Thalidomide Combination Therapy Research Articles

Thalidomide Combined With Azathioprine as Induction and Maintenance Therapy for Azathioprine-Refractory Crohn's Disease Patients.

The combination therapy of thalidomide and azathioprine (AZA) offers an alternative in clinical practice for Crohn's disease (CD) patients experiencing a loss of response to AZA monotherapy. However, little is known about the efficacy and safety of this combination therapy for patients with CD. This was a retrospective study of 122 consecutive CD patients who lost response to AZA therapy and had switched to a combination therapy of thalidomide and AZA. The primary outcomes were clinical response and clinical remission rates at week 24. Patients who had an initial response to combination therapy were continued on the treatment for remission maintenance. The secondary outcomes were the proportion of clinical relapse throughout maintenance. The Kaplan–Meier method was used to calculate cumulative rates, and Cox regression analysis was used for multivariate analysis. During induction, 80.3% (98/122) patients achieved clinical response within a median duration of 6.5 weeks, (interquartile range, 4.3–8.1 weeks). The rate of clinical remission at 24 weeks was 70.5%. During follow-up, 22.4% (22/98) of the patients that were maintained on combination therapy experienced clinical relapse. The proportions of patients in remission status at 12, 24, and 36 months were 85.1, 78.3, and 70.1%, respectively. Multivariate analysis revealed C-reactive protein >10 mg/L at disease relapse on AZA monotherapy [adjusted hazard ratio (HR), 4.72; 95% CI, 1.19–18.75, P = 0.027] and 6-thioguanine nucleotides level ≥235 pmol/8 × 108 erythrocytes at AZA monotherapy (adjusted HR, 5.32; 95% CI, 1.40–20.14, P = 0.014) were associated with disease relapse on combination therapy. The endoscopic remission rate was 63.6%. Mucosal healing was achieved in 23.6% of the patients. Both Crohn's Disease Endoscopic Index of Severity (13.4 ± 4.92 vs. 6.12 ± 5.24, P < 0.001) and Rutgeerts scores (3.23 ± 0.73 vs. 1.77 ± 1.59, P = 0.003) were significantly decreased with the use of combination therapy. Adverse events occurred in 62 (50.8%) patients, but only 13 (10.7%) necessitated therapy discontinuation. Thalidomide combined with AZA was effective in inducing clinical remission and sustaining long-term steroid-free remission in CD patients who lost response to AZA monotherapy.

Rituximab and thalidomide combination therapy for Castleman disease

Rituximab and thalidomide combination therapy for Castleman disease

Cyclosporin A and thalidomide in patients with myelodysplastic syndromes: Results of a pilot study

We reported 37 patients with myelodysplastic syndromes (MDS) of refractory cytopenia with multilineage dysplasia or refractory anemia with excess blasts who were treated with cyclosporin A (CyA)/thalidomide combination therapy. Of them, 19 patients (19/37, 51.4%) achieved a hematologic improvement and erythroid response (HI-E); 9 patients (9/29, 31.0%) achieved hematologic improvement and platelet response (HI-P) and 7 patients (7/33, 21.2%) achieved hematologic improvement and neutrophil response (HI-N). 15 of 32 (46.9%) transfusion-dependent patients achieved independence from transfusion. The median response duration of HI-E, HI-P and HI-N were 88 (4–108) weeks, 78 (8–84+) weeks and 78 (10–84+) weeks, respectively. Some patients presented with I or II grade hepatic or nephritic impairment, constipation, lethargy, dizziness, edema, rash or sense of numbness. Therefore, CyA combined with thalidomide appears to be useful and is relatively well-tolerated for patients with MDS.

Phase II Multicenter Study of Association of Arsenic Trioxide (ATO) and Ascorbic Acid in Myelodysplastic Syndrome.

