Future strategies for myeloma: An overview of novel treatments In development

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1 Future strategies for myeloma: An overview of novel treatments In development Dr. Matthew Streetly Guys and St. Thomas NHS Trust How far have we come? Melphalan and prednisolone VAD Autologous SCT Thalidomide Velcade Revlimid????? ? Three new treatments available in the last 12 years, but still an urgent need for improved treatments and more options 1

2 Improved survival with new drugs Average survival after relapse from transplant has doubled since introduction of new drugs (thalidomide, Velcade and Revlimid) Taken from: Kumar SK, Blood (2008) 111: Cancer survival rate Office of National Statistics: Five year survival rates in myeloma in the UK show largest increases compared to other cancers. Published 10 April

3 What improvements are needed? Improve patient outcome Control symptoms and complications Increase response rates and depths of response Increase lengths of remission and survival Decrease side-effects Improve quality of life Current issues Which drugs are best used as first-line treatment? Which drugs are best used for relapse? Which combination of drugs work best together? Which combinations of drugs are least likely to cause serious side-effects Which treatment for which patient? more genetic testing, moving towards personalised treatment 3

4 Individualised treatment plans Prognostic Factors Age / fitness Disease stage Prior response to treatment β2 microglobulin levels Myeloma cell genetics Cytogenetic / FISH Gene profiling Finding new drugs Drug evolution Old targets New targets Future targets DNA Hormones Cellular scaffold Nuclear scaffold Immune system Genetic markers Cell signalling Gene expression profile Cell growth Cell death Proteasome Blood vessel formation 4

5 Getting a drug to the clinic Drug Screening Non-specific Laboratory studies Often involves screening thousands of compounds against thousands of tumour types Getting a drug to the clinic Drug Screening Myeloma Lab Studies Pre-clinical studies for myeloma Establishes that compound can target myeloma cells and how it does it Allows for prediction of suitable combinations 5

6 Getting a drug to the clinic Drug Screening Myeloma Lab Studies 1 1 study Establishes drug tolerability Are there any side effects? Often dose escalation study Usually single agent Responses are observed but not the end-point Getting a drug to the clinic Drug Screening Myeloma Lab Studies study Establishes drug activity Usually at a single dose Can be in combination Not usually in comparison to other treatments Provides rationale for further studies 6

7 Getting a drug to the clinic Drug Screening Myeloma Lab Studies study Compares new therapy against gold standard E.g. CRD v CTD (new patients) Demonstrates if drug is better or equal to current therapy Required for licensing / EMEA / FDA Required for NICE Getting a drug to the clinic Drug Screening Myeloma Lab Studies study Post authorisation safety study Ensure the drug is not more toxic than reported 7

8 Are there many clinical studies for myeloma? All clinical studies (worldwide) are registered at ClinicalTrials.gov Currently 529 studies registered as ongoing 23 open in UK Over 30 different new drugs Sample collection / data bank Transplant studies Vaccination studies Clinical trials Single agent Combination 1, 2 or 3 Newly diagnosed or relapsed Latest developments New immunomodulatory agent Next generation proteasome inhibitor Monoclonal antibodies Histone deacetylase (HDAC) inhibitors Existing chemotherapy drugs used in new ways 8

9 Pomalidomide Immunomodulatory drug (IMiD) Closely related to thalidomide and Revlimid More potent in the lab than both Targets myeloma cells in a number of different ways Given as a tablet Daily or similar to Revlimid (day 1 21 on a 28 day cycle) In studies given alone or with dexamethasone Generally tolerated well Pomalidomide A number of clinical trials already Responses in 30 60% of patients Responses last from 6 months+ Depends on how many previous therapies BUT works for many patients who have previously had Revlimid and/ or Velcade Main side effects Low white cells (32%) Fatigue (17%) Lacy MQ, et al. J Clin Oncol. 2009;27:

10 Pomalidomide in the UK III NIMBUS study For relapsed or refractory patients, who have had at least 2 previous lines of treatment Pomalidomide + low-dose dex Pomalidomide; Days 1-21 Low-dose dex; Days 1,8,15,22 28-day cycle Until progression vs High-dose dex High-dose dex Days 1-4 Days 9-12 Days day cycle Until progression Other studies are planned Carfilzomib Next-generation proteasome inhibitor More selective than velcade Less severe side effects Especially peripheral neuropathy Given as intravenous infusion for 2 days every month Responses in 25 55% of patients Active after velcade Main side effects Low platelets (<15%) Infusional reactions 10

