors or extramedullary plasmacytomas.⁷ Treatment selection is influenced by the age, general health of the patient, prior therapy, presence of complications of the disease (e.g., renal dysfunction), presence of complications of previous therapies (e.g., neuropathy), whether a stem cell transplantation (SCT) is planned, and patient preference.

Treatment Goals and Assessment

For the majority of patients with multiple myeloma, the goal of therapy is prolonging survival, relief of symptoms and disability due to the disease, and maximizing quality of life. Treatment programs are evaluated by the proportion of patients achieving an objective response, the duration of that response, survival, and adverse effects. Only a minority of patients—predominantly those with isolated plasmacytomas—have truly curable myeloma.¹⁰ Approximately 60 percent respond to initial conventional chemotherapy; complete remissions are rare and nearly all patients relapse resulting in estimated survival rates of 25 percent at 5 years and <10 percent at 10 years.¹⁷ For patients with progressive disease after initial therapy, response rates decrease for each subsequent treatment. Melphalan-based high-dose chemotherapy with hematopoietic stem-cell support increases the rate of complete remission and extends event-free and overall survival. However, most patients still relapse, and options for salvage therapy are limited.

Several sets of response criteria exist. It is critical that the efficacy of an intervention for myeloma be reported in the context of the response criteria used. Response criteria include the Chronic Leukemia and Myeloma Task Force criteria originally published in 1968, the Southwest Cancer Chemotherapy Study Group criteria published in 1972, MRC Myelomatosis Trials criteria published in 1992, and the EBMT/IBMTR/ABMTR criteria (also known as the Blade criteria) published in 1998.¹⁷ The definition of complete response (CR) has been fairly consistent across the different sets of criteria (Figure 8), although some authors will report "near CR" in addition to CR. "Near CR" is persistent evidence of monoclonal protein by immunofixation (IFE) but normalization of all other parameters of the illness.²¹

Partial responses are variably reported. Most are reported in terms of the M-protein response (a.k.a. paraprotein response, PPR), since the majority of multiple myelomas have an overabundance of this monoclonal protein. There are usually corollary response cut-offs for Bence Jones proteins, although the absolute numbers for the expected response in the urine are usually higher. The Blade criteria also specify Minimal Response criteria corresponding to a PPR of 25-49 percent. Some authors present their own response standard, starting as low as a PPR of 25 percent. As described in Figure 9, we have attempted to normalize PPR across studies starting with an objective response rate of at least 25 percent, but also reporting PPRs at the various levels to accommodate to the various ways that PPR is reported.

The Blade criteria are presented in an abbreviated format as part of Figure 8.¹⁷

Treatment Options

Patients with asymptomatic (smoldering, indolent) multiple myeloma who have no lytic bone lesions and normal renal function may be safely observed by "watchful waiting."²² In a randomized trial of 145 asymptomatic multiple myeloma patients comparing oral melphalan plus prednisone started at diagnosis versus at the time of disease progression, there was no difference in overall survival (OS) or myeloma paraprotein response (PPR). With a median followup of 95 months, the median survival was 69 months. The overall response rate was 55 percent and the median duration of response was 48 months. A Cochrane Systematic Review on early versus delayed treatment for early stage multiple myeloma included 3 randomized trials and 262 participants.²³ Early treatment delayed myeloma progression (odds ratio (OR)=0.16, 95 percent CI: 0.09-0.29), with a trend towards reduced vertebral compression (OR=0.18, 95 percent CI: 0.02-1.59). No significant effects on mortality and response rate were seen (OR=1.11, 95 percent CI: 0.67-1.84, and OR=0.63, 95 percent CI: 0.33-1.23, respectively). Early treatment may have increased the risk of acute leukemia (OR=3.20, 95 percent CI: 0.55-18.73).

For patients with symptomatic myeloma, the therapy is matched to the patient's overall physical health, ability to tolerate the interventions, prognosis, and personal preferences. Conventional oral chemotherapy, a less aggressive route, typically includes alkylating agents with prednisone (e.g., oral melphalan and prednisone (MP) or cyclophosphamide and prednisone (CP)). These oral programs improve prognosis as compared to no therapy with a median survival of 24 to 30 months and a 10-year survival of 3 percent.⁴ Length of treatment is usually 1 to 2 years, continuing until the patient responds or disease stabilizes.¹²

More aggressive infusional regimens have more risk of toxicity but higher chances of response. A systematic review and meta-analysis of 27 trials comparing MP versus combination chemotherapy (CCT) was conducted in 1992 and then updated in 1998.²⁴ A total of 6,633 patient participants were included, for whom individual patient data were provided to reviewers for 4,930 and data were abstracted for the remaining 1,703.