Abstract 943 Introduction:Arsenic trioxide (ATO) inhibits angiogenesis, induces apoptosis and differentiation in variety of malignant cells. Two multicenter phase II studies have documented that ATO has as a moderate activity both in low and high risk myelodysplasia with 19-21% haematological improvement. Ascorbic acid in “vitro” increases in tumor cells the activity of ATO by depleting GSH and inhibiting NF-kb. High EVI-1 levels have been reported to predicted the response to arsenic trioxide and thalidomide combination therapy. We report the results of a multicenter phase II study with combination of arsenic trioxide and acid ascorbic in myelodysplastic patients. Patient eligibility included:a) pts with 3q26 rearrangement or high EVI-1 levels; b) non-RAEB pts at low-intermediate/1 risk who failed a previous therapy; c) RAEB or high-intermediate-2 risk patients not elegible to chemotherapy and/or bone marrow transplant. Study design:Arsenic trioxide was administrated intravenously over 1 hour at the loading dose of 0.30 mg/kg/day for 5 consecutive days, followed by0.25 mg/kg/day twice weekly for 15 weeks. Ascorbic acid 1000 mg was given IV within 30 minutes after each arsenic trioxide infusion. Response evaluation was scheduled after two and four months of treatment according to the IWG criteria (Cheson 2000) Patients:44 pts were enrolled .Median age was 71 years (range 47–80). WHO categories were non-RAEB (15 pts), RAEB-1 (12 pts), RAEB-2 (17 pts). 23 patients had a low/intermediate-1 IPSS score; 18 had a high/intermediate-2 risk. Risk category, could not be assessed in 3 pts lacking of cytogenetic data. Before starting therapy EVI-1 was highly expressed in 13 out of 34 evaluated pts (38%); high WT-1 levels was documented in 25 out of 35 pts (71%). 31 pts (57%) were transfusion dependent at baseline. Results:Ten out of 44 evaluable patients obtained a response (23%). They included 1 complete remission, 2 major erythroid hematologic improvement (HI-E major), 3 minor HI-E, 2 major neutrophil improvemet (HI-N) and 2 major trilineage responses. Response rate was 35% in lower risk IPSS patients and 6% in higher risk pts (p 0.05).Only 3 pts with high EVI-1 expression achieved a response. In 8 out of ten responders, the response was evident within the first 8 weeks of treatment. Twenty three (52%) patients discontinued treatment because disease progression (11%), severe adverse events (32%), drug unrelated adverse events (5%), withdrawal of consent (5%). Severe neutropenia and thrombocytopenia were observed respectively in 45% and 23% pts. The other G3-4 adverse events observed were: ATRA-like syndrome (9%), cardiotoxicity (11%) infection (11%), hepatotoxicity (9%). No toxic death was observed. Summary and Conclusions:The combination of ATO and ascorbic acid is tolerable and it is active in about 25% of MDS patients. The addition of ascorbic acid to ATO does not increase neither the toxicity nor the response rate to ATO. The tolerability of this regimen is reduced in elderly and high risk patients. In our study high EVI-1 transcript levels were not confirmed to predict the response to ATO. Disclosures:Off Label Use: Arsenic trioxide is yet approved for the treatment of MDS, even if its efficacy has been shown in other phase II studies.

Infection Complications in Patients with Multiple Myeloma Treated with New-Drug Combinations Including Thalidomide.

Abstract 2828Poster Board II-804Studies including thalidomide showed a rate of severe infection that can be life-threatening complication or compromise compliance to therapy ranging from 6% to 22%. Therefore, antibacterial prophylaxis has become a routine clinical practice despite its role in the new-drugs era has to be defined.We performed a post-hoc analysis of patients treated with thalidomide based combinations within controlled trials in order to assess time, type and outcome of infections. We analysed the main demographic and disease related variables to search for factors affecting onset of infections during induction and build a risk model in order to perform targeted prophylaxis.Two hundred and twenty four patients were eligible for this study. Median age was 70 years (range 31-90 years) and 141 patients (63%) had more than 65 years. Fifty three percent of patients had de novo MM whereas the remaining had received thalidomide as second or subsequent lines of therapy. ISS stage 2-3 and renal impairment were present in 156 (69%) and 38 (17%) of patients, respectively. Induction therapy consisted in the following protocols: ThaDD (160 patients: 71.5%), ThaDD-V (42 patients: 19%), VMPT (9 patients: 4%), TD (8 patients: 3.5%) and VTD (5 patients: 2%). Prophylaxis for infections was administered to 168 patients (75%) and consisted of quinolones (72%) or thrimethoprim-sulphamethoxazole (28%).Eighty six patients (38.5%) developed an infection resulting of grade 3-4 in 39 of them (17.5%) (12% grade 3, 5.5% grade 4). Probability of infection at six months was 39% although that of severe infection was 20% (18% at 4 months and just 2% from 4 to 6 months). Among the 39 patients with severe infection, 23 (59%) developed pneumonia, 9 FUO (23%), 6 bacteremia (1 septic shock) and 1 an orbital abscess. Aetiology of severe infection was recognized in 7 patients (4 Gram-negative bacteria, 1 Gram-positive bacteria, 1 CMV and 1 probable fungal infection). Eighty percent of severe infections occurred during the first 3 courses of induction therapy and only 12% during neutropenia. Fifteen percent of patients undergoing antibiotic prophylaxis developed infection vs 25% of patients who did not (p= 0.084). There were no difference between quinolones and thrimethoprim-sulphamethoxazole prophylaxis regarding incidence of infections. The majority of infections were empirically treated and cured with wide spectrum antibiotic therapy except when a specific aetiology was recognized. Only one patient died because of septic shock during neutropenia and 2 patients withdrawn from protocol because of infection. In univariate analysis monoclonal component > 2 g (p=0.021), platelets < 130.000/ml (p= 0.005), newly diagnosed MM (p=0.083) and antibiotic prophylaxis (p=0.061) were factors predicting severe infection development whereas age, sex, ECOG performance status, MM type, D-S stage, plasmacell infiltration in bone marrow, haemoglobin concentration, serum b2-microglobulin, serum albumin, ISS, serum C-Reactive Protein, serum creatinine, previous stem cell transplantation were not. Cox regression analysis selected monoclonal component > 2 g (p=0.015 HR= 1.8) and platelets < 130.000/ml (p=0.003 HR= 2.3) as covariates associated to severe infection. The 25 patients without adverse factors, the 125 with 1 and the 74 with 2 adverse factors had a probability of severe infection equal to 4%, 17% and 32 % (p= 0.023), respectively. This model remains useful apart from prophylaxis since the probability of severe infection in patients with at least 1 risk factors receiving prophylaxis is 17% vs 4% in patients without risk factors. Of note, patients developing severe infection had a significantly higher incidence of deep venous thrombosis (DVT) compared with patients who did not (20.5% vs 9%: p= 0.041). DVT occurred after a median time of 0.9 months (range 0.1-5 months; 75% within 2 months) from infection onset.In conclusion, despite antibiotic prophylaxis, patients receiving thalidomide combination therapy can develop severe infections particularly pneumonia. Wide spectrum antibiotic therapy is effective in the majority of cases since viral or fungal infections are very rare. Patients with large size of disease, represented by high MC and low platelets count, are at higher risk of severe infection that in turn significantly increase the risk of DVT. Therefore, these patients at high-risk should receive more suitable antimicrobial prophylaxis. Disclosures:Off Label Use: Thalidomide, Bortezomib and Doxil.

Clinical Outcomes in Metastatic Gastroenteropancreatic Neuro-endocrine Tumors (NETs) with Temozolomide and Thalidomide Combination Therapy

Purpose: Gastroenteropancreatic NeuroEndocrine Tumors (NETs) are heterogenous group of neoplasms which have limited response rates and significant toxicity with standard chemotherapy. Temozolomide is considered as a less toxic alternative for NETs. Combination with thalidomide is postulated to increase the efficacy by inhibiting the angiogenic pathways, but there is limited data available. Methods: The study was a retrospective study of patients with metastatic NETs, who received an oral thalidomide and temazolamide combination. Clinical data including patient's age, gender, race, type of cancer, previous therapies, clinical, radiological and tumor marker response to chemotherapy and toxicity was recorded. Results: The study group consisted of 12 patients with metastatic NETs, of which 5 were males and 7 females. The median age of diagnosis was 67 yrs (Range 47-79 yrs). Six patients had NET and 6 had carcinoid tumors. The primary sites of the tumor were pancreas ( n=4), small bowel (n=4), colon (n=2) and lung (n=2). The tumor markers secreted were as follows: chromogranin(n=10), serotonin (n=6), gastrin (n=2) and pancreatic polypeptide(n=1). The median chromogranin level at diagnosis was 47 Units/L (Range 5-122,000). Sites of metastases were liver (n=12), omentum (n=6), lungs (n=5) and bones (n=2). All patients had received sandostatin and received prior chemotherapy ranging from 1 to 3 regimens. Patients received a median of 1.5 (Range 1-9) cycles of temozolomide and thalidomide combination. Six patients came off thalidomide for toxicity and remained on temozolomide for another 4 cycles. Clinical, radiological and marker response could be evaluated in 8 patients; four patients were too early for response evaluation. Clinical best response was as follows: partial response (n=3), stable disease (n=4) and progression (n=1). Best radiographic response was as follows: partial response (n=2), stable disease (n=5) and disease progression (n=1). Tumor marker response was recorded as follows: partial response (n=2), stable disease (n=5) and progression (n=1). The reasons for discontinuation of regimen were toxicity (n=7) and disease progression (n=1). The most frequent treatment related adverse events were lymphopenia (n=4), abnormal LFTs (n=3), venous thromboembolism (n=2), peripheral neuropathy (n=2) and cardiomyopathy (n=1). Median survival was not obtained as 11 patients were still alive. Conclusion: The temozolomide and thalidomide combination regimen is effective in patients with metastatic NETs refractory to conventional chemotherapy and is worthy of further study. This regimen has treatable toxicities and patients should be monitored closely.

Arsenic trioxide, thalidomide and retinoid acid combination therapy in higher risk myelodysplastic syndrome patients

Objective To evaluate the clinical efficacy and safety of arsenic trioxide, retinoic acid and thalidomide combination therapy in higher risk MDS. Methods Twenty-one patients diagnosed with higher risk MDS were administered 10 mg/day arsenic trioxide intravenously for 10 days, 40 mg/day retinoic acid orally for 2 weeks and 100 mg/day thalidomide orally for 4 weeks per cycle. Results After at least two treatment cycles, 10 patients showed hematologic responses. One achieved CR, one achieved PR, three patients achieved major hematological improvements. The efficacy rate was 24% (5/21), and the response rate was 48% (10/21). The schedule was tolerated well by all patients and toxicities were moderate and reversible. Conclusion The combination of arsenic trioxide, retinoic acid and thalidomide could have therapeutic benefit in higher risk MDS with safety.

Phase II study of topotecan and thalidomide in patients with high-risk myelodysplastic syndromes

This phase II trial investigated the safety and preliminary efficacy of a topotecan/thalidomide combination therapy in patients with myelodysplastic syndrome who had refractory anemia with excess blasts (RAEB), RAEB with transformation, or chronic myelomonocytic anemia. Patients received three 21-day cycles of topotecan 1.25 mg/m2 on days 1–5, which was repeated for two additional cycles in patients whose bone marrow blast percentages did not decrease. Oral thalidomide was then started at 100 mg/day (with the dose escalated up to 300 mg/day if well tolerated) for up to 1 year. Patients were monitored throughout the trial for hematologic and clinical adverse events, and efficacy was assessed using International Working Group (IWG) criteria. Forty-five patients, mostly elderly (median age 68 years; range 52–79 years), were enrolled. Therapy was generally well tolerated compared to high-dose chemotherapy. Three patients died from disease progression/infections during topotecan therapy, and four patients discontinued topotecan because of high-grade neutropenia (two patients), syncope (one patient), or hip surgery (one patient). Of 24 patients who received thalidomide, three discontinued because of treatment-related toxicity. Thirty-eight patients were evaluable for response: nine (24%) had hematologic improvement and 13 (34%) had stable disease. Responses occurred in patients with all disease subtypes. Six patients achieved transfusion independence, and one patient had a trilineage response. Approximately one-third of the patients had decreases in bone marrow blasts of ⩾50%. Therefore, a topotecan and thalidomide combination therapy is promising, although further studies are needed to determine the optimum doses and schedule.

Phase II study of thalidomide, Interleukin-2 (IL-2), and granulocyte macrophage-colony stimulating factor (GM-CSF) in patients (pts) with metastatic renal cell carcinoma (MRCC)

4717 Background: Thalidomide’s immunomodulatory and anti-angiogenic effects may augment the antitumor activity of IL-2. The early efficacy and safety findings observed in low dose subcutaneous (SQ) IL-2/thalidomide combination therapy for treatment of MRCC (ASCO, 2003) form the foundation for the current study. GM-CSF is an important cytokine for the generation and propagation of antigen presenting cells and for priming cellular immune responses. The primary objective is to improve the antitumor activity by adding GM-CSF to the thalidomide plus IL-2 regimen. Methods: Eligibility: histologic diagnosis of confirmed clear cell carcinoma, excluding papillary, sarcomatoid, or collecting duct tumors, measurable MRCC, normal organ/marrow function, life expectancy ≥12 weeks, Zubrod performance status (ZPS) ≤2, no prior chemo or immunotherapy, no active CNS involvement. Wk 0, thalidomide was administered orally at 200mg and increased to 400mg after 48 hrs, IL-2 at 7mIu/m2 and GM-CSF at 250mcg/m2 were injected SQ, starting at wk 1, days 1–5, wks 1–4, with a rest period at wks 5, 6. Response was assessed every 2 therapy cycles. Stable or responding pts completed 6 cycles, then were placed on maintenance thalidomide. Six pts are inevaluable for response secondary to CNS toxicity, non-compliance, or early progressive disease. Pt characteristics: 21 male/7 female, aged 57–73 (median 64) years; 28 pts had confirmed RCC. All pts had metastatic involvement. Sites included: lung (N=24), nodal (N=6), liver (N=5), bone (N=2), kidney (N=1), eye (N=1). Number of metastatic sites: 1 (N=16), 2 (N=9), 3 (N=3). ZPS 0 (N=25) and ZPS 1 (N=3). Results: 28 pts were enrolled: 3 complete responses, 6 partial, 6 stable, 7 progressive disease, and 6 not evaluable. Grade 1/2 toxicity included: somnolence, constipation, rash, flu-like symptoms, fluid retention, hypotension, hypothyroidism, sinus bradycardia, and peripheral neuropathy. Hematologic changes consisted of: leukocytosis associated with neutropenia, lymphocytosis and eosinophilia. Conclusion: Enrollment is ongoing. Data regarding response rate, time to progression, and toxicity will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene, Chiron Celgene, Chiron, Endocyte

Low Dose Single Agent Thalidomide Is Tolerated in Patients with Primary Systemic Amyloidosis, but Responses Are Limited.

