Maintenance Therapy After. Myeloma?

Transcription

1 Maintenance Therapy After Autologous Transplantation for Myeloma? Steven Rosinski, MD, PhD Faculty Discussant: William Bensinger, MD

2 CC: Back pain Case Presentation HPI: 70 yo women who reported a ten month history of back pain. She initially presented to a sports medicine clinic in March of 2008 with the chief complaint of low back pain. The pain was thought to be due to her known degenerative joint disease, and she was treated with physical therapy. She experienced some relief and she discontinued her physical therapy. She then represented in November with worsening back pain. An MRI of her lumbar region showed multiple lesions in the pelvis, spine, and right femur. I then saw her in the SCCA hematology clinic i in December 2008 for a further diagnostic workup.

3 Case Presentation PMH 1. History of low back pain and muscle spasms 2. History of hypothyroidism and s/p replacement therapy 3. Scoliosis 4. Injury after lifting a heavy object in History of chest pain with a negative workup 6. Only mammogram was in No colonoscopy or fecal occult blood testing PSH 1. Tonsillectomy at age Resection of meningioma in Reconstructive surgery for fracture of the left tibia plateau in 1999

4 Case Presentation Medications: none FH: Her mother died of thyroid storm four days after her birth; her father committed suicide approximately three weeks later. The remainder of the family history is unknown. SH: The patient was a registered nurse. She was living alone on an alpaca farm caring for 50 animals. She has 5 children. She had several miscarriages. She smoked about 1 pack per day for 3 years, but quit over 40 years ago. She occasionally drinks alcohol, but denies the use of illicit drugs.

5 Case Presentation ROS: As per HPI, ECOG 2, pruritis, and hair loss. PE: Unremarkable. Laboratory Values: HCT-31, MCV-99, normal WBC count, and normal platelet count. Ca-9.1, β-2 microglobulin-9.1. SPEP with immunofixation showed monoclonal IgA lambda quantified at 0.2g/dl. Quantitative IgA 319 mg/dl (65-420), IgG 453 mg/dl ( ), IgM 16 mg/dl (40-350). UPEP showed Bence Jones proteins, quantified at 84% by electrophoresis. Lamda free light chains were 1260mg/dl, and kappa free light chains were 0.79 mg/dl. 24-hour urine collection demonstrated 7.88 grams of total protein.

6 Case Presentation BM: Diagnostic biopsy demonstrated >35% plasma cells by morphology, which was an underestimation as there was some areas that showed only sheets of plasma cells. CD138 stain of the core biopsy estimated that plasma cells comprised 60% of the cells, and flow cytometry documented that 7.6% of the total white cell component were abnormal plasma cells. Cytogenetic report documented an abnormal female karyotype with loss of the X chromosome and trisomy of chromosomes 5, 9, and 15. FISH: showed gain of chromosomes 5, 9, and 15.

7 Case Presentation Bone Survey: 1.The known lesions in the lumbar spine and pelvis were poorly visualized radiographically. C5 spinous process lesion was concerning for myeloma involvement. No definite lytic lesions in the thoracic spine were identified. 2. Parietal skull lesion was likely myeloma. 3. Multiple l lucencies in the pelvis, right femur and right humerus were concerning for myeloma lesions. 4. Degenerative changes of cervical, thoracic and lumbar spine with L4 compression fracture.

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9 International staging system (ISS) Stage I - B2M <3.5 mg/l and serum albumin 3.5 g/dl Stage II- neither stage I nor stage III Stage III - B2M 5.5 mg/l Median overall survival of 29 months.

10 Case Presentation Clinical Course: The patient received four cycles of Lenalidomide and Dexamethasone with a complete response. The patient underwent G-CSF and Plerixafor mobilization with the collection of progenitor cells on May 6, The patient received an autologous transplant following Melphalan 140mg/m2 treatment in July Staging studies performed 90 days after autologous transplant demonstrated a continued CR.

11 Case Presentation Protocol 2253: Bortezomib and vorinostat as maintenance therapy after autologous stem cell transplant for multiple myeloma: - started November Bortezomib 1.3 mg/m2 IV D2 and D5 per 28-day cycles for total of 12 cycles Vorinostat 200 mg orally daily D1 through D14 per 28-day cycle for total of 12 cycles. After the first three cycles, Vorinostat was increased to 300 mg per dose for 2 cycles, then 400 mg per dose for 7 cycles. Maintenance concluded 11/10. Aspirate on 12/10 documented presence of 0.048% abnormal plasma cells by flow cytometry. SPEP with immunofixation negative. Aspirate 3/11 documented 0.48% abnormal plasma cells by flow cytometry. SPEP with immunofixation documented a faint IgA lambda component detectable by immunofixation, and not conventional electrophoresis.

12 Conventional 18 alternating ti cycles of VMCP and BVAP every 3 wks VMPC (vincristine 1mg iv day 1; melphalan 5mg/m2 d1, d4; cyclophosphamide h 110mg/m2 d1, d4; prednisone 60mg/m2 d1,d4); BVAP (exchanges melphalan and cyclophosphamide h for carmustine 30mg/m2 d1; doxorubicin 30mg/m2 d1) High Dose 4 to 6 alternating cycles of VMCP and BVAP. Autologous transplant with melphalan 140mg/m2 with 8 Gy TBI Maintenance Interferon 3e6 U/m2 3xwk Why Maintenance? 1.) Tandem Auto 2.) Auto Mini-Allo 3.) Maintenance Attal et al. N Engl J Med. 1996;335:91-97.

13 Maintenance Therapy What is the goal of maintenance therapy? Is it cure or control? If the goal is control, then treatment has to be inexpensive, i well tolerated, t and provide a long survival benefit as compared to instituting the therapy at the time of relapse or symptoms. If the goal is cure, then the treatment has to have that potential.

14 Interferon in Maintenance Symptoms were mainly flu-like. Nine patients in the interferon arm needed dose modification and four discontinued (epilepsy, nephrotic syndrome, psoriasis, work related). Cunningham et al. Br J Haematol 1998;102:

15 Thalidomide in Maintenance 4-cycles of induction and thalidomide then, 3-4 cycles of VAD then, RETRACTED June 11 th 2009 Thallidomide and Dex then, conventional chemo then, Published JCO 2009 Hicks et al. Cancer Treat Rev 2008;34:

16 Retraction June 11 th, 2009 Thalidomide in Maintenance

17 TOTAL THERAPY 2 +/- Thalidomide Barlogie et al. NEJM 354;10, 2006

18 TOTAL THERAPY 2 +/- Thalidomide Discontinuation rates for Thalidomide 30% at 2 yrs, 60% at 4 yrs. Cardiac pacemakers were implanted in 1/3 of the 38 patients with symptomatic bradycardia. Barlogie et al. NEJM 354;10, 2006

19 Thalidomide in Maintenance Hicks et al. Cancer Treat Rev 2008;34:

20 Thalidomide in Maintenance Attal, 2006 Spencer, 2009

21 Barlogie et al. Blood :

22 ASH auto-auto patients were then randomized to (Thal-Dex) for 1 year or observation. 84% of patients did not complete the therapy. No difference between survival for patients with or without thalidomide maintenance.

23 Lenalidomide in Maintenance Interim Analysis of Two Randomized Phase III Trials of Lenalidomide (LEN) Versus Placebo For Maintenance After AHSCT Presented at ASCO and ASH 2010 CALGB (568 enrolled), 109 not randomized, IFM (614 randomized) Eligibility <1yr from diagnosis, >2months induction, at least stable disease, age<70, Eligibility Age<65, non progressive disease after AHSCT Treatment d post AHSCT melphalan 200mg/m2, LEN started at 10mg/day, escalated to 15mg/day after 3 months continued until disease progression. Treatment Consolidation with LEN 25mg/d 21days/month for 2 months then either placebo or LEN (10 to 15mg/day) until progression. Median Followup 17.5 months from AHSCT, unblinded due to superiority Median Followup 34 months, unblinded due to superiority Placebo LEN Placebo LEN TTP 21.8 M 42.3 M Median PFS 24M 42M Stopped 2%AE,6%other 12%AE,13%other AE 5% 8% Philip McCarthy No overall survival benefit reported in either trial. Michel Attal

24 Bortezomib o in Maintenance a HOVON-65/GMMG-HD4 Protocol ASH 2010 Enrolled: 744pts 3-cycles of VAD (vincristine, doxorubicin, dex); then 1 to 2 auto transplants followed by thalidomide maintenance for two years. Versus 3-cycles of PAD (bortezomib, doxorubicin, dex); then 1 to 2 auto transplants followed by bortezomib maintenance for 2years. Median follow up 40 months, B vs. T HR=0.74, p=0.05

25 Summary The benefit of Interferon maintenance after autologous transplantation is unclear. Thalidomide maintenance after autologous transplantation t ti is poorly tolerated. t Lenalidomide maintenance after autologous transplantation increases PFS, but no difference in OS is yet noted. The role of bortezomib maintenance is unclear.

26 Maintenance Therapy What is the goal of maintenance? Cure versus control? If the goal is control, then treatment has to be inexpensive, well tolerated, and provide a long survival benefit as compared to instituting the therapy at the time of relapse or symptoms. If the goal is cure, then the treatment has to have that potential. Does lenalidomide have curative potential as treatment in the maintenance setting?

27 Dual Mechanism of Action We hypothesize that an immune mediated effect can cure myeloma patients in the setting of minimal residual disease. Davies F, Baz R, Blood Reviews 24 Suppl. 1(2010) S13-S19

28 Induction of CDK inhibitors (p15, p16, p21, p27) Early-response transcription factors Egr1, Egr2, Egr3 Activate caspases 3, 8, and 9, synergistic effect with dexamethasone Davies F, Baz R, Blood Reviews 24 Suppl. 1(2010) S13-S19

29 1.) In vitro culture increases NK-cell expression of death effector molecules, and secretion of IFN-gamma. 2.) Enhanced CD8 T cell activity in a CD8/DC/virus in vitro co-culture system. Increase in antigen specific antibodies and T cell response if vaccine occurs after lenalidomide treatment as compared to before.. I think this is a hypothesis, as I have not seen data supporting this conclusion Davies F, Baz R, Blood Reviews 24 Suppl. 1(2010) S13-S19

30 Conclusion Unless maintenance therapies are affordable, well tolerated, t and provide overall survival advantages, as compared to beginning treatment at relapse, then the goal of maintenance therapy should be curative intent. It is unclear if the immunomodulatory mechanisms of lenalidomide have an anti-myeloma effect. Further experimental evidence is needed to link the immunomodulatory mechanism of lenalidomide to eradication of myeloma cells. For example, documenting T cell and NK cell killing of myeloma cells from patients undergoing treatment with lenalidomide.