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. Blood. 2015;125(20):3085-3099; Dimopoulous et al. Blood Adv 2017; 1: 449 Treatment related factors: Peripheral neuropathy

• Agents may aggravate PN • Agents without major • PIs neurotoxicity • Bortezomib • Lenalidomide • Carfilzomib: less likely • Pomalidomide • Ixazomib: less likely • Monoclonal Abs • Thalidomide • Daratumumab • Vincristine • Elotuzumab

Nookaa,a et al. Blood. 2015;125(20):3085-3099 Treatment related factors: Thrombosis

• Agents may aggravate VTE • Agents without major VTE • IMIDs risk • Thalidomide • Pis • Lenalidomide • Bortezomib • Pomalidomide • