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Part 4. Thalidomide for Multiple Myeloma (continued)
The search strategy yielded 250 articles. The selection process is described below:
Identified by search strategy (N=250)
|------ Excluded based on review of abstract (N=115)
Included based on review of abstract (N=135)
|------ Unable to locate (N=6)
|------ Excluded based on full-text review (N=31)
| 16 not phase II-III for efficacy
| 3 Review article
| 3 no primary or original data (review article)
| 2 CS not selected on response
| 2 wrong drug
| 2 wrong outcome
| 1 wrong disease
| 1 CS selected on AE
| 1 No quantification of association
Included in full-text review and evidence tables (N=96)
The 96 included reports comprised 62 full reports and 34 abstract-only publications. Each report and the sections within this review in which they fell (i.e., efficacy, adverse effects, predictors) is reviewed in the Included Studies table.
There was a total of 69 studies that presented some efficacy findings. Among these, study designs included 7 phase III controlled clinical trials and 62 phase II trials. Of the phase III trials, two were published as full text articles. Neither presented unblinded results. The five remaining phase III trials were published in abstract form only.
Quality of the studies was generally poor (Appendix B and Tables 1a, 1b and 1c). Less than half of studies achieved a threshold quality score of 4/6. Quality was poor across all study types—efficacy, adverse effects, and predictors. The large volume of abstracts that could not be assessed from a quality standpoint made overall quality even more concerning.
A review of all studies included in this report, including phase, thalidomide dose, comparator, size, and quality is presented in Table 1. Efficacy studies are broken down into category corresponding to thalidomide drug combinations and presence or absence of prior myeloma therapies (Figure 10; Tables 2-8). Adverse effect tables are presented according to those that match studies presented in the efficacy tables (Table 9) and independent studies representing adverse effect findings (Table 10). Predictors are organized by mechanism of action (Table 11), demographic factors (Table 12) clinical predictors (Table 13), and predictors related to thalidomide dosage or response (Table 14).
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Part 1. Efficacy
Efficacy is presented in Tables 2-8. The studies naturally segregated into eight groups according to Figure 10.
Table 2 presents two phase II studied of thalidomide only for asymptomatic multiple myeloma. Total number of patients represented is 35. Doses ranged widely from 50-800 mg. Thalidomide achieved CR rates of 16-25 percent and overall paraprotein responses (25 percent) of 66-81 percent, with PPR 50 percent of 34-38 percent. Length of followup was not long enough to allow meaningful comparison to historical survival controls.
Table 3 presents 19 studies with 1 in abstract form. A total of 891 patients with advanced/refractory/resistant multiple myeloma were given thalidomide, in varying doses ranging from 50-800 mg. Thalidomide achieved CR rates of 2-9 percent and overall paraprotein responses (25 percent) of 34-100 percent, with PPR 50 percent of 8-43 percent. The study by Barlogie, et al., in 2001 involving 169 participants with advanced refractory myeloma had a median followup of 22 months.43 Estimated overall survival (OS) at 12 months was 70 percent, and event free survival (EFS) was 25 percent. The estimated 2-year OS was 48 percent ± 6 percent with 2-year EFS at 20 percent ± 6 percent. Responses were generally achieved quickly with PPR 50 percent of 30 percent. Of patients achieving PPR 25 percent, 70 percent achieved that response within 2 months and 90 percent within 4.5 months. Similar patterns were seen in other studies. The ideal dose was difficult to determine. Researchers tried to decrease the dose, without clear diminution in effect, however in the Barlogie, et al., study higher total doses predicted superior response and survival.43
Table 4 presents six studies of which four are presented in abstract form; two of the abstracts are phase III. Over 447 untreated multiple myeloma patients were given thalidomide in combination with dexamethasone (thal-dex). The thalidomide dose ranged from 50-600 mg. Thalidomide achieved CR rates of 8-16 percent and overall paraprotein responses (25 percent) of 54-92 percent, with PPR 50 percent of 17-64 percent. The Rajkumar, et al., study presented in abstract form in 2005 randomized 202 participants to thal-dex versus dex alone.66 Thal-dex rendered higher response rates with 50 percent response rates of 58 percent for thal-dex and 42 percent for dex alone (p=0.0164). The Ludwig, et al., study presented in abstract form in 200563 is a randomized controlled trial (RCT) of thal-dex versus oral melphalan and prednisone. Only 137 of a goal 350 participants have been randomized and only 93 were evaluable for this analysis. Overall, thal-dex and melphalan plus prednisone were achieving similar results except for more CRs with thal-dex (13 percent vs. 4 percent) and shorter time to best response with thal-dex (11 weeks vs. 39 weeks). In both of these studies, thalidomide was dosed at 200 mg.