11 Carfilzomib in the UK III ASPIRE trial For relapsed patients who have had no more than 3 prior treatments Carfilzomib Revlimid Low-dose dex CFZ; 4-6 doses/cycle Revlimid; Days 1-21 Low-dose dex Days 1, 8, 15, day cycle Until progression vs Revlimid Low-dose dex Revlimid Days 1-21 Low-dose dex Days 1, 8, 15, day cycle Until progression Carfilzomib in the UK III FOCUS trial For relapsed and/or refractory patients who have had 3 or more prior treatments Carfilzomib 4-6 doses/cycle 28-day cycle vs Best supportive care Dex or pred; every other day Optional; cyclophosphamide Daily 11

12 Other proteasome inhibitors MLN9708 Orally active proteasome inhibitor, more advanced in development than NPI-0052 Being tested as a monotherapy in relapsed/refractory patients Being tested in combination with melphalan and prednisolone in newly diagnosed patients NPI-0052 (Marizomib) Structurally different to but more potent than Velcade Orally active Early dose-finding and safety studies being carried out Monoclonal antibodies Drugs designed to specifically target markers on myeloma cells or molecules required for myeloma cell growth Myeloma cell CD38, CD66 or CS1 DKK1 Blocking antibodies to: CD38, CD66 CS1 (Elotuzumab) IL-6 DKK1 IL6 12

13 Elotuzumab Binds to CS1 surface protein on myeloma cells and directs the immune system to destroy the myeloma cells Given intravenously 1 2 doses every 2 weeks Doesn t appear to work very well on its own But when given with Velcade or Revlimid appears to work much better Response rates 40 80% Responses even after previous Velcade or Revlimid Responses appear durable Tolerated well Infusion nausea / headache (~20%) Chills (14%) Elotuzumab in the UK III ELOQUENT 1 or 2 trial For New or relapsed patients Elotuzumab Revlimid Low-dose dex Elo; 4-6 doses/cycle Revlimid; Days 1-21 Low-dose dex Days 1, 8, 15, day cycle Until progression vs Revlimid Low-dose dex Revlimid Days 1-21 Low-dose dex Days 1, 8, 15, day cycle Until progression 13

14 HDAC inhibitors Two drugs being investigated Vorinostat and panabinostat Given orally Different schedules Being studied in combinations with: Bortezomib, lenalidomide, dexamethasone In maintenance and relapsed settings Side effects Nausea, diarrhoea Other strategies Existing chemotherapy drugs e.g. bendamustine MUK one bendamustine/thalidomide/dex Different routes of administration e.g. intravenous vs subcutaneous injection Change in dosing / schedule e.g. once a week vs twice a week 14

15 Expectations Many new developments in the pipeline patients are more informed and finding out about them sooner Not all treatments under development get through. They can fall at any clinical study hurdle Be realistic about treatment outcome there is still no magic bullet Treatments are not routinely approved and provided to appropriate patients Living with myeloma Research is starting to focus more on quality of life and supportive care Specific studies looking at the role of supportive care and benefits of exercise Better management of complications, including pain control management of peripheral neuropathy Individualised care-management plans, with a multidisciplinary approach 15

16 A bright future? Lots of new drugs Velcade Revlimid Responses improving HDACi Carfilz Poma Antibodies Toxicity better managed Personalising medicine Making myeloma a chronic disease and moving towards a cure Current MUK Clinical Trials MUK No. Test Drug Company Details Status MUK one Bendamustine Napp MUK three CHR3996 & Tosedostat Chroma MUK four Vorinostat MSD Bendamustine (60 vs 100 mg/m 2 ) + thalidomide + dexamethasone in patients with relapsed/refractory multiple myeloma. CHR Tosedostat in patients with Relapsed, Refractory Multiple Myeloma. Vorinostat + bortezomib + dexamethasone (VVD) in patients with relapsed or relapsed refractory multiple myeloma. Closed to recruitment, analysis Open to patient recruitment Submitted MUK five Carfilzomib Onyx MUK six Panobinostat Novartis tbc Pomalidomide Celgene tbc Sotatercept Celgene Carfilzomib, cyclophosphamide and dexamethasone (CCD) vs cyclophosphamide, Velcade and dexamethasone (CVD) for first relapse in myeloma patients. VTD-panobinostat in relapsed and relapsed/refractory multiple myeloma patients. Site initiation Site initiation Under discussion Under discussion 16

17 For information Infoline: