Controversies in Multiple Myeloma Outline • Myeloma: Introduction • Relapsed refractory case • Definition of relapsed/refractory • When to treat • Why treatment • The Who, When, and Why of Treatment • https://www.ashclinicalnews.org/features/controversies-myeloma- treatment/ Multiple Myeloma • Median age at diagnosis: 69 yrs • 5-yr survival has improved substantially (43% in 2002- 2008 vs 28% in 1987-1989) due to novel agents • Sensitive to treatment, but not curable • Progression inevitable Multiple Myeloma • Median age at diagnosis: 69 yrs • 5-yr survival has improved substantially (43% in 2002- 2008 vs 28% in 1987-1989) due to novel agents • Sensitive to treatment, but not curable • Progression inevitable • Goal of treatment: induce a long-term, disease-free survival with normal quality of life • For a long-term, disease-free survival depth of response is important Natural History of Multiple Myeloma Asymptomatic Symptomatic 100 ACTIVE 2. RELAPSE MYELOMA REFRACTORY 50 1. RELAPSE RELAPSE MGUS or M Protein (g/L) M Protein smoldering myeloma Plateau 20 remission First-line Rx Second-line Rx Third-line Rx Newly Dx15,000/year in US 45,000/year in US IMWG Criteria for Diagnosis of Multiple Myeloma MGUS Smoldering Myeloma Multiple Myeloma § M protein < 3 g/dL § M protein ≥ 3 g/dL § Clonal BM plasma cell > § Clonal plasma cells in BM (serum) or ≥ 500 mg/24 10% or Extramedullary < 10% hrs (urine) plasmacytoma § No myeloma defining § Clonal plasma cells in § AND 1 or more events BM ≥ 10% to 60% myeloma defining § No myeloma defining events events § ≥ 1 CRAB* or § SLiM feature *C: Calcium elevation (> 11 mg/dL or > 1 mg/dL higher than ULN) R: Renal insufficiency (creatinine clearance < 40 mL/min or serum creatinine > 2 mg/dL) A: Anemia (Hb < 10 g/dL or 2 g/dL < normal) B: Bone disease (≥ 1 lytic lesions on skeletal radiography, CT, or PET-CT) § SLiM: Sixty percent of plasma cells in BM; Serum free Liight chain ratio ≥ 100; > 1 MRI focal lesion (>5 mm each) § MDE Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548. Smoldering Multiple Myeloma 100 Smoldering MM MGUS 80 27% will convert in 15 years 78 Roughly 2% 73per year 66 60 27% more will convert in remaining 15 yrs 51 ~ 2% per yr 40 51% will convert in first 5 yrs ~ 10% per yr 20 21 Probability of Progression (%) 16 4 10 0 0 5 10 15 20 25 Yrs Since Diagnosis Kyle RA, et al. N Engl J Med. 2007;356:2582-2590. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420. For SMM Smoldering Myeloma 2014 • The Mayo Clinic model (2007-2008) uses • M-protein (≥3 g/dL), § M protein ≥ 3 g/dL (serum) or ≥ 500 mg/24 • BMPC% (≥10%), hrs (urine) • and the ratio oF involved to uninvolved serum Free light chains (FLCr) § Clonal plasma cells in (≥8) BM ≥ 10% to 60% • categorize patients into three risk categories, with a 76% risk oF § No myeloma defining events progression in 5 years among those with all three oF the above characteristics. • The Spanish model uses • the proportion oF BMPCs with aberrant PC phenotype on Flow cytometry (≥95%) and reduction in uninvolved immunoglobulins (immunoparesis) to identify high-risk patients. • Abnormalities detected on imaging oF spine or whole body using magnetic resonance imaging (MRI), and underlying cytogenetic abnormalities also guide clinicians in identifying high-risk patients. Blood Cancer Journal (2018)8:59. For SMM New risk classification will (possible) be available Smoldering Myeloma • Arjun Lakshman1, S. Vincent Rajkumar1, Francis K. Buadi1, et al. § M protein ≥ 3 g/dL (serum) or ≥ 500 mg/24 reported in Blood Cancer Journal (2018)8:59. hrs (urine) § Clonal plasma cells in BM ≥ 10% to 60% 0 § No myeloma defining 1 events >2 1 2 BMPC% > 20%, 3 M-protein > 2 g/dL, and FLC ratio > 20 at diagnosis M-protein (≥3 g/dL), BMPC% (≥10%), and the ratio of involved to uninvolved serum free light chains (FLCr) (≥8) • Arjun Lakshman1, S. Vincent Rajkumar1, Francis K. Buadi1, et al. For SMM reported in Blood Cancer Journal (2018)8:59. Smoldering Myeloma § M protein ≥ 3 g/dL (serum) or ≥ 500 mg/24 hrs (urine) § Clonal plasma cells in BM ≥ 10% to 60% § No myeloma defining events BMPC% > 20%, 0 M-protein > 2 g/dL, 1 and FLC ratio > 20 at diagnosis >2 92 (47.8%) BMPC% > 10%, 1 M-protein > 3 g/dL, 2 and FLC ratio > 8 at diagnosis 3 For SMM New risk classification will be available Smoldering Myeloma • Arjun Lakshman1, S. Vincent Rajkumar1, Francis K. Buadi1, et al. reported in Blood Cancer Journal (2018)8:59. § M protein ≥ 3 g/dL (serum) or ≥ 500 mg/24 hrs (urine) § Clonal plasma cells in BM ≥ 10% to 60% § No myeloma defining events 0 1 1 2 >2 3 BMPC% > 20%, M-protein > 2 g/dL, and FLC ratio > 20 at diagnosis can be used to risk stratify patients with SMM. Case 62 years-old female, ECOG 1-2 without