Among the CCT arms, chemotherapeutic intensity was standardized to the Southwest Oncology Group (SWOG) 7704/7705 regimen of vincristine, melphalan, cyclophosphamide, and prednisone (VMCP) alternating with vincristine, carmustine (BCNU), doxorubicin, and prednisone (VBAP). CCT varied and included VMCP + VBAP/VCAP (N=6 studies, VCAP=VBAP with cyclophosphamide substituted for the carmustine), regimen with another anthracycline (N=3 studies), VMP (N=2 studies, VMP=MP with vincristine added), VMCP alone (4 studies), VBCMP (N=3 studies, VBMCP=vincristine, carmustine, melphalan, cyclophosphamide, and prednisone), MOCCA (N=2 studies, MOCCA=vincristine, cyclophosphamide, lomustine, melphalan, and methylprednisolone), MCBP (N=3 studies, MCBP=melphalan, cyclophosphamide, carmustine, and prednisone), other chemotherapy (N=7 studies). The VAD regimen (vincristine, doxorubicin, and dexamethasone) was not included in this review.

The review did not specify whether patients were previously untreated or treated, however inspection of over half of the individual studies included suggests that the studies were of previously untreated patients. Overall, there was no significant difference in survival between patients allocated to CCT or MP (p=0.6). The point estimate for the proportional reduction in the annual odds of death was 1.5 percent in favor of CCT but the 95 percent CIs ranged from an 8 percent benefit in favor of CCT to a 5 percent benefit in favor of MP. This range corresponded to an absolute difference in survival, at 3 years, of between 3 percent in favor of CCT or 2 percent in favor of MP. Median survival in both CCT and MP arms was 29 months and 5-year survival was 24 percent. Among all included participants age <50 years (N=526, 11 percent) the 5-year survival was 31 percent, age 50-64 (N=2,150, 44 percent) 5-year survival was 27 percent, age 65-74 (N=1,617, 33 percent) 5-year survival was 21 percent, and age 75 (N=497, 10 percent) 5-year survival was 12 percent. The main finding supporting CCT over MP was that response rates were significantly higher with CCT (60 percent vs. 53.2 percent; p< 0.00001). Response rates were not standardized across a PPR norm, but rather trials were scored according to whatever PPR was reported for that trial.

Three randomized studies of VBCMP were included in the systematic review just described.^25-28 The U.S. Eastern Cooperative Oncology Group (ECOG) study published in 1997 included the greatest number of patients (N=479).²⁵ Previously untreated patients with multiple myeloma patients were randomized to VBCMP (N=235) or MP (N=230). VBCMP is given intravenously plus orally while MP is oral. Forty-two percent were Durie-Salmon Stage I-II, 58 percent were Stage III. Median age for VBCMP was 64 (range 26-85) with 27 percent age 70; median age for MP was 64 (range 21-84) with 26 percent age 70.

Objective responses were defined as a M-protein PPR of 50 percent or a Bence Jones decrease by 90 percent. Objective responses were higher for VBCMP at 72 percent compared with MP at 51 percent (p<0.001). Response duration with VBCMP was longer with median 24 months vs. MP median 18 months (p=0.007). Three year response duration was 34 percent for VBCMP and 20 percent for MP. There was no significant difference in survival with median survival for VBCMP of 29 months and for MP 27 months (p=0.30). There were more early deaths with VBMCP (35 vs. 20). VBCMP early deaths were predominantly among those of advanced age 70 (57 percent) or Stage III (71 percent), with 40 percent having both advanced age and stage. At least some Grade 3 or 4 toxicity was described for 64 percent of VBMCP patients as opposed to 54 percent of MP patients (p<0.035).