Table 5 presents nine studies of which one is presented in abstract form; none are phase III. A total of 427 advanced/refractory/resistant multiple myeloma patients were given thal-dex. The thalidomide dose ranged from 50-800 mg. Thalidomide achieved CR rates of 0-13 percent and overall paraprotein responses (25 percent) of 54-75 percent, with PPR 50 percent of 22-55 percent. Palumbo and colleagues treated patients with 50-100 mg of thalidomide and monthly pulsed dex.75 The study included 120 patients treated with thal-dex and a group of poorly matched controls who received conventional chemotherapy. Despite its limitations this was the largest and one of the highest quality studies within this group. Patients who received thal-dex were more likely to respond to the intervention and had better overall survival (OS: conventional chemotherapy=21 mo; thal/dex=27 mo; p=0.05). Across this group of studies patients routinely received smaller doses of thalidomide (50-100 mg daily) without any obvious diminution of response.
Table 6 presents nine studies of which seven are presented in abstract form; two are phase III. A total of 510 untreated multiple myeloma patients were given thalidomide with a variety of chemotherapy combinations including oral and parenteral conventional chemotherapy, bisphosphonates, and bortezomib. The thalidomide dose ranged from 100-400 mg. Efficacy results are not summarized into a single numeric range for this group of studies as the interventions are too diverse. Two phase III studies evaluating thalidomide in combination with melphalan are of particular interest. One study has not presented any data yet.78 The study by Palumbo and colleagues identified a substantial improvement in complete response rates when thalidomide was added to standard melphalan and prednisone (CR: 26 percent vs. 4 percent) as well as improved EFS at 26 months (68 percent vs. 32 percent, p<0.001).79
Table 7 presents 18 studies of which 9 are presented in abstract form; none are phase III. A total of 741 advanced/refractory/resistant multiple myeloma patients were given thalidomide with a variety of chemotherapy combinations including oral and parenteral conventional chemotherapy, bisphosphonates, interferon, and bortezomib. The thalidomide dose ranged from 50-1000 mg. Efficacy results are not summarized into a single numeric range for this group of studies as the interventions are too diverse. The most interesting message across this group of studies was the breadth of clinical options for thalidomide with reasonable tolerability. Oral combinations like thalidomide plus corticosteroids and cyclophosphamide or melphalan looked most promising and combinations with interferon least promising.
Table 8 presents combinations of thalidomide used before or after SCT as part of the upfront therapy or maintenance program. There are six studies presented, of which three are in abstract form only; three are phase III. These data are still maturing; two studies only present blinded data. Overall, thalidomide can be used in the peri-transplant setting, but, one abstract from a randomized trial suggests that thalidomide used as part of the maintenance program after SCT may diminish options for salvage chemotherapy when it is needed in the future.110 Lower doses of thalidomide as part of a maintenance program are likely to be better.113 (Select Figure 11.)
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Part 2. Adverse Effects
Adverse effects are summarized on Tables 9 and 10. Table 9 includes studies presented in the previous efficacy analysis that also included adverse events information. Table 10 represents studies that were presented as reports of adverse events only.
Review of Table 9 highlights six main themes:
- Using data from studies of thalidomide only, thalidomide side effects include constipation (3-11 percent grade 3 and 4), neurotoxicity predominantly evident as peripheral neuropathy (1-7 percent grade 3 or 4) and sedation (3-13 percent grade 3 or 4), cardiac insufficiency due to bradycardia (2-6 percent grade 3 or 4), leukopenia (2-31 percent grade 3 and 4), and blood clots (2-10 percent grade 3 or 4).
- In many instances, patients with more advanced multiple myeloma have more side effects, as would be expected, but not overwhelmingly more.