other comorbidity • Diagnosed of MM since 2006 (2549) (12 years ago)(52yo) • VAD was given 6 cycles, CR after 3rd cycle • Evaluate by BM, SPEP, IFE • Bisphosphonate was given every cycle of treatMent and after reMission every 3 Mo. for 2 years, then every year Vincristine Doxorubicin DexaMethasone Symptomatic Multiple Myeloma: Frontline Therapy Initial Approach to Treatment of Myeloma Nontransplant Candidate Transplant (based on age, performance Candidate status, and comorbidities) Induction treatment Induction treatment (4-6 cycles) Maintenance Stem cell harvest Stem cell transplantation Consolidation therapy? Maintenance ASCT: Eligibility Despite novel agents, ASCT remains a standard component of MM treatment Candidates Treatments • Eligibility can depend on • NCCN Category 1 transplant center • VD, VTD, PAD (Bor/doxo/dexa) • Factors/considerations: • Lenalidomide/dexamethasone (RD) • Age • NCCN Category 2A • Cytogenetic abnormalities • CyBorD • Disease status/stage • Bor/len/dex (VRD) • Type of frontline therapy and response • Carfil/len/dex (CRd) • Organ function Phase III Trials: Novel Agent Induction for Transplant-Eligible Patients Trial Regimens n ≥ VGPR, % Median OS, % PFS, After Induction After First ASCT Mos [1] Harousseau VD 240 38 P < .001 54 P < .001 36 3 yr: 81 VAD 242 15 37 30 3 yr: 77 [2] Cavo VTD 413 62 P < .001 79 P < .001 3 yr: 68% 3 yr: 86 VAD 414 28 58 3 yr: 56% 3 yr: 84 [3] Sonneveld PAD 413 42 P < .001 76 P < .001 35 5 yr: 61 VAD 414 14 56 8 5 yr: 55 Rosiñol[4] VTD 130 60 56 4 yr: 74 TD 127 29 NR 28 4 yr: 65 VMBCP/ 129 36 36 4 yr: 70 VBAD/B Moreau[5] VTD 100 49 74 26 P = .05 P = .02 NR VD 99 36 58 30 RaJKumar[6] RD 223 42 50 3 yr: 92 P < .001 P = .04 NR Rd 222 24 40 NR 1. Harousseau JL, et al. J Clin Oncol. 2006;24:431-436. 2. Cavo M, et al. Lancet. 2010;376;2075-2085. 3. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955. 4. Rosiñol L, et al. Blood. 2012;120:1589-1596. 5. Moreau P, et al. Blood. 2011;118:5752-5758. 6. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. MM Induction in Transplant-ineligible MM Patients: Triplets vs Doublets • Some comparative efficacy data available[1] • VTD superior to TD, – MPT superior to MP including in pts with t(4;14)[2] – VMP superior to MP • VTD superior to VD • CyBorD similar to VTD – MPR superior to MP • Triplet vs doublet still subject to some debate, due in part to lack of randomized data • Appropriate use of doublet therapy? • Ineligibility issues, especially in the elderly • Transplant eligibility affects choice of regimen 1. Rajkumar SV. ASH Education Book. 2012;1:354-361. 2. Cavo M, Et al. Lancet. 2010;376:2075-2085. 62 years-old female, ECOG 1-2 without other comorbidity • Diagnosed of MM since 2006 (2549) (12 years ago)(52yo) • VAD was given 6 cycles, CR after 3rd cycle • Evaluate by BM, SPEP, IFE • Bisphosphonate was given every cycle of treatMent and after reMission every 3 Mo. for 2 years, then every year • Five years later (7 years ago), she developed More aneMia, bone pain and increase plasma cell in BM in 2011 (2554) When to treat R/R myeloma? • Symptomatic relapse • Asymptomatic relapse • CRAB symptoms • Significant paraprotein relapse • New extramedullary • Doubling of the paraprotein in 2 plasmacytoma months • High-risk disease • Aggressive disease at diagnosis • Renal failure • Extramedullary plasmacytoma • High LDH • Light chain escape/non- secretory MM Laubach, et al. IMWG recommendation for RRMM. Leukemia. 2015 Dec 29. [Epub ahead of print] Dimopoulos, et al. Cancer Treatment Reviews. 2015; 41: 827–835 Factors should be considered in R&R treatment 1.Patient factors: Age, ECOG, toxicity from previous treatment and any comorbidity 2.Disease related factors: high risk cytogenetic ??, duration of response from previous treatments, cytogenetics data 3.Treatment related factors -Previous treatments -Duration of response -Previous toxicity? Patient related factors: renal insufficiency • Agents not requiring renal dose • Agents requiring renal dose adjustment adjustment • Lenalidomide • Bortezomib • CrCl 30-60 mL/min: 10 mg PO qDay; • Carfilzomib • CrCl <30 mL/min (not requiring dialysis): 15 mg PO every other day • If elevated serum creatinin not attributed to carfilzomib • CrCl <30 mL/min (requiring dialysis): 5 mg PO q Day; on dialysis days • Thalidomide • Ixazomib • Pomalidomide • Only in ESRD: reduced dose to 3 mg • Liposomal doxorubicin • Melphalan • Monoclonal Abs • CrCl 30-50 mL/min: 50% dose • Daratumumab reduction • Elotuzumab • Avoid if CrCl < 30 mL/min • Cyclophosphamide • CrCl < 10 mL/min: 50% dose reduction When use carfilzomib in renal insufficiency, serum creatinine should be closely monitored • 35% of patients had a reduction of eGFR >25% Nookaa,a et al.