The unique activity of the thalidomide molecule against plasma cells offers a promising therapy for multiple myeloma, particularly in combination with dexamethasone (thal-dex). Many studies of this combination have shown response rates comparable to those achieved in relapsed/refractory patients.

In 2004, thal-dex was included in the clinical practice guidelines issued by the National Comprehensive Cancer Network (NCCN) as suitable firstline therapy for patients who present with advanced (Durie-Salmon Stage II or III) myeloma (NCCN, 2004). In the thalidomide multiple myeloma panel discussion proceedings held in 2003, thal-dex was also deemed appropriate for patients with newly diagnosed myeloma (both transplant-eligible and -ineligible). (Stewart et al, 2003) Thal-dex was found to be appropriate as an induction therapy in a retrospective analysis of 200 patients entered in consecutive trials from 1996 to 2004. In fact, response rates of thal-dex were superior to standard chemotherapy with vincristine-doxorubicin-dexamethasone (VAD) (76% compared with 52%) given 4 months prior to peripheral stem cell collection and autologous transplantation and thal-dex produced a more significant reduction in myeloma cell mass of both IgG and IgA types. (Cavo et al, Blood 2005;1182/blood-2005-02-0522;)

The addition of bortezomib (Velcade) to the combination of thalidomide and dexamethasone for the treatment of newly-diagnosed multiple myeloma has also demonstrated superiority to previous regimens used for these patients. The rate of remission was 55% with the 3-drug combination was double that observed with bortezomib alone (Alexanian R et al, 2005. ASH Abstract #210).

Results of the randomized Phase III study of thal-dex in newly-diagnosed, symptomatic patients conducted by the Eastern Cooperative Oncology Group (ECOG) were reported at the American Society of Hematology (ASH) meeting in December, 2004 (Rajkumar et al. ASH Abstract 205.) In this study, the patients who received 200 mg/day of thalidomide and dexamethasone (n=103) had a response rate of 59% at 4 months compared with a response rate of 42% seen in patients receiving dexamethasone alone (n=104). Corrected response rates were slightly higher (see table below).

Prior to ECOG, two smaller Phase II studies demonstrated significant responses to thal-dex in newly diagnosed patients. Rajkumar et al. showed a greater than 50% reduction in M protein (J Clin Oncol. 2002;20:4319-4323), while Weber et al showed a response rate of 72%, with a CR rate of 16% in these patients (J Clin Oncol. 2003;21(1):16-19).

Phase III ECOG Thal-dex Trial: Response Rates

Response within 4 cycles* Thal-Dex (n=98) Dex (n=98) Best response 58% 42% Corrected response 69% 51%

*Response was defined as a ≥50% decrease in serum and urine M protein; a ≥90% decrease was needed if only the urine M protein was measurable. Corrected response was obtained by using serum M protein levels in patients in whom a measurable urine M protein was unavailable at follow-up

Phase III ECOG Thal-dex Trial: Major Grade 3-4 Toxicities

Toxicity Thal-dex (N=102) Dex (n=101) Grade ≥3 DVT 18% 3% Rash 4% 0% Rapid heartbeat 1% 0% Neuropathy 7% 4% Grade ≥4 Toxicity of any type 34% 17% Total 46% 20%

Summary of Recent Combination Thalidomide-Dexamethasone Trials in Newly Diagnosed Myeloma (previously untreated)

Study Date No. of patients Thal dose (mg/day) Response (% of patients) Safety/Comments Rajkumar et al (ASH Abstract 205) 2004 103 (Symptomatic) 200 58%* See Table Above Cavo et al(ASH #1635) 2003 50 (Symptomatic, candidates for double autologous transplant) 200 70% (CR, 8%) Grade 3-4 toxicities: Constipation: 12% Fatigue: 10% Neuropathy: 6% Skin rash: 2% DVT: 18% Weber et al 2003 40 (Symptomatic) 100-400 72% (CR, 16%) Numbness/tingling: 50% Constipation: 55% Fatigue: 55% Rash/dry skin: 55% Edema: 35% DVT/PE: 15% (seen in patients receiving low-dose anticoagulation) Kumar et al (ASCO #2343)†† 2003 27 (Eligible for stem cell transplant) not discussed 100% not discussed Wang et al (IMMW #352) 2003 17 (High-tumor mass) 150-200 71% (CR, 12%) DVT/PE (1 pt.) Dehydration (1 pt.) Hospitalizations for infection (3 pts.) Rajkumar et al 2002 50 (Symptomatic) 200-800† 64%* Among the first 7 patients receiving up to 800 mg/day, 2 had Grade 3-4 skin toxicity Grade 3-4 toxicities: Blood clot (6 pts.) Constipation (4 pts.) Rash (3 pts.) Trouble breathing (2 pts)

*Response defined as >50% reduction in M protein and/or reduction in Bence Jones protein by >75%; for all others, response was defined as ≥25% reduction in M protein. ¹After the first 7 patients, the thalidomide dose was kept constant at 200 mg/day. ¹¹Retrospective review comparing overall response rates among patients receiving thal-dex (n=27; 100%), dexamethasone (n=43; 79%), or VAD (n=80; 79%) as induction therapy. ASH = American Society of Hematology meeting ASCO = American Society of Clinical Oncology meeting IMMW = International Multiple Myeloma Workshop DVT = deep vein thrombosis PE = pulmonary embolism

The efficacy of thalidomide in combination with chemotherapy in newly diagnosed, treatment-naïve patients has been demonstrated in numerous studies. The most common drug combinations being evaluated in this patient population include:

• Melphalan, prednisone, and thalidomide
• Doxil® (liposomal doxorubicin, Ortho Biotech), vincristine, dexamethasone, and thalidomide (DVd-T)
  
  
• Thalidomide, Adriamycin® (doxorubicin), and dexamethasone (TAD)

The table below summarizes some of the major recent trials of combination therapy with thalidomide in previously untreated myeloma. Several smaller studies have examined various combinations of thalidomide with cyclophosphamide and dexamethasone (Williams et al, Blood, 2004, abstract.), and vincristine, adriamycin and dexamethasone (VAD) (Chanan-Khan et al, 2004) with favorable results and minimal toxicity observed.

Summary of Recent Combination Thalidomide-Chemotherapy Trials in Newly-diagnosed Myeloma (previously untreated)

Study Date No. of patients Treatment Reduction in M protein (% of patients) Safety/Comments ≥90% ≥75% ≥50% Palumbo et al (ASCO #6549) 2004 42 Melphalan, prednisone, thalidomide 26%* 19%† 12%   36% Thal increased the hematological toxicity of MP. Major adverse events: Infections: 26% DVT: 19% 1 death due to septicemia 1 death due to pulmonary embolism Zervas et al 2004 39 DVd-T (response evaluated after 4 cycles) 10%*   64% Grade 3 or 4 adverse events: Neutropenia: 15% Thrombocytopenia: 15% DVT: 10% Constipation: 10% Neuropathy: 5% Alexa- nian et al 2004 132 Velcade, dexa- methasone, thalidomide (VDT)   76%   Grade 3-4 toxicities: Non-neutropenic infection (2) Orthostatic hypotension (1) Neutropenia (1) Thrombocytopenia (1) Huang et al (ASH #5118) 2002 11 Melphalan, prednisone, thalidomide 27%*   18% No AE's more severe than Grade 2 were reported Agrawal et al (ASH #831) 2003 50 DVd-T 46%     Protocol amended to include antibiotics, growth factors and anticoagulants, due to increased incidence of neutropenia and DVT

*Denotes complete response †Denotes disappearance of M protein but positive immunofixation ASCO = American Society of Clinical Oncology meeting ASH = American Society of Hematology meeting IMMW = International Multiple Myeloma Workshop

The Arkansas Cancer Research Center has developed a regimen for newly diagnosed patients called Total Therapy II. This efficacy of Total Therapy II is being evaluated with and without added thalidomide in a Phase III trial. This regimen consists of four phases of treatment: induction, transplant, post-transplant consolidation, and maintenance. Thalidomide is added during each phase of treatment. (See figure below.)

TOTAL THERAPY II FLOWCHART

Complete data are available on 668 patients enrolled; 85% completed first transplant and 67% completed a second. Increases in CR were seen in the THAL arm from 43% to 62%. 5-year overall survival was superior with transplant plus THAL compared to transplant alone: 68% vs. 63%. (Barlogie et al.2005 ASCO abstract LBA6502.)

Original safety data available on 475 of the patients showed that the aggressive Total Therapy II regimen was associated with significant toxicity but low overall treatment-related mortality (2%). (Anaissie et al. Blood. 2003;102(11). Abstract 1657.) Severe Grade 3 or Grade 4 toxicity was seen in 93% of patients and occurred throughout treatment, including hematologic (93%), metabolic (78%), gastrointestinal (60%), infectious (51%), neurologic (43%), and cardiovascular problems (41%). Greater toxicity was seen in the thalidomide arm, including thrombosis/embolism, weakness, neuropathy, dizziness, tremor, fainting, and red cell transfusion requirements. The increased incidence of clotting events attributed to the combination of thalidomide and doxorubicin was reduced with appropriate anticoagulation. (Zangari et al. Blood. 2002;100(11). Abstract 1546.)