Thalidomide has been tested in numerous combination therapies with good results. This section will examine the more common combinations. The combination of thalidomide and dexamethasone appears to be a very effective therapy for relapsed and refractory myeloma. Patients who don't respond to thalidomide alone often respond to the combination. With thalidomide and dexamethasone, 50% reductions in M protein or more have been achieved in 48% to 78% of patients in recent trials, which are summarized in the table below.

Patients who fail to respond to standard chemotherapy and autologous transplant (AT) are an especially difficult subgroup to treat effectively, and no ideal therapy has yet been identified. Investigators in Italy evaluated the combination of thalidomide and dexamethasone and found it to produce significantly greater therapeutic response after relapse and post-AT, compared to other therapies containing combinations of doxorubicin, cyclophosphamide, etoposide and cisplatin (Palumbo, 2004). The response rate to thal-dex was 19% near complete remission, 28% partial remission, and 35% stable disease, while the rates for salvage chemotherapy were 16% partial response, 32% stable disease, and the majority (53%) had progressive disease. These findings suggest that thal-dex is a superior salvage therapy to standard follow-up chemotherapy in patients who fail a first course of high-dose chemotherapy and AT.

Patients who cannot tolerate high dose therapy with thal-dex may still be able to take the combination with lower doses of thalidomide, particularly when combined with a third agent. Many of these studies are summarized in the next section.

Response rates to thal-dex reported from selected studies are summarized in the table below.

Summary of Recent Combination Thalidomide-Dexamethasone Trials in Relapsed and Refractory Myeloma

Study Date No. of patients Response* (% of patients) Safety / Comments Palumbo et al (ASH abstract #2396) 2004 90 NCR = 19% PR = 28% SD = 35% NR Anagnostopoulos et al 2003 47 CR = 13% Other response = 34% Grade 3 adverse events included neuropathy, rash, ileus, DVT, pulmonary embolism Caravita et al (IMMW #333) 2003 30 PR = 57% Minor R = 21% 6 patients discontinued due to neurotoxicity or DVT Durie et al (IMMW #325) 2003 36 11/36 relapsed patients had dex added due to non-response; 6 of the 11 (55%) responded Limiting toxicity for all patients was neuropathy, requiring dose reduction 26 14/26 relapsed patients had >50% response when the combination was given up front Palumbo et al (IMMW #324) 2003 122 In patients who had received 1 line of chemo, M protein reduction of 50%-100%: Thal-dex = 56% Chemo = 46% PFS for 3 years: Thal-dex = 38% Chemo = 6% Estimated OS 3 years: Thal-dex = 60% Chemo 26% Case-matched controlled analysis. Grade 2 toxicity seen in 12% of patients, Grade 3 in 4%. In the earlier phases of the disease (1 previous line of chemo), thal-dex was superior to conventional chemo. In more advanced stages of disease (2 or more previous lines of chemo), thal-dex was equivalent to conventional chemo.

*CR = complete response (typically defined as the absence of M protein); NCR = near complete response (typically defined as a ≥90% reduction in M protein) Major R = major response (typically defined as a ≥75% reduction in M protein); PR = partial response (typically defined as ≥50% reduction in M protein); SD = stable disease Minor R = minor response (typically defined as <50% reduction in M protein) PFS = progression free survival OS = overall survival IMMW = International Multiple Myeloma Workshop

Combining chemotherapy with thalidomide may increase the antitumor effects compared with either strategy alone. When thalidomide is used in combination with chemotherapy, responses (defined as a 25% reduction in M protein or more) have been achieved in 30% to 80% of patients.

Various thalidomide-containing drug regimens have been evaluated in relapsed and refractory disease, including:

• Cyclophosphamide, dexamethasone, thalidomide (CDT)
• Cyclophosphamide, thalidomide, etoposide, dexamethasone (CTED)
• Dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide (DT-PACE)
• Doxil® (liposomal doxorubicin, Ortho Biotech), vincristine, dexamethasone, thalidomide (DVd-T)
• Vincristine, Adriamycin® (doxorubicin), dexamethasone, thalidomide (VAD-T)
• Velcade® (bortezomib, Millennium), thalidomide
• Melphalan, thalidomide, dexamethasone (MTD)
• Cyclophosphamide, thalidomide and prednisone (CTP)

The tables below summarize results of select trials evaluating thalidomide-containing regimens in relapsed and refractory myeloma.

