Relapsed / Refractory Multiple Myeloma

1. Relapsed / Refractory Multiple Myeloma Dr. E.Elhassadi Consultant Haematologist University Hospital Waterford MMI, Nov 2016

3. Myeloma (C90): 1971-2011 Age-Standardised One-Year Net Survival, England and Wales Please include the citation provided in our Frequently Asked Questions when reproducing this chart: http://info.cancerresearchuk.org/cancerstats/faqs/#How Prepared by Cancer Research UK Original data sources: Survival estimates were provided on request by the Cancer Research UK Cancer Survival Group at the London School of Hygiene and Tropical Medicine. http://www.lshtm.ac.uk/eph/ncde/cancersurvival/

4. Introduction • Almost all patients with multiple myeloma (MM) who had initial treatment will eventually relapse and require further therapy. However many patients achieved a durable disease free period. • Relapsed or refractory MM is usually identified on routine surveillance performed during treatment or after the completion of therapy

5. Definitions • Progressive Disease (PD) is defined as a 25 % increase from the lowest response value in any of the Myeloma Biomarkers . • Refractory myeloma is defined as disease that is non-responsive while on therapy, or progresses within 60 days of last therapy. There are two categories of refractory myeloma • Relapsed-and-refractory myeloma • Primary refractory myeloma

6. Laboratory Investigations • FBC and U/E • Serum M-protein • Difference in the kappa and lambda FLC levels (FLC ratio must be abnormal and absolute change must be >10 mg/dL) • Urine M-protein (absolute increase of ≥200 mg/24 hours) • Bone marrow plasma cell percentage in patients who lack measurable M protein levels • The development of an otherwise unexplained serum calcium >11.5 mg/dL is also a marker of PD

7. Relapsed MM: Hallmarks of myeloma: CRAB (also known as myeloma defining events). C = Calcium SPEP & UPEP R = RenalInsufficiency Recurrent infections* *Not an MDE, yet relatively common • New bone or soft tissue lesions (eg, plasmacytomas) B = Bone Disease A = Anemia Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

8. Overview • Selecting Therapy Based on Specific Patient and Disease Features • Current Recommendations and Treatment Options for Relapsed/Refractory Myeloma • Future Directions in the Salvage Setting

9. When to Consider Retreatment • Need to consider biochemical vs symptomatic relapse • Patients with asymptomatic rise in M-protein can be observed to determine the rate of rise and nature of relapse • Caveat: Patients with known aggressive or high-risk disease should be considered for salvage, even in the setting of biochemical relapse

10. Treatment options for patients with relapsed or refractory MM include hematopoietic cell transplantation (HCT), a re-challenge of the previous chemotherapy regimen, or a trial of a new regimen. • Factors used to determine the choice of therapy include a risk stratification of myeloma (ie, high or standard risk disease), prior treatments used, and the duration of response to these treatments.

11. Risk Stratification • Patients who relapse less than 12 months from first-line therapy or relapse on therapy (ie, refractory disease) are considered to have high risk disease even if evaluation by FISH and cytogenetics previously classified their disease as standard risk. • On the other hand, patients previously diagnosed with high risk disease by cytogenetics and/or FISH who relapse more than two years from initial therapy can be considered as having standard risk disease at the time of relapse in the absence of new additional high risk cytogenetic abnormalities

12. When and Why Should a Clinical Trial Be Considered? • Before organ damage occurs (preferred) • Clinical trials (preferred) • Emphasize pros—benefits—of clinical trials • Access to new drugs • Collect information in logical manner • Can benefit pt, others • Cons and risks also exist and should be discussed with pts, caregivers • Stringent monitoring, placebo, etc Ghobrial IM, et al. Blood. 2014;124:3380-3388.

13. Factors in Selecting Treatment for Relapsed/Refractory Myeloma • Disease-related factors • Duration of response to initial therapy • High-risk vs low-risk status • Biochemical disease progression, or symptomatic? • Other co-morbid conditions • Treatment-related factors • Previous therapy exposure (relapsed or refractory) • Toxicity of regimen (combination vs single agent) • Mode of administration (eg, oral or IV) • Patient-related factors

14. Relapsed/Refractory Myeloma: Preferred Regimens • NCCN Category 1 • Bortezomib • SC vs IV administration • Bortezomib/PLD • Carfilzomib /Lenalidomide/ Dexamethasone • Panobinostat / Bortezomib/ Dexamethasone • Lenalidomide/ Dexamethasone • NCCN Category 2A • Repeat primary induction therapy if relapse at > 6 mos • Bortezomib combinations • With Dex; len / Dex; Thalidomide • Carfilzomib • Cyclophosphamide • High-dose or with Bort /Dex or Len/Dex • Pomalidomide /Dexamethasone • Thalidomide/ Dexamethasone • DCEP, DT-PACE, or VTD-PACE

