Long-Term Follow-Up of Patients Treated with Bortezomib Alone and in Combination with Dexamethasone as Frontline Therapy for Multiple Myeloma.
Sundar Jagannath, MD1,
Brian G.M. Durie, MD1,
Jeffrey Lee Wolf, MD1,
Elber S. Camacho1,
David Irwin, MD1,*,
Jose Lutzky, MD1,*,
Marti McKinley, BSN1,*,
Afshin Eli Gabayan, MD1,*,
Amitabha Mazumder, MD1,
John Crowley, PhD2 and
Robert Vescio, MD1,*
1 Medical Oncology, Aptium Oncology Research Network, Los Angeles, CA, USA and 2 Cancer Research & Biostatistics, Seattle, WA, USA.
Introduction: Novel therapeutic agents, such as bortezomib (VELCADE®;btz), thalidomide, and lenalidomide, are being used in combinationwith dexamethasone (dex) as frontline therapies in MM. Phase2 and 3 trials with limited follow-up have reported a high responserate and feasibility of high-dose therapy and stem cell transplantation(HDT-SCT). Here we present longer follow-up on our phase 2 trialof btz±dex as frontline therapy.
Methods: Patients (pts) with measurable disease and KPS 50%received btz 1.3mg/m2 on days 1, 4, 8 and 11 of a 3-week cyclefor up to 6 cycles. Oral dex 40mg was added on the day of andday after btz for pts achieving < partial response (PR) after2 cycles or < complete response (CR) after 4 cycles. Responseswere assessed using European Group for Blood and Marrow Transplantationcriteria, with the addition of near CR (nCR; CR but positiveimmunofixation).
Results: 48 pts were accrued and were evaluable for response;a further 2 registered on the trial declined to proceed. Medianage was 60 years, 46% were male, 64% had IgG and 21% IgA, and50% were Durie-Salmon stage III. At the end of btz±dextreatment, overall response rate (ORR; CR+nCR+PR) was 90% with19% CR/nCR; an additional 8% achieved a minimal response (MR).Response to btz alone was rapid; response rate by end of cycle2 was 50%, including 10% CR/nCR. Dex was added for 36 (75%)pts: 17 at cycle 3, 18 at cycle 5, and 1 at cycle 6. Additionof dex improved best responses to btz in 23 (64%) pts, with12 improving from stable disease to MR or PR, 9 from MR to PR,1 from PR to nCR, and 1 from nCR to CR. Median time to bestresponse was 1.9 months. For all 48 pts, with a median follow-upof 24 months, median time to alternative therapy (TTAT) was7 months (range: 225; this includes pts who went on toHDT-SCT), and median overall survival (OS) has not been reached;1-year survival rate was 90%. For pts not proceeding to HDT-SCT,median TTAT was 22 months, median OS has not been reached; 1-yearsurvival rate was 80%. 23/48 pts proceeded to HDT-SCT. MedianCD34+ harvest was 12.6 x 106 cells/kg (range: 5.140.4x 106) from a median of 2 collection days (range: 18).All pts had complete hematologic recovery; median time to neutrophil(ANC >1000/mm3) and platelet (>100,000/mm3) engraftmentwas 11 days (range: 813) and 17 days (range: 1098),respectively. In the 23 HDT-SCT pts, median TTAT and OS havenot been reached; post-transplant 1-year survival rate was 90%.The most common grade 2 adverse events for btz±dex weresensory neuropathy/neuropathic pain (37%), fatigue (20%), constipation(16%), nausea (12%), and neutropenia (12%). Two pts developedgrade 4 events (1 neutropenia, 1 thrombocytopenia).
Conclusion: Btz±dex is an effective frontline therapyfor MM, with an ORR of 90%, including 19% CR/nCR, and OS rateof 80% at 1 year. The treatment is well tolerated and toxicitieswere manageable and reversible. Addition of dex to btz providesimproved responses. TTAT for patients not undergoing HDT-SCTwas 22 months. The regimen does not prejudice subsequent HDT-SCT;stem cell harvest and engraftment were successful in all ptsproceeding to transplant. Consolidation with HDT-SCT furtherincreases the response rate and durability of response. Btz+dexis being compared to VAD as induction therapy prior to HDT-SCTin a phase 3 study.