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Natural course of myeloma Treatment for relapsed and/or refractory myeloma Dr Kim Orchard Consultant Haematologist Southampton General Hospital 1st line treatment 2nd line treatment 3rd line treatment MGUS: Monoclonal gammopathy of undetermined significance Some definitions Plateau: Stable disease following good response to treatment, reduced but detectable paraprotein levels Relapse: Disease progression following a previously successful course of treatment Refractory: No response to treatment whether initial treatment or treatment at relapse Relapsed and refractory: Disease progression on a specific treatment or within 60 days of stopping treatment 100 Paraprotein Remission: Absence of paraprotein in blood and myeloma cells in bone marrow following treatment Relapse 50 Treatment Relapse: Increase in pp by 25% from baseline RELAPSE Repeat tests to confirm 20 REMISSION When to start treatment? Treatment decisions at relapse Factors to consider: Haematologist • Patient related factors - prior or on-going toxicity - other medical problems, general ‘fitness’ - number of previous relapses - patient preference • Disease specific factors - duration of previous response Treatment required if symptoms return ‘CRAB’ rules Calcium, Renal impairment, Anaemia, Bone lesions Relapse options - risk factors e.g. cytogenetics/FISH, • Regimen related factors - likely toxicities and previous toxicities - benefit vs risk balance Refractory options • No standard approach to treatment at relapse • Try different treatment • Same again? • Sequence of treatments similar to relapse • Try different treatment?– may be governed by NICE approval • Consider taking part in a clinical study - can take part at any point - provides another ‘line of treatment’ - must meet study criteria • Supportive treatment as necessary • Clinical study – good option as newer drugs can still be effective First relapse Treatment at first relapse • Progression of myeloma in the absence of treatment following successful initial treatment Paraprotein (g/L) 100 100 1st line 2nd line 50 20 50 20 1st RELAPSE 1st 1st REMISSION REMISSION Velcade • Originally IV injection, moving more towards subcutaneous injections • Once or twice weekly • Generally combined with dexamethasone • 21-day cycle (3rd week rest week) • 4 – 8 cycles Velcade • Also known as bortezomib • Is the first proteasome inhibitor to be used in myeloma • Current NICE-approved 2nd line treatment • Single agent (monotherapy) - 40% response rate • Velcade + dexamethasone - 55% response rate • Cyclophosphamide, Velcade + dex – 65% response rate • Velcade, thalidomide + dex – up to 90% response rate • Better responses if used early in disease course and in combination with other drugs Other options at first relapse • Same treatment again if first remission lengthy • Second transplant if first transplant remission >14 months • Enter a clinical study • Potential side-effects: - Weakness, fatigue - Peripheral neuropathy - Low blood counts especially platelets - Nausea, diarrhoea or constipation - Postural hypotension Second Relapse Treatment at second relapse Duration of remission usually shorter Paraprotein (g/L) 100 • Oral, 3 weeks on one week off3rd line Dexamethasone 1st•line 2nd linepulses • Continue until myeloma progresses 50 1st Relapse 20 Revlimid • Also known as lenalidomide • Immunomodulatory drug (IMiD), similar to thalidomide but more potent and less toxic • Current NICE approval at 3rd line and beyond, in combination with dexamethasone 2nd Relapse • Revlimid monotherapy – 29% response rate • Revlimid + dex – 65% response rate • Revlimid, cyclophosphamide + dex – 75% response rate Myeloma changes in character – drug resistance develops Revlimid Second transplant • Oral capsule taken daily on days 1 - 21 of 28-day cycle • Recommended starting dose of 25mg (lower for patients with kidney damage) • Dose continued or modified, until disease progression • Emerging data to show that second transplant may be of benefit - Myeloma X showed increased TTP compared to chemotherapy only Potential side-effects: • Less constipation and neuropathy than thalidomide • Neutropenia and thrombocytopenia • Increased risk of blood clots • Fatigue • Muscle cramp Timing of second transplant: • If second transplant is delayed for relapse, long term outcome is no different from two at beginning - Patients with poor response to first may benefit from early second transplant Allogeneic (donor) transplant in Myeloma Factors to consider: Next lines of treatment • Consider previous treatments that have given lengthy remission Age – younger patients possible ablative conditioning co-morbid problems disease risk group • Consider mini-allogeneic (donor) transplant for • Other strategies such as DT-PACE or ESHAP • Non-approved drugs via access schemes • Enter clinical study some patients if appropriate Clinical trial when possible Bendamustine • Also known as Levact or Treanda • Chemotherapy drug developed in former E. Germany 1970’s • Licensed for use in newly diagnosed patients unable to have thalidomide or Velcade • Access at relapse via Individual Funding Request or Cancer Bendamustine •Intravenous infusion on days 1 + 2 or days 1 + 8 of a 28-day cycle • Effective as a monotherapy but better in combination with other drugs e.g. thalidomide and/or dexamethasone • Potential side-effects: - nausea, vomiting - neutropenia, thrombocytopenia Drugs Fund • Good response rates Clinical Studies Novel drugs Summary • No standard best approach to treatment at relapse • IMiDs - Pomalidomide • Proteosome inhibitors - Kyprolis (carfilzomib) - MLN 9708 (Ixazomib) • Monoclonal antibodies - Elotuzumab - Daratumumab • Histone deacetylase Inhibitor - Panobinostat - adapting to meet patients’ needs important - identifying the best sequence of treatments is challenging • Relapse options - Consider same treatment if lengthy first remission - Thalidomide-based treatment if not had it before - Velcade-based treatment if previously treated with thalidomide - Revlimid-based treatment at subsequent relapse - Clinical studies - Second transplant, allogeneic transplant Future Managing Myeloma as a chronic condition • Treatment episodes • Possible intensive therapy • Monitoring • Managing side-effects, complications • Costs • • Monsiderable research New agents (30+ in development) For information: www.myeloma.org.uk 0800 980 3332