Background: Primary systemic amyloidosis (AL) is an incurable plasma cell dyscrasia with limited therapeutic options. Based on the observed 25 to 50% partial response rates in myeloma patients, thalidomide has been tried in patients with AL. Two reports (Dispenzieri et al, Amyloid 10:247; 2003; Seldin et al, Clinical Lymphoma 3:241; 2003) have demonstrated that standard dose, single agent thalidomide (≥ 200 mg per day) has a higher than expected rate of adverse events in AL patients without hematologic or organ response, potentially due to rapid patient attrition. We therefore performed a prospective clinical trial using low dose, single agent thalidomide in patients with AL.Methods: In August 2001, we began accrual to a phase II trial of low dose thalidomide for patients with AL. Eligibility included: age ≥ 18 years, creatinine <3mg/dL, total bilirubin < 3 mg/dL, ANC ≥ 1 x 10(9)/L, left ventricular ejection fraction of >45%, histochemical proof of amyloid and a monoclonal plasma cell dyscrasia, symptomatic organ involvement, and ability to supply informed consent. Patients were started with thalidomide 50 mg per day, with a dose escalation to a maximum dose of 400 mg per day over a 19 week period as tolerated. Patients were evaluated monthly by their physician. These office visits were staggered with telephone toxicity checks monthly by the primary investigator. The endpoint of the study was hematologic and organ response by 12 months.Results: Eighteen patients were treated. The median age was 66 years (range 43–83). Eight were male. Twenty-eight percent had an ECOG performance status of 2 or 3. Five patients (28%) had received no prior therapy. Five had received one prior regimen; 6, two prior; and 2, ≥ three. Three had received prior PBSCT. Sixteen patients had a monoclonal lambda plasma cell disorder; two, monoclonal kappa. Immunoglobulin heavy chains were IgG (n=9), IgM (n=5), IgA (n=1), and none (n=3). Twelve patients (67%) had cardiac involvement; twelve (67%) renal; two liver; two symptomatic gastrointestinal; one pulmonary; and two nerve involvement. Study participants had significant symptomatology at baseline with dyspnea (n=12), light-headedness (n=6), and edema (n=13). Median number of organs involved was 1, range (1 to 4). Median time on study drug was 5.6 months, range 0.7–24 months. Reasons for discontinuation included: progression, 7 (39%); 3 each (17%) for adverse events, death, and patient refusal; and other causes in 2. The median tolerated dose was 100 mg. There were no hematologic responses observed. The overall organ response rate was 11%. There was one renal response at 1 year and a gastrointestinal response at 3 months with 24 hour fecal fat changing from 21 to 8.7 grams. The most common adverse effects attributable to thalidomide were: constipation (78%), edema (44%), sinus bradycardia (17%), dyspnea (11%), and paresthesias (11%). Light-headedness, rising creatinine, thrombosis, infection, syncope, and rash was attributed to the thalidomide in 5.6% of patients.Conclusions: Low dose thalidomide is tolerable in this fragile group of patients, but as a single agent efficacy is limited. Further study of combination therapy of thalidomide and low dose dexamethasone may be warranted. A study using the next generation immune modulatory drug Revlimid is scheduled to open to accrual. Funded by NIH grant CA 91561 and Celgene.

A randomised phase II study of interferon alpha alone or in combination with thalidomide in metastatic renal cancer

4742 Background: Interferon alpha is the standard treatment for patients with metastatic kidney cancer. Single agent thalidomide may have some activity in renal cancer. To investigate whether the combination of Interferon alpha (INF) and thalidomide is feasible and more efficacious than interferon alone as the first line therapy we initiated an ongoing phase II randomised study. Methods: The main aims were to assess safety, toxicity, therapeutic efficacy and biological activity of the combination compared to INF alone. Patients were randomised [interferon arm; INF 9 MIU subcutaneously thrice a week, INF + Thalidomide arm: INF as above and thalidomide 100 mgs once daily then 200 mgs once daily after two weeks] and stratified by prognostic groups. Toxicity analysis and QOL assessments were performed every 3 weeks. Disease response evaluation was performed 12 weekly. Results: A total of 34 patients have been recruited so far (males: 22, females: 12). Median age 57 years (range 44–76). 16 patients were randomised to receive INF and 18 patients received INF + thalidomide. 20 patients who received >= 12 weeks of therapy were evaluable for disease response: INF arm; [complete response 1, stable disease (SD) 9, progressive disease (PD) 2 and in INF + thalidomide arm; partial response (1), SD (2), PD (5)]. All others received < 12 weeks of therapy due to toxicity or early PD. A total of 13 patients came off therapy due to toxicity [INF (5), INF + thalidomide arm (8)]. The common grade III or IV toxicities were: INF arm; anorexia (1), fatigue (6), vomiting (1), nausea (1), flu like symptom (1), thrombocytopenia (1), neutropenia (2) and in INF + thalidomide arm: anorexia (1), fatigue (2), dizziness (2), drowsiness (1), skin rash (2), anaemia (4) and neutropenia (2). Conclusions: Interferon + thalidomide combination therapy is safe. The toxicity is comparable with INF alone though dizziness, drowsiness, skin rash and anaemia were more severe in the combination arm. Preliminary analysis suggests no significant advantage in the combination arm with regards to disease response. No significant financial relationships to disclose.

A randomised phase II study of interferon alpha alone or in combination with thalidomide in metastatic renal cancer

4742 Background: Interferon alpha is the standard treatment for patients with metastatic kidney cancer. Single agent thalidomide may have some activity in renal cancer. To investigate whether the combination of Interferon alpha (INF) and thalidomide is feasible and more efficacious than interferon alone as the first line therapy we initiated an ongoing phase II randomised study. Methods: The main aims were to assess safety, toxicity, therapeutic efficacy and biological activity of the combination compared to INF alone. Patients were randomised [interferon arm; INF 9 MIU subcutaneously thrice a week, INF + Thalidomide arm: INF as above and thalidomide 100 mgs once daily then 200 mgs once daily after two weeks] and stratified by prognostic groups. Toxicity analysis and QOL assessments were performed every 3 weeks. Disease response evaluation was performed 12 weekly. Results: A total of 34 patients have been recruited so far (males: 22, females: 12). Median age 57 years (range 44–76). 16 patients were randomised to receive INF and 18 patients received INF + thalidomide. 20 patients who received >= 12 weeks of therapy were evaluable for disease response: INF arm; [complete response 1, stable disease (SD) 9, progressive disease (PD) 2 and in INF + thalidomide arm; partial response (1), SD (2), PD (5)]. All others received < 12 weeks of therapy due to toxicity or early PD. A total of 13 patients came off therapy due to toxicity [INF (5), INF + thalidomide arm (8)]. The common grade III or IV toxicities were: INF arm; anorexia (1), fatigue (6), vomiting (1), nausea (1), flu like symptom (1), thrombocytopenia (1), neutropenia (2) and in INF + thalidomide arm: anorexia (1), fatigue (2), dizziness (2), drowsiness (1), skin rash (2), anaemia (4) and neutropenia (2). Conclusions: Interferon + thalidomide combination therapy is safe. The toxicity is comparable with INF alone though dizziness, drowsiness, skin rash and anaemia were more severe in the combination arm. Preliminary analysis suggests no significant advantage in the combination arm with regards to disease response. No significant financial relationships to disclose.

Relapsed multiple myeloma.

The treatment of relapsed multiple myeloma remains a challenge for clinicians. Most salvage therapies result in transient responses, with median survival from relapse ranging from 6 to 18 months. No randomized trials comparing salvage therapies have been performed. In the absence of a "gold standard" salvage therapy, relapsed patients should be considered for clinical trials. In light of the recent observation that thalidomide alone brings about a 30% to 35% response rate with manageable toxicities, this is the most promising single agent available to treat relapsed disease. The maximum effective dose appears to be 400 mg/d; virtually all responses are evident within 2 months of starting therapy. Combination therapy of thalidomide with pulse dexamethasone or other chemotherapeutic agents has shown promise in pilot trials. Even with thalidomide-responsive disease, the response duration is brief, ranging from 3 to 6 months. Therefore, the authors recommend that patients under the age of 78 years who have acceptable physiologic organ function, chemotherapy-sensitive disease, third-party financial coverage, and adequate hematopoietic stem cells be considered for high-dose therapy with autologous hematopoietic stem cell transplant. High-dose therapy with hematopoietic stem cell transplant provides the highest response rate, response duration, and survival compared with historical controls treated with conventional therapy. Patients under the age of 70 years who have human leukocyte antigen-compatible donors should be considered for immune-based therapy using nonmyeloablative preparative regimens with allogeneic hematopoietic stem cell transplant.