Treating myeloma. Dr Rachel Hall Royal Bournemouth Hospital

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1 Treating myeloma Dr Rachel Hall Royal Bournemouth Hospital

2 Treatment overview When to treat? Aim of treatment Which treatment? Monitoring response to treatment Prevention of complications What happens at relapse? New treatments

3 Myeloma Treatable but not curable After many years with little change several new drugs Survival improving Area of very active research clinical trials Initial treatment good information from trials current standard treatments Relapsed disease no standard but several options now

4 Treating myeloma is more than just anti-myeloma drugs Symptom control Supportive care Transfusions, EPO Treatment of infections etc General measures back care, hydration etc Pastoral / spiritual care

5 When to treat? Calcium increased Renal Impairment Anaemia Bone disease Hyperviscosity Spinal Cord compression

6 Emergency treatment Steroids Emergency radiotherapy Other treatments: antibiotics, transfusion, pain killers, bisphophonates + fluids, dialysis

7 Aim of Treatment Reduce myeloma activity Chemotherapy Strengthen bones Bisphosphonates Alleviate symptoms Improve quality of life Prevent further bone and organ damage

8 Treatment of bone disease BISPHOSPHONATES Sodium clodronate tablets Zeledronate intravenously Pamidronate intravenously Strengthen bones Stop myeloma driven bone breakdown Direct anti-myeloma effect

9 Kyphoplasty

10 Chemotherapy Chemotherapy Cancer

11 Myeloma treatment initial Divided into two groups: Younger patients (<70 years) who are candidates for autologous stem cell transplant Older patients, other patients not fit for autologous stem cell transplant

12 Younger patients The aim of standard initial treatment is to induce remission to spare stem cells (avoid melphalan at this stage) Then collect stem cells (peripheral blood) Then proceed to high dose melphalan (200mg/m 2 ) followed by blood stem cell rescue (autograft / autologous transplant)

13 Which chemotherapy in newly diagnosed myeloma? Myeloma IX Trial Eligible for Transplantation Not eligible for Transplantation Induction C-VAD or CTD MP or attenuated CTD Stem cell harvest Maximal response Consolidation Autologous transplantation Consider mini-allogeneic transplantation Maintenance No treatment or thalidomide

14 Induction chemotherapy High response rates Most regimens are given as an outpatient May require a tunnelled central line insertion Steroids important component & synergistic

day 1-4 Dexamethasone (steroids) days 1-4 and 12-15 Cycle

15 Intravenous treatment : C-VAD Cyclophosphamide weekly orally day 1,8,15 Vincristine and Adriamycin intravenously via pump day 1-4 Dexamethasone (steroids) days 1-4 and Cycle repeated every 3 weeks 4-6 cycles Alternatives: VAD, C-VAMP, Z-DEX One cycle

16 Thalidomide: How it works

17 Thalidomide: Side effects Dose mg daily Side effects : drowsiness constipation peripheral neuropathy thrombosis

18 Oral treatments MPT Melphalan day 1-7 Prednisolone day 1-7 Thalidomide daily 1-28 Cycle repeated 4 weekly 6-9 courses CTD Cyclophosphamide weekly Thalidomide daily Dexamethasone in pulses Cycle repeated 3-4 weekly 4-9 courses

19 Which regimen for which patient? MPT Generally patients >70 Very well tolerated Not ideal in renal failure or if stem cell collection planned CTD (a) Generally patients <70 Patients in whom stem cell collection being considered Dexamethasone can give SEs

20 Treatment complications Gout Thrush Shingles Pneumonia

21 Treatment prophylaxis Drugs needed in addition to the chemotherapy to prevent side effects / complications: Anti-nausea drugs Antacids (omeprazole) Antivirals (aciclovir) Anti-gout drugs Antibiotics Antifungals (fluconazole) Laxatives Blood thinners (clexane)

22 Markers of disease activity Healthy plasma cells Antibodies Paraprotein (M-Protein) Myeloma plasma cells (cancer cells) Light chains (M-Protein) Serum free light chains SFLC Urinary BJP

