Thalidomide in Multiple Myeloma: current status and future prospects
Thalidomide as a single agent for the treatment of myeloma
Whatever its exact mechanism of action, thalidomide has impressive activity in myeloma, as first reported by Barlogie and colleagues in 1999 (Singhal et al, 1999). In this pivotal study, 84 patients were treated with thalidomide at a starting dose of 200 mg/day, increasing in 200 mg increments every two weeks to a maximum dose of 800 mg/day. All patients had progressive disease and over 90% had received at least one high dose procedure. Two thirds of the patients tolerated 600 mg od but only half were able to take the maximum 800 mg dose. The total response rate was 32%, as defined by a fall in paraprotein level of at least 25%. Responses were associated with a reduction in bone marrow (BM) infiltration by malignant plasma cells and increases in haemoglobin levels.
However, there was no clear correlation between responses and any reduction in BM microvascularity. In responders, a reduction in paraprotein level (>25%) was achieved within two months in 78% of cases. Response rates were inversely correlated with the plasma cell labelling index (PCLI). For cases with a PCLI <0.2% the response rate was 48%, whereas only 9% of those with a PCLI >0.2% responded. Approximately one third of the patients experienced side-effects, mainly somnolence, constipation and fatigue. These adverse events were classified as WHO Grade 3-4 in >10% of cases and were related to the dose taken. After 12 months of therapy, 44% of the patients had shown evidence of progression. The 12 month event-free survival was 22% and the 12 month overall survival was 58%.
This report has been updated (Barlogie et al, 2001a), at which time 169 patients had been treated with an overall response rate of 36%. Responses were more frequent in patients with a low PCLI and normal cytogenetics. Overall, the two year event free and overall survivals were 20% and 48% respectively, with superior outcomes for those patients who actually responded to thalidomide (EFS 34% and OS 69%).
However, 62% of patients showed evidence of disease progression and were withdrawn from the study. Thromboembolic events occurred in less than 5% of patients. Similar findings in smaller series of patients have been reported by others (Juliusson et al, 2000; Rajkumar et al 2001a; Oakervee et al 2001; Grosbois et al 2001). Overall, approximately 30-45% of patients with relapsed or refractory disease have achieved a partial response in these studies, so confirming the activity of thalidomide as a single agent in advanced myeloma (See Table I).
| No of patients | RR (>minor response) | Comments | Reference |
| 84 | 32% | OS 12m 58% | Singhal et al 1999 |
| 169 | 36% | OS 24m 48% | Barlogie et al 2001a |
| 23 | 52% | Juliusson et al 2000 | |
| 32 | 31% | >PR only reported | Rajkumar et al 2001a |
| 32 | 53% | Oakervee et al 2001 | |
| 120 | 32% | Grosbois et al 2001 | |
| 44 | 25% | Weber et al 1999 | |
| 36 | 44% | Low dose (50- 200mg thal used) |
Durie et al 2001 |
| No of patients | RR (partial response) | Comments | Reference |
| 28 | 36% | Weber et al 2001 | |
| 16 | 38% | Rajkumar et al 2001b |
RR = response
rate
OS = overall survival
PR = partial response (>50% reduction in paraprotein)
MR = minor response (>25% reduction in paraprotein)
The optimal dose of thalidomide has yet to be defined. Barlogie and colleagues (2001a) have suggested that there is evidence of a dose-response effect with higher response rates being observed in those patients who receive more than 42g of thalidomide within the first three months (54% vs. 21% response rate, p=0.001). In contrast, other investigators have observed similar response rates with doses varying from 50-200 mg per day (Durie et al, 2001; Wechalekar et al 2001). Similarly, when utilising an escalating dose regimen, responses are usually first observed when patients are taking only 200 mg per day (Oakervee et al, 2001). Therefore, the optimal thalidomide dose remains uncertain and this issue can only be resolved by appropriate prospective clinical trials.
Thalidomide has been used alone in untreated, asymptomatic patients (dose 100-400mg od) with a response rate of 36% with a median duration of response of greater than 12 months (Weber et al, 2001) with other groups reporting similar results (Rajkumar et al, 2001b).
Thalidomide analogues
Certain of the thalidomide analogues demonstrate enhanced in vitro activities that might predict superior clinical anti-tumour efficacy. In addition, these analogues do not have the teratogenic effects of thalidomide and it is also hoped that they will have a better side-effect profile than the parent drug. IMiD 3 (CC-5013, Celgene Corporation) is amongst the most promising analogues in vitro and displays significantly increased potency in inhibiting TNF-α production following LPS stimulation of peripheral blood mononuclear cells (PBMC). Likewise, CC5013 is 50-2000 times more active than thalidomide at stimulating T-cell proliferation and 50-100 times more active in augmenting the production of IL-2 and IFN-γ following TCR ligation of PBMC and T-cells respectively (Corral et al, 1999). Furthermore, the IMiDs display a greater ability than thalidomide in inhibiting myeloma cell DNA synthesis in vitro (Hideshima et al, 2000).