15. Initial treatment with Bortezomib Underlying PN Treating Indolent, Slow-Growing Myeloma in First Relapse Transplant-Based Salvage PI-Based Salvage IMiD-Based Salvage • Initial treatment with IMiD • Previous bortezomib therapy but good or long response • Renal dysfunction • Transplant not part of initial therapy • Long remission post transplant

16. Treating Relapsed/Refractory Myeloma Pomalidomide-Based Salvage Carfilzomib-Based Salvage Other Salvage • Intolerance or resistance to bortezomib • Dexamethasone-sparing treatment as part of a combination • Intolerance to IMiDs • Lenalidomide refractory • Refractory to standard-dose PI • Pts with del(17p)? • Refractory to pomalidomide and carfilzomib • Monoclonal antibody candidate • Clinical trials

17. DCEP vs DT-PACE Oral vs IV chemo Performance status of pt plays important role Treating Aggressive Myeloma With Rapid, Multiple Relapses Likely Combination Therapy Do Not Wait for Symptomatic Relapse Chemotherapy + Novel Agent Transplant-Based Salvage Chemotherapy-Based Salvage • Combinations of lenalidomide/ bortezomib and other chemotherapy agents • Likely to be short lived • Rapid disease control • Reconstitute marrow

18. Summary of Combination Therapy in RR MM Median Lines of Tx: ORR PFS/TTP OS Median Lines of Tx: 2 3 4 5 2 3 4 5 100 NR 80 35 30 29 87 85 26 30 60 71 70 67 65 65 25 20 64 60 NR 55 40 NR NR 20 NR 13 ORR (%) Survival (Mos) 11 11 15 10 10 20 10 31 9 10 4 4 0 5 0 Vd*[5] Pd*[9] Pd*[9] Kd[10] Kd[10] RD*[1] RD*[1] PVd[4] PVd[4] CPd[8] CPd[8] CRD[7] KPd[11] KPd[11] KRd*[2] KRd*[2] RVD*[3] RVD*[3] CyBorD[6] CyBorD[6] *Data from phase III trials, all others from phase I or II trials 1. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. 2. Stewart AK, et al. N Engl J Med. 2015;372:142-152. 3. Richardson PG, et al. Blood. 2014;123:1461-1469. 4. Lacy MQ, et al. ASH 2014. Abstract 304.5. Mikhael JR, et al. Br J Haematol. 2009;144:169-175. 6. Monge J, et al. ASCO 2014. Abstract 8586. 7. Morgan JG, et al. Br J Haematol. 2007;137:268-269. 8. Baz R, et al. ASH 2014. Abstract 303. 9. San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066. 10. Lendvai N, et al. Blood. 2014;124:899-906. 11. Shah JJ, et al. ASH 2013. Abstract 690.

19. Salvage Auto Transplant in the Relapsed Setting: Reasonable Option? • Recent data from Mayo Clinic Transplant Center suggests that auto SCT2 appears safe and effective treatment for relapsed MM (N = 98) • ORR: 86%; median PFS: 10.3 mos; median OS: 33 mos • Rate of TRM: 4%, suggesting a favorable benefit-to-risk ratio • Shorter TTP after auto SCT1 predicts shorter OS post auto SCT2 Gonsalves WI, et al. Bone Marrow Transplant. 2013;48:568-573.

20. Maintenance Therapy • Factors influence maintenance therapy decision : • previous maintenance therapy • Treatment continuation until disease progression • Side effects and toxicities profile • Patients preference • Availability of alternative maintenance therapy • Disease risk

21. “Best” Treatment for the Pt? • With so many available therapies, how does one choose the “best”? • Guidelines exist to “guide” decision making • Consider: • Prevention of further organ damage (if present) • Age, morbidities, desire, financial, social status • Biomarkers/cytogenetic risk group (high or low) • 2 drugs, 3 drugs, or more? • Pt preferences and goals • Clinical trial availability • Quality of life Palumbo A, et al. J Clin Oncol. 2014;32:587-600. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-3548.

23. New Agents and Regimens Approved for RRMM in 2015 *Carfilzomib monotherapy 20/56 mg/m2 IV previously approved for pts with RRMM.

24. CASTOR: PFS in Total Study Population 1.0 1-yr PFS 0.8 60.7% 0.6 PFS (%) 0.4 DVd Vd Median PFS, Mos NR 7.2 26.9% 0.2 HR: 0.39 (95% CI: 0.28-0.53; P < .0001) 0 0 3 6 9 12 15 Mos Palumbo A, et al. ASCO 2016. Abstract LBA4. Reproduced with permission.

25. CYBORD RVD ZDEX LD CATD TIDE CPD VD ASCT Ben VD

26. DARA

27. Overall Conclusions • Triplet combination approaches should be considered when appropriate • Combination treatment with either Bortezomib, Carfilzomib, and/or Pomalidomide with Dexamethasone active and well tolerated • Novel agents in combination can achieve prolonged responses even in relapsed disease • Optimal management approaches should emphasize improving QOL by identifying potential complications of therapy and minimizing long-term toxicity • New classes of agents and second-generation agents have activity and are of considerable interest