MAINTENANCE AND CONTINUOUS THERAPY OF MYELOMA. Myeloma Day 11/18/2017 Aric Hall, MD Assistant Professor UW School of Medicine & Public Health

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1 MAINTENANCE AND CONTINUOUS THERAPY OF MYELOMA Myeloma Day 11/18/2017 Aric Hall, MD Assistant Professor UW School of Medicine & Public Health

2 Disclosures I have no significant conflicts of interest to disclose. I have no financial relationship with any institution profiting from pharmaceutical sales, diagnostic testing, or any type of medical technology.

3 Outline Introduction and reasoning for continuous therapy Current Approaches Future directions

4 MYELOMA - The GOOD: Progress and new agents Seven new drugs approved in the last ten years Most important and revolutionary are the so-called novel agents Proteosome Inhibitors: Bortezomib, Carfilzomib IMiDS: Thalidomide, Lenalidomide, Pomalidomide Though antibodies are probably making a run for it (particularly daratumumab) Have led to a move away from cytotoxic chemotherapy (except autologous transplant)

5 But there is still a group that does poorly Myeloma remains incurable for the majority This means that depending on age, myeloma still has a reasonable chance to shorten life New agents have helped but not fixed high risk disease Palumbo et al. JCO

6 And we only see part of the disease

7 Justifications to focus on consolidation / Maintenance Incremental benefit with additions to upfront therapy? Therapy better tolerated in a minimal disease state? Increased chemo-sensitivity in minimal disease state? Increased survival? Cure?

8 What endpoint matters? Overall survival (OS) = how long you live harder to study in diseases with longer life expectancies obviously what really matters Progression free survival (PFS) = how long til your disease grows back A LOT easier not sure if it s important VARIABILITY In some diseases PFS correlates to OS, MM this is less clear

9 Oncodoxes Don t over-treat incurable disease Don t miss a chance to prolong life / prevent complications PFS isn t important Patients like being off therapy PFS is important /is a marker of OS Patients like being in remission Most People do well Maintenance therapy is expensive You re making more resistant disease Some people get septic Cost shouldn t matter We might cure people

10 Constant Tension What do I think? What do I know? What can I prove? Benefit Cost = Strength of my recommendation

11 History of maintenance 1980 s Oral chemotherapy (melphalan) : Not easy to take, hard on counts, lots of secondary cancers, sometimes PFS improvement, no OS None of these established as standard, 1990 s Interferon injections: Flu in a syringe, chills, mood changes, muscle aches, low counts, marginal benefit on PFS and OS all hard to take and benefit questionable 2000 s (early) Thalidomide: Very difficult due to constipation and neuropathy, usually improved PFS, very mixed data on benefiting OS (suggestion worse survival after progressed)

12 Maintenance Post Transplant Like all of MM, bortezomib & lenalidomide change everything! GIMEMA and NMSG : Bortezomib Lenalidomide can safe, be given improves easily post-transplant PFS significantly and prolongs response GIMEMA & IFM CALGB HOVON / GMMG: Lenalidomide safe, improves Bortezomib PFS significantly pre and post transplant markedly helps poor risk myeloma live longer IMPROVES SURVIVAL

13 And without transplant S AVERAGE OVERALL SURVIVAL 44 MOS 6 mos of lenalidomide & dexamethasone ± bortezomib Followed by lenalidomide maintenance Median PFS = 43 months Greipp et al. JCO Durie. Lancet

14 While relapsed disease is moving toward continuous use of an agent Relapsed studies within the last four years using continuous therapy (three agents indefinitely) Tourmaline: Ixazomib / Len / Dex ELOQUENT : Elotuzumab / Len / Dex CASTOR: Daratumumab / Bortezomib / Dex POLLUX: Daratumab / Len / Dex All have median PFS > 18 mos

15 Perhaps continuous therapy is what is needed But Metanalysis of three trials showing advantage to continuous therapy over fixed duration therapy both in PFS and OS Only 1/5 of patients got autosct, none got a regimen with lenalidomide and bortezomib Benefit of continuous due to suboptimal therapy? Palumbo. JCO

16 Costs of maintenance Mccarthy. NEJM Palumbo. Lancet Onc. 2014

17 Financial Costs $563 / pill Daily lenalidomide after autologous stem cell transplant : $205,500/yr Majhail et al Holbro et al $1428/ dose Bortezomib for one year: $54,000/yr Autologous Stem Cell Transplant: $90,000