For all of these reasons, CC5013 and similar compounds (e.g. CC4047) are being investigated in early Phase clinical studies. Two Phase I, dose-escalating studies have recently been reported (Richardson et al, 2001; Zangari et al, 2001a). Somnolence, constipation and neuropathy were not observed although myelosuppression appears to be a problem and a single case of thromboembolism occurred. Although these are not primarily efficacy studies, it is encouraging to note that 12/19 evaluable patients in the Dana Farber study showed at least a 25% paraprotein reduction. On the basis of these results, Phase II/III trials are being designed.
Thalidomide plus dexamethasone
The activity of thalidomide as a single agent in advanced myeloma, along with in vitro evidence of synergistic effects, has prompted investigation of the combination of thalidomide with dexamethasone. In one such study from the MDACC, 44 evaluable patients with relapsed or refractory disease were initially treated with thalidomide alone and 26% achieved a PR (Weber et al, 1999). Thalidomide was started at 200 mg per day, increasing every two weeks to a maximum of 800 mg per day. Of note, all responses were observed with doses less than or equal to 400 mg per day. Of the non-responders, approximately 35% went on to show a response to the combination of thalidomide with pulsed dexamethasone suggesting synergy between these two agents in the clinical setting.
Two similar small studies have been reported, although there were differences in the thalidomide dose (100 mg rising to 600 mg and 100 mg at a fixed dose respectively) and in the exact pulsed dexamethasone regimen (Tosi et al, 2001; Palumbo et al, 2001) (Results summarised in Table II). PR rates of 26% and 48% were observed respectively. In the latter study, thalidomide/dexamethasone treated patients were compared with pair-mates treated with melphalan and prednisolone. Similar response rates were observed but with reduced toxicity. In none of these three studies was an excess of thromboembolic events reported.
| No of patients | RR (partial response) | Comments | Reference |
| 26 | 35% | All refractory to thal alone |
Weber et al 1999 |
| 27 | 26% | Tosi et al 2001 | |
| 44 | 48% | Palumbo et al 2001 | |
| 7 | 43% | Failed thal alone | Durie et al 2001 |
| No of patients | RR (partial response) | Comments | Reference |
| 26 | 77% | Rajkumar et al 2001c | |
| 16 | 69% | Weber et al 2001 |
RR response rate
partial response >50% reduction in paraprotein
These results in patients with advanced myeloma have prompted the investigation of this combination in newly diagnosed patients. A major potential advantage of this regimen is that it obviates the need for a long-term central venous catheter with its associated risks of infection and line-related thrombosis.
Rajkumar and colleagues (2001c) from the Mayo Clinic have reported on the first 50 patients with active myeloma treated in this manner. Thalidomide was initially escalated up to 800 mg per day but after the occurrence of unexpected, severe skin rashes in two of the first seven treated patients, the dose was fixed at 200 mg. The observed PR rate was 64% which is comparable to VAD-like regimens. Venous thromboembolism was seen in 10% of patients, a significantly higher incidence than that generally observed with this regimen in patients with relapsed disease. This Phase II study has led the Eastern Cooperative Oncology Group (ECOG) to initiate a randomised study for patients with newly diagnosed myeloma where patients receive pulsed dexamethasone with or without thalidomide at 200 mg per day with the aim of proceeding to high dose melphalan and stem cell rescue after four months of induction therapy.
Thalidomide plus chemotherapy
There have been encouraging reports concerning the efficacy of thalidomide combined with dexamethasone and chemotherapy. 12/14 (86%) patients with advanced myeloma achieved a PR to the combination of hyperfractionated cyclophosphamide, dexamethasone and thalidomide ('Hyper-CDT') (Kropff et al, 2000). Responding patients were maintained on pulsed dexamethasone and thalidomide with no progression observed after a median of 7 months.
In a second study, 42 patients with advanced disease were treated with T-CED (thalidomide, cyclophosphamide, etoposide and dexamethasone) and 78% achieved at least a PR (Moehler et al, 2000). No excess of thrombotic events was reported in either study. A further study in previously treated patients examined the efficacy of pulsed thalidomide, cyclophosphamide and dexamethasone with the aim of reducing the side-effect profile associated with continuous thalidomide. Partial responses were seen in 12/24 patients (Dimopoulos et al, 2001) (Table III).
| Regimen | No of patients | RR (partial response) | Advanced/de novo disease | Reference |
| HyperCDT | 14 | 86% | Advanced | Kropff et al 2000 |
| TCED | 42 | 78% | Advanced | Moehler et al 2000 |
| TCD | 24 | 50% | Previously treated | Dimopoulos et al 2001 |
| TVAD | 12 | 100% | 11/12 de novo patients; 1 advanced |
Oakervee et al 2002a |
| MPT | 13 | 38% | Newly diagnosed | Oakervee et al 2002b |
| MPT | 9 | 44% | Relapsed | Oakervee et al 2002b |
| BLT-D | 55 (40 evaluable) | 93% | 46 advanced disease | Coleman et al 2001 |
RR: response rate
PR: partial response >50% reduction in paraprotein
Hyper-CDT:cyclophosphamide, dexamethasone and thalidomide
TCED: thalidomide, cyclophosphamide, etoposide and dexamethasone
TCD: pulsed thalidomide, cyclophosphamide and dexamethasone
TVAD: thalidomide, vincristine, adriamycin and dexamethasone
MPT: melphalan, prednisolone and dexamethasone
BLT-D: clarythromycin (Biaxin) low dose thalidomide and
dexamethasone
The largest study in previously treated patients, who had not received a prior autograft, has been conducted at The University of Arkansas for Medical Sciences (Tricot et al, 2001; Barlogie et al, 2001b). Patients were initially treated with two cycles of DT-PACE comprising dexamethasone and thalidomide with infusional cisplatin, doxorubicin, cyclophosphamide and etoposide. Stem cells were collected in all patients achieving at least a partial response (PR) who were then randomised to undergo tandem autograft procedures or further cycles of DT-PACE. The purpose of this study was to answer the question as to whether further DT-PACE could substitute for tandem autografts in DT-PACE sensitive disease.
The two year EFS and OS in the tandem autograft and further DT-PACE groups were 63%/81% and 65%/79% respectively. The number of thromboembolic events was not reported as being unexpectedly high. Although these outcomes are no different, it is difficult to draw firm conclusions from this study since 58% of patients in the further DT-PACE arm crossed over to the tandem autograft arm because of failure to achieve predefined levels of response. Furthermore, only 40% of eligible patients were actually randomised. Nevertheless, the investigators felt able to conclude that DT-PACE is an excellent induction regimen for previously treated myeloma patients but that high dose therapy is still required for durable disease control.
These impressive results observed in patients with advanced disease have encouraged the initiation of studies examining the combination of thalidomide with conventional chemotherapy in newly diagnosed patients with myeloma. The largest such study again is being conducted at The University of Arkansas for Medical Sciences. Patients are treated with sequential chemotherapy and tandem autografts (Total Therapy II) with or without thalidomide (Barlogie et al, 2001b). This study is on-going and results are awaited with interest.
Two feasibility studies are being conducted by the UKMF concerning the combination of thalidomide with chemotherapy. Patients for whom high dose melphalan is felt to be appropriate are eligible for the T-VAD protocol (thalidomide at 200-400 mg with VAD). Because of early concerns that prior exposure to thalidomide might interfere with stem cell mobilisation (Munshi et al, 1999), patients are treated initially with a single cycle of VAD chemotherapy prior to a first 'back-up' stem cell harvest. They then receive concurrent VAD and thalidomide to maximum response, a second stem cell harvest and consolidation with high dose melphalan and stem cell rescue utilising the second harvest.
Of 12 patients so treated, 11/12 successfully mobilised stem cells at the first and 10/11 at the second attempt (Oakervee et al, 2002a). The patient who failed initial mobilisation still had high disease bulk at the time whereas the single patient who failed to mobilise for a second time had been previously treated with oral melphalan and C-VAMP. Therefore, it appears that T-VAD does not interfere with subsequent stem cell mobilisation. Of note, 12/12 patients achieved at least a PR. Four thrombotic events have been observed; three line-related and one PE.
A second UKMF study is examining the combination of melphalan and prednisolone with thalidomide (MPT) in patients for whom high dose therapy is not felt to be appropriate. 22 patients have been treated (13 untreated, 9 previously treated) with an overall 55% PR rate. However, 3/13 previously untreated patients developed DVT/PE (Oakervee et al, 2002b). This was felt to be more than expected and the study was therefore closed prior to the accrual of 25 planned patients.
Another approach in advance disease has been to combine low dose thalidomide (50-200mg) with dexamethasone and clarythromycin (Biaxin) (BLT-D). Coleman et al (2001) have reported 55 patients (49 with myeloma) treated on this regimen. Of 40 evaluable patients, 93% have had at least a partial response and 13% have achieved complete responses.