These toxicities for VBMCP and MP respectively were Grade 3 or 4 infection (14 percent vs. 14 percent, p=not significant), Grade 2 nausea/vomiting (31 percent vs. 10 percent, p<0.001), Grade 2 peripheral neuropathy (24 percent vs. 2 percent, p<0.001), Grade 1 alopecia (25 percent vs. 7 percent, p<0.001), Grade 3 or 4 neutropenia (46 percent vs. 37 percent, p=0.07), and Grade 3 or 4 thrombocytopenia (23 percent vs. 23 percent, p=not significant).

The traditional infusional VAD regimen was first described by Barlogie, et al., in 1984.²⁹ Patients receive vincristine (0.4 mg) and doxorubicin (9 mg/m², a.k.a. Adriamycin) daily by continuous infusion for four days plus dexamethasone (dex) 40 mg orally daily on days 1 to 4, 9 to 12, and 17 to 20 of each of the monthly cycles. Results for the infusional VAD program have been reported for both previously untreated patients, as well as those with relapsed or resistant disease. In the original report of VAD, 14/20 (70 percent) patients with relapsing or refractory myeloma resistant to alkylating agents had a PPR of 75 percent and 3/9 (33 percent) resistant to doxorubicin had a PPR of 75 percent.²⁹ 

In the first major report of VAD for previously untreated patients published in 1990, 32 participants treated with VAD achieved an overall response of 84 percent, with 28 percent entering a complete remission (CR).³⁰ Response was rapid, with near-maximum response occurring after two courses of treatment. Median response duration was 18 months. Projected median survival was 44 months, with 75 percent of all patients and 83 percent of responders being alive at 2 years. In a report in which infusional VAD given as initial therapy to 75 untreated myeloma patients, the overall and complete response rates were 84 percent and 27 percent, respectively, and median survival was 36 months.³¹

In the same report, 67 patients with relapsed or refractory disease treated with VAD had overall and complete response rates of 61 percent and 3 percent, respectively, and median survival was 10 months. Besides overall adverse effects related to therapy, a major limitation of the infusional VAD regimen is that vincristine and doxorubicin have to be administered through a central venous catheter, with risks of sepsis and thromboembolic events. Infectious complications have been reported at 54-60 percent, depending upon whether prophylactic antibiotics are used.³²

In 1998, Mineur, et al., reported a randomized trial of VAD vs. VBCMP in 105 patients who had progressed after treatment with CP.³³ Mean age for VAD (N=50) was 62 (SD 10) and mean age for VBCMP (N=53) was 63 (SD 9). Response was defined as a PPR of 50 percent. After 4 months of therapy, response rates for VAD were 22 percent and VBCMP 13 percent. There were 5 deaths with VAD (12 percent) and 8 with VBCMP (15 percent). Median survival was 17 months and not significantly different between interventions (VAD 16 months, VBCMP 17.5 months, p=0.75). Specific toxicity rates were not described. Neutropenic infections led to four deaths (VAD 2 and VMBCP 2). Corticosteroids were responsible for major toxic effects in two cases both in the VAD arm (pancreatitis and diabetes mellitus for one case, candidal esophagitis for the other). One patient developed cardiotoxicity after three cycles of VAD and in another patient hematological toxicity after VAD required treatment modification.

The traditional VAD regimen has been modified to a rapid infusion regimen and a regimen that substitutes liposomal doxorubicin (Doxil, VDD). Both eliminate the need for an indwelling central venous catheter. Segeren, et al., reported a phase II study of the rapid infusion regimen in 139 patients with untreated multiple myeloma (median age 53, range 32-65).³² The doxorubicin was administered over 30 min daily for 4 days instead of as a continuous infusion. Patients still needed to present for treatment daily for 4 days each cycle. PPR of 50 percent was achieved in 86 percent with CR in 7 percent. Among a total of 416 cycles of rapid infusion VAD administered, toxicity of Grade 2 included nausea/vomiting 2 percent, mucositis 2 percent, liver test abnormalities 2 percent, renal insufficiency 1 percent including one patient who developed renal failure, and cardiac problems in 1 percent (arrhythmias, myocardial infarction). A total of 18 percent of patients developed neurotoxicity and 27 percent developed infections.