18 What do I know? Modern maintenance therapy using bortezomib and/or lenalidomide is near universally associated with a significant benefit in progression free survival You are very likely to have a longer first remission with maintenance than without it Modern maintenance seems to be associated with advantages in overall survival over populations but magnitude of benefit probably less dramatic or more messy In general maintenance is associated with better overall survival in multiple myeloma vs no maintenance

19 What (else) do I know There will be patients harmed by maintenance Maintenance costs a lot There are groups of patients who did and will continue to do very well without maintenance I wish I knew which patients went into each group

20 What do I do MAINTENANCE YES High risk disease logical argument, if PFS is likely to be short no matter what buying more time helps development stay in front of disease Patients who want to defer transplant based on studies showing benefit of continuous therapy focused on nontransplant studies and data for great outcomes deferring tx used maintenance

21 What do I do MAINTENANCE NO Standard risk patients who I cannot find a maintenance approach with mild toxicity. Patients with unexpected / severe / not completely explained toxicity from first line therapy who I cannot justify exposing to risk with no apparent disease

22 What do I do MAINTENANCE MAYBE Most standard risk patients with responsive disease postautologous transplant after discussion about risks/ benefits. Most of the time after second and third line therapy if can be managed without undue toxicity

23 How to do better / the future

24 Low hanging fruit E1A11 (STAMINA) trial randomizes patients to 2 years of lenalidomide maintenance versus until progression, ongoing Multiple European Studies looking at consolidation approaches of time limited post-transplant therapy CTN1302 is a trial of donor transplant for high risk myeloma that will look at ixazomib as a maintenance after donor transplants (minimal data in this realm so far)

25 Minimal Residual Disease (MRD) Series of tests looking for much smaller levels of disease than seen on standard bone marrow exam Appealing because they directly at cancer burden rather than surrogate (paraprotein)

26 MRD (Minimal Residual Disease) Being studied on a series of clinical trials Incredibly powerful as a prognostic biomarker (appears markedly better than standard VGPR, CR, scr criteria) Spanish metanalysis showed able to identify a population with a median progression free survival of > 12 years! Pre bortezomib and lenalidomide Lahuerta. JCO

27 MRD to guide therapy Currently, we know being clear of MRD is a good sign.. This is common sense if your myeloma is sensitive to what we treated it with you are likely to live longer We do not have studies yet to show escalation or de-escalation of therapy based on MRD is a good / safe approach

28 One example of MRD guided trial - Lenalidomide 1 more year stop Melphalan autologous SCT Len maintenance (2 yrs) Assess MRD + Lenalidomide + ixazomib

29 Immunotherapy - the immune system as a self perpetuating maintenance Vaccinations, donor transplants, and CAR-T cells as one time immune stimulation activities CTN1401, CTN 1302, and various CAR-T trials Limited duration checkpoint inhibitor therapy Pembrolizumab after autologous SCT Pembrolizumab and Elotuzumab after second autologous SCT

30 Ultimately Maintenance is going to create a tricky dynamic with the goal of myeloma cure To prove we ve cured someone we need to stop medications; can never happen if we re worried to stop medications Hopefully MRD and other techniques will allow us to show for each patient how much therapy they need and for how long

31 Questions?

32 THANK YOU

33 References Palumbo, A. et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J. Clin. Oncol. JCO (2015). doi: /jco Sonneveld, P. et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J. Clin. Oncol. 30, (2012). Neben, K. et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. 119, (2012). Palumbo, A. et al. Autologous Transplantation and Maintenance Therapy in Multiple Myeloma. N. Engl. J. Med. 371, (2014). McCarthy, P. L. et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N. Engl. J. Med. 366, (2012). Attal, M. et al. Lenalidomide maintenance after stem-cell transplantation for multiple m. N. Engl. J. Med. 366, (2012). Durie, B. G. M. et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet 6736, 1 9 (2016). Moreau, P. et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 374, (2016). Lonial, S. et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med (2015). doi: /nejmoa Dimopoulos, M. A. et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 375, (2016). Palumbo, A. et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 375, (2016). Palumbo, A. et al. Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data. Lancet. Oncol. 15, (2014). Majhail, N. S., Mau, L. W., Denzen, E. M. & Arneson, T. J. Costs of autologous and allogeneic hematopoietic cell transplantation in the United States: a study using a large national private claims database. Bone Marrow Transplant. 48, (2013). Holbro, A. et al. Safety and cost-effectiveness of outpatient autologous stem cell transplantation in patients with multiple myeloma. Biol. Blood Marrow Transplant. 19, (2013). Lahuerta, J.-J. et al. Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials. J. Clin. Oncol. JCO (2017). doi: /jco