Summary of Recent Combination Thalidomide-Chemotherapy Trials in Relapsed and Refractory Myeloma

Cyclophosphamide, Dexamethasone, Thalidomide (CDT) Study Date No. of patients Response* (% of patients) Safety / Comments Williams et al (ASH abstract #1499) 2004 29 refr/ 17 relaps Min R = 50% NR = 50% CR/PR = 71% (relapsed) CR/PR = 83% (refractory) Minimal side effects, Grade 1 and 2. 2 pts had Grade 3 toxicity (DVT) 2 pts developed neutropenia Dimopoulos et al 2004 53 PR = 60% Pulsed CTD regimen. Toxicities were mild to moderate. Cumulative incidence of DVT (4%) and neuropathy (2%) was lower than expected when thal is administered on a continuous basis Gonzalez-Porras et al (IMMW #326) 2003 59 CR = 4% PR = 57% Most adverse events were mild to moderate; 6 infections, 2 cases of DVT, 1 pulmonary embolism Kropff et al 2003 60 CR = 4% PR = 68% Minor R = 12% Most common Grade 3 and 4 toxicities included neutropenia, infection, thrombocytopenia, and neuropathy Di Raimondo et al (ASH #5268) 2003 43 CR = 21% Major R = 29% PR = 21% Minor R = 21% Cyclophosphamide was temporarily discontinued in 23 patients due to low white blood counts; 9 patients discontinued thal. Kyriakou et al (ASH #5270) 2003 37 Major R = 57% PR = 24% Minor R = 3% 12 infections, 3 cases of DVT, mild to moderate neuropathy and constipation Caravita et al (ASH # 5258) 2003 23 PR = 22% Minor R = 11% Most adverse events were mild to moderate; 2 cases of neutropenia, no DVT Sidra et al (ASH #5125) 2002 26 18 patients underwent stem cell collection; 16 underwent autologous transplant; 3 achieved CR Low risk of DVT seen; regimen enables a portion of VAD-refractory cases to achieve CR following high-dose therapy Thalidomide, Cyclophosphamide, Etoposide, Dexamethasone, (TCED) Study Date No. of patients Response* (% of patients) Safety / Comments Moehler et al (ASH #2562) 2003 119 CR = 4% PR = 52% Minor R = 19% Used as induction therapy prior to auto or mini-allo transplant; Grade 3 or 4 myelosuppression (60%), infection requiring hospitalization/IV antibiotics (24%) Dexamethasone, Thalidomide, Cisplatin, Doxorubicin, Cyclophosphamide, Etoposide (DT-PACE) Study Date No. of patients Response* (% of patients) Safety / Comments Lee et al 2003 236 After 2 cycles: CR = 7% NCR = 9% PR = 16% MR or PR = 54% Wide variety of Grade 3 or 4 adverse events; patients with chromosome 13 deletion responded equally well as other patients Doxil® (liposomal doxorubicin, Ortho Biotech), Vincristine, Dexamethasone, Thalidomide (DVd-T) Study Date No. of patients Response* (% of patients) Safety / Comments Agrawal et al (ASH #831) 2003 50 After a median of 6 cycles of therapy (45 evaluable patients): CR + NCR = 47% SD or better = 89% Protocol amended due to increased incidence of neutropenia, infections, paraesthesia and DVD. Incidence of pneumonia was reduced to 0/25 patients and DVD reduced from 33% to 10% Vincristine, Adriamycin® (doxorubicin), Dexamethasone, Thalidomide (VAD-T) Study Date No. of patients Response* (% of patients) Safety / Comments Oakervee et al (ASH #1560) 2002 23 Of 19 evaluable patients: CR =16% Major R = 32% PR = 32% Thrombotic events: 4 line-related and 1 pulmonary embolism. The addition of thal to VAD as induction therapy did not appear to adversely affect PBSC harvest or hematologic recovery in these newly diagnosed or relapsed patients; Velcade® (bortezomib), Thalidomide Study Date No. of patients Response* (% of patients) Safety / Comments Zangari et al (ASH #830) 2003 56 After 4 cycles: PR = 55% Minor R = 15% After 8 cycles: CR + NCR = 22% Toxicities were reported to be generally manageable and included gastrointestinal events, fatigue, peripheral neuropathy, and hematologic toxicities; no cumulative grade 3 or 4 neuropathy was observed during the first 4 cycles of therapy. The combination appears to be active in patients who had previously received thal. Dexamethasone was added if less than a PR by cycle 4. Melphalan, Thalidomide, Dexamethasone (MTD) Study Date No. of patients Response* (% of patients) Safety / Comments Srkalovic et al 2002 21 Of 20 evaluable patients: CR = 5% Major R = 40% Minor R = 10% Retrospective study; Grade 3 or 4 adverse events included anemia, neutropenia, thrombocytopenia, fatigue, neuropathy; 5 hospitalizations for neutropenic fevers, 2 deaths from neutropenic complications Cyclophosphamide, Thalidomide, Prednisone Study Date No. of patients Response* (% of patients) Safety / Comments Suvannasank et al (ASCO #6591) 2005 37 22 of 37 patients (63%) were evaluable CR = 22% NCR = 6%, PR = 41% Hoosier Oncology Group study of patients assessed after median of 7 cycles (1-12 total). Two did not receive study drug due to progression and patient preference. Major adverse effects included neutropenia (5 patients each Grades 3 and 4) and neuropathy (4 patients Grade 3, 2 patients Grade 3).

*CR = complete response (typically defined as the absence of M protein); NCR = near complete response (typically defined as a ≥90% reduction in M protein); Major R = major response (typically defined as a ≥75% reduction in M protein); PR = partial response (typically defined as ≥50% reduction in M protein); Minor R = minor response (typically defined as <50% reduction in M protein) SD = Stable disease ASH = American Society of Hematology meeting. IMMW = International Multiple Myeloma Workshop