The VDD is advantageous as it is expected to have less cardiotoxicity and does not require a central venous catheter. In 2003, Dimopoulos, et al., described a randomized trial of VAD administered as intravenous bolus injection vs. VDD for patients with previously untreated myeloma.³⁴ Median age for bolus VAD (N=127) was 66 (37-88) and median age for VDD (N=132) was 65 (37-88). PPR of 50 percent was achieved in 61 percent with CR in 13 percent with either regimen. Median time to progression was 24 months. Median overall survival had not been reached and was expected to exceed 40 months in both arms.

Toxicities in the bolus VAD and VDD arms respectively were Grade 2 neutropenia (20 percent vs. 15 percent, p=0.7), Grade 2 thrombocytopenia (10 percent vs. 5 percent, p=0.2), Grade 2 nausea/vomiting (4 percent vs. 5 percent, p=0.8), Grade 1 alopecia (55 percent vs. 37 percent, p<0.001), Grade 2 mucositis (7 percent vs. 15 percent, p=0.3), Grade 2 erythrodysesthesia (2 percent vs. 13 percent, p=0.03), and Grade 2 neurotoxicity (13 percent vs. 15 percent, p=0.9). Steroid-related side-effects occurred with equal frequency in both arms; Cushingoid features were noted in approximately one-fifth of patients, hyperglycemia in 15 percent of patients treated with bolus VAD bolus and in 12 percent treated with VDD, mood changes in <10 percent of patients in either arm and peptic ulcer disease, hiccups and proximal muscle weakness each occurred in <5 percent of patients.

Infections, which required antibiotics, including neutropenic fever, were noted in 17 percent of patients treated with bolus VAD and 18 percent treated with VDD. Eleven patients (9 percent) in the bolus VAD arm and 14 (11 percent) in the VDD arm died within the first 4 months of treatment. Among the 11 patients treated with bolus VAD, three deaths were due to infections and 2 were due to heart failure and/or myocardial infarction. Of the 14 early deaths in the VDD arm, 4 were due to infections and 3 were due to heart failure and/or myocardial infarction.

Response rates with PPR 50 percent can be summarized as follows:

• Untreated multiple myeloma treated with VBCMP: 72 percent.
• Refractory/relapsed multiple myeloma treated with VBCMP: 13 percent.
• Untreated multiple myeloma treated with VAD: 61-86 percent.
• Refractory/relapsed multiple myeloma treated with VAD: 22-70 percent.

Direct comparison of VBCMP and VAD suggests that VAD is somewhat superior. While response rates are higher than traditional MP and CP chemotherapy, CCT regimens including VBCMP do not improve survival over MP and VAD does not improve survival over VBCMP. Earlier remission is an advantage in patients with hypercalcemia or renal failure, and the VAD regimen is safer in patients with renal failure, since the drugs are not excreted by the kidneys.   The same regimen of dexamethasone alone has also induced a rapid remission, but the response rate was 15 percent lower than that with VAD.⁸ Because of the rapid remission induced by either VAD or dexamethasone alone, usually no more than two courses are necessary to determine whether the myeloma is responding to treatment.

Further improvements in prognosis have occurred due to the introduction of newer therapies such as pulse corticosteroids, thalidomide, bortezomib, and autologous and allogeneic stem cell transplantation. For those patients who can tolerate it, high dose chemotherapy followed by single or double autologous SCT improves survival over combination chemotherapy alone.⁸ In a trial of 399 participants under age 60 and of adequate performance status initially randomized to VAD treatment followed by single or double autologous SCT, the probability of surviving event-free for seven years after the diagnosis was 10 percent in the single-transplant group and 20 percent in the double-transplant group (p=0.03). The estimated overall seven-year survival rate was 21 percent for single and 42 percent for double-transplants (p=0.01).

The Technology

A large body of recent work demonstrates a major role for bone marrow angiogenesis in the biology of multiple myeloma.⁸ The degree of marrow angiogenesis correlates with measures of cell proliferation, such as the plasma cell labeling index (PCLI) and the stage of the disease.^8,20,35 The role of angiogenesis in the progression of malignancies including myeloma provided the rationale for the use of antiangiogenic therapy for myeloma.