- The profile of side effects shifts when dex is combined with thal. There is less peripheral neuropathy (2 percent grade 3 or 4). There are two columns for the Weber study.67 Patients represented in the column with N=28 received thal only while those in the N=40 column received thal-dex. Sixty-eight percent of patients who received thal developed some peripheral neuropathy, as opposed to 50 percent of those who did not receive dex. A similar pattern was seen in the Weber study for decreased constipation with thal-dex (68 percent vs. 55 percent). However, with dex there was more weakness/fatigue/lethargy and edema. Thromboembolic events and skin reactions appear to increase when dex is included as well.
- Combining thalidomide with other agents increases side effects further.
- Side effects increase as multiple myeloma advances or the patient has been exposed to other treatments.
- Outside of the addition of dex, adding other chemotherapeutic agents generally increases the side effect profile.
Table 10 demonstrates the growing insight around thalidomide and its side effects that is rapidly accumulating in the literature. Fahdi and colleagues demonstrated that the incidence of bradycardia was 53 percent in their population of patients receiving thalidomide.117 Thalidomide does not increase the incidence of avascular necrosis when it is combined with steroids.114 Work by Badros, et al., suggests that subclinical hypothyroidism with TSH >5 is about 13 percent more common with thalidomide than with conventional chemotherapy.115 Hall, et al., reviewed skin reactions associated with thal and thal-dex, documenting the risk of severe exfoliative reactions like toxic epidermal necrolysis.118 Hattori, et al., verified the cytopenias seen with thalidomide and documented that the neutropenia can be ameliorated with GCSF.45 Tosi documented that the neurotoxicity rate with thalidomide was nearly the same for newly diagnosed myeloma patients and those with refractory or resistant disease.77 Tosi and colleagues also documented that the peripheral neuropathy associated with thalidomide accumulates and worsens over time.121 And finally, a growing body of work from Zangari and colleagues carefully documents that the incidence of DVT is approximately 24-36 percent higher when patients receive thalidomide, that DVTs occur approximately 6 weeks after initiation of thalidomide, they may be associated with chromosome 11 abnormalities, and they do not alter the efficacy of thalidomide.122-126 Zangari and colleagues also document that low dose warfarin does not mitigate the DVT risk with thalidomide, but low dose enoxaparin does decrease the risk to baseline levels.
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Part 3. Predictors
The predictors tables have been divided into four sections:
- Table 11 reviews reports of predictors related to the presumed mechanism(s) of action of thalidomide.
- Table 12 reviews reports related to patient demographic factors.
- Table 13 reviews reports related to known clinical diagnostic tests.
- Table 14 reviews reports that are related to thalidomide dosage and response factors.
Each detailed table is preceded by a summary table.
Bone marrow angiogenesis has a role in the biology of multiple myeloma,8 and the anti-angiogenic properties of thalidomide provided the initial rationale for using this drug for this disease.35 Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are the most potent and specific factors to be known to be involved in angiogenesis. Measurement of these appears to relate to angiogenic activity and increased microvessel density. Growth of multiple myeloma is also regulated by another pro-angiogenic cytokine network where TNF-alpha and IL-6 play a key role.128 Thalidomide has strong immunomodulatory and anti-inflammatory activity and modulates T-cell subset function and cytokine production in addition to angiogenesis.128
In Table 11, the most notable finding among the predictors potentially related to the mechanism of action of thalidomide listed is the lack of consistency among any of the positive findings. None of these are consistent predictors of thalidomide response or survival with thalidomide. The heterogeneity across this group of studies is supportive of what is known—and needs to be known—in order to better elucidate the mechanism of action of thalidomide in multiple myeloma. Of note, hepatocyte growth factor (HGF) levels are reflective of tumor burden and not an indicator of specific effect of thalidomide. It is expected to decrease with tumor response and was used as a control condition for one of the studies.129
Review of the summary tables for Tables 12 and 13 suggests that the long known prognostic factors hold up with thalidomide, including age, performance status, cytogenetic abnormalities, albumin, beta-2 microglobulin, and others.
Table 14 confirms that paraprotein response with thalidomide corresponds to multiple myeloma tumor response including bone marrow response and early response predicting later response. Also, two studies suggested that higher doses of thalidomide predicted survival.60,134
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