23 Response to treatment

24 Treatment Jargon Paraprotein Complete response (CR) Partial response (PR) Abnormal antibody or protein made by myeloma cancer cells No abnormal protein (M-protein) detectable in blood or urine for > 6 Weeks < 5 % Plasma cells in bone marrow > 50 % reduction in blood M- protein and/or 90 % reduction in urine light chains Plateau No evidence of continuing myeloma- related organ damage Stable M-protein levels for > 3 months

25 Autologous stem cell transplant Used in selected younger patients (<70yrs) Used to consolidate the response and increase the duration of response Stem cells collected with chemo and GCSF High dose melphalan (HDM) used and the bone marrow rescued with patients own stem cells High risk chemotherapy with many side-effects. Mortality 1-3 %

26 How to replace the bone marrow autologous stem cell transplantation

27 Collect stem cells Chemo GCSF High-dose melphalan Stem cells returned Recovery Remission

28 Side-effects of stem cell transplant Mucositis Infection Bleeding Fluid retention Breathing difficulties

29 Maintenance treatment Thalidomide Figure 1. Event-free survival according to treatment arm Reference: Attal, M. et al. Blood 2006;108:

30 Treatment of relapsed myeloma If first remission lengthy (>1 year) consider same treatment again If not already had thalidomide consider thalidomide (with dexamethasone) Bortezomib (with dexamethasone) Bortezomib with liposomal doxorubicin Lenalidomide with dexamethasone Clinical trials Dexamethasone alone Supportive care

31 Not Suitable for transplant Treatment of relapse First Relapse Suitable for transplant Initial treatment with MPT or CTDa Initial treatment With VAD type regimen And HDT HDT not part of 1st line treatment and PBSC available > 6 months < 6 months < 12 months post autograft > months post Autograft. Retreat with MPT or CTDa CTD or velcade regimen CTD or Velcade 2 nd Autograft Autograft Second or later Relapse CTD velcade or C-weekly / dexa or lenalidomide or Other new agents

32 The Velcade three 29 th March 2007: The National Institute for Health and Clinical Excellence s (NICE) announced a review of its own ruling denying patients NHS access to Bortezomib (Velcade) Jacky Pickles, Janice Wrigglesworth and Marie Morton

33 Velcade : How it works

34 Side-effects of bortezomib Nausea Constipation Diarrhoea Low platelets Neuropathy

35 Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma (APEX study) Bortezomib, an inhibitor of proteasomes (sites of protein degradation in cells), has activity against advanced multiple myeloma This study compared bortezomib with highdose dexamethasone in relapsed myeloma Bortezomib was superior to dexamethasone in all end points and prolonged overall survival

36 Bortezomib (Velcade) Response in % as single agent Response 50 % if used with dexamethasone Licensed for relapsed and refractory disease Major toxicities are neuropathy, thrombocytopenia IV therapy 1.3 mg/m 2 days 1,4,8 and 11. Dexamethasone tablets days 1,2,4,5,8,9,11,12

37 Lenalidomide

38 Lenalidomide Strong data for 2 nd line use onwards Weber D et al Lenalidomide plus Dexamethasone for Relapsed Multiple Myeloma in North America. NEJM 2007;357:21 Dimopoulos M et al Lenalidomide plus Dexamethasone for Relapsed or Refractory Multiple Myeloma. NEJM 2007;357: patients in these trials Lena + Dexa vs Placebo + Dexa Patients who had progressed after >= 1 therapy 48 weeks Lena arm vs 20 weeks Dexa alone ORR 65%

39 Lenalidomide Related to thalidomide Oral medication taken D1 21 in a 28 day cycle Well tolerated Less sleepiness, constipation, neuropathy Clots Much more suppression of bone marrow (low white cells and platelets) fatigue

40 Future Risk stratified treatment Development of new targeted treatments New regimes using thalidomide, velcade and lenalidomide Development of other thalidomide analogs Continue to improve quality of life

Background Information Myeloma

Background Information Myeloma Myeloma FAST FACTS Myeloma, also known as multiple myeloma, is a type of cancer that develops from plasma cells which originate in the bone marrow 1 Myeloma is the second most common type of blood cancer