Thalidomide (α-N-³⁶ glutarimide, C₁₃H₁₀N₂O₄), a glutamic acid derivative, was initially introduced as a sedative in the late 1950s. It was subsequently withdrawn from the market because of its teratogenic effects. Clinical observations dating back to 1965 supported the potential beneficial effect of thalidomide in multiple myeloma and advanced cancers,³⁷ but its antiangiogenic properties were not realized until the mid-1990s. The use of thalidomide for multiple myeloma escalated rapidly after a 1999 publication by Singhal, et al., documenting objective responses with thalidomide in patients with refractory myeloma.³⁵

Thalidomide undergoes rapid interconversion between the R-enantiomer and the S-enantiomer and spontaneous cleavage to more than 12 metabolites in solutions at physiologic pH.³⁸ Study of its mechanism of action has proven difficult because its activity in most in vitro assays is moderate at best, and its effects in animal models are dependent on the species and the route of administration. Proposed mechanisms include the inhibition of tumor necrosis factor alpha (TNF-alpha), prevention of free-radical-mediated DNA damage, suppression of angiogenesis, increased in cell mediated immunity, alteration of the expression of cellular adhesion molecules, inhibition of NF-kB, and decreased inflammation.⁸

On July 16, 1998, the Food and Drug Administration (FDA) approved thalidomide for use in treating leprosy (Hansen's disease). Evaluation of the medication for symptoms related to AIDS, management of rheumatologic disease, and control of cancer quickly followed.

To prevent fetal exposure to thalidomide, the drug's manufacturer developed the System for Thalidomide Education and Prescribing Safety (STEPS) program. Only registered physicians may prescribe the drug to patients and those patients—both male and female—must comply with mandatory contraceptive measures, patient registration, and patient surveys. Thalidomide may be dispensed only by licensed pharmacists who are registered in the S.T.E.P.S. program and have been educated to understand the risk of severe birth defects if thalidomide is used during pregnancy.

In addition, female patients' prescriptions will not be filled without a physician's written report of a negative pregnancy test that has been conducted within 24 hours of starting thalidomide therapy. Pregnancy testing is required weekly during the first month of use, then monthly thereafter in women with regular menses, or every two weeks if menses are irregular. Prescriptions are only for one month's supply. A female patient must abstain from sexual intercourse or use two highly effective methods of birth control at the same time for at least 1  month before receiving thalidomide and continue their use until 1 month after the last thalidomide dose. All patients must participate in a mandatory registry that will provide followup to detect any adverse effects of using thalidomide and will hopefully identify areas in which safeguards need to be improved, if problems occur.

Thalidomide itself has been off patent for decades.³⁹  Celgene, the U.S. producer of thalidomide, has patented the drug delivery system, S.T.E.P.S., instead. They originally started selling thalidomide capsules in the U.S. as an AIDS wasting medication. Prices have increased as the medication has started to be used for cancer. Celgene is seeking FDA approval to market thalidomide for multiple myeloma; currently, since the drug is only approved for leprosy, Celgene sales representatives aren't allowed to directly promote it for other uses. In October 2004, Celgene received a FDA approvable letter for potential accelerated approval of thalidomide in multiple myeloma; results of their final submission are outstanding.

Thalidomide is usually administered in a dosage of 200 mg per day, which is increased to 400 mg per day after two to four weeks, if tolerated. Lower doses (50 to 100 mg) are being investigated. Doses above 200 mg are generally avoided by using thalidomide in combination with corticosteroids or chemotherapy.

Scope and Key Questions

The key questions for this review were developed with experts in the field of oncology, health economics, and health policy. The key questions are as follows:

1. For patients with relapsed or refractory multiple myeloma, what is the effect of thalidomide compared to standard chemotherapy regimens (e.g., VBMCP [vincristine, carmustine, melphalan, cyclophosphamide, and prednisone] and VAD [vincristine, doxorubicin, and dexamethasone]) on 2-year survival, disease-free survival, CR, PR (m-protein), and quality of life?
2. For patients with relapsed or refractory multiple myeloma, what is the effect of thalidomide compared to standard chemotherapy regimens (e.g., VBMCP [vincristine, carmustine, melphalan, cyclophosphamide, and prednisone] and VAD [vincristine, doxorubicin, dexamethasone]) on adverse effects, tolerability and compliance?
3. What patient or tumor characteristics distinguish treatment responders from non-responders and have potential to be used to target therapy?

As there was emerging information regarding the role of thalidomide for newly diagnosed and smoldering multiple myeloma, these groups were also considered as part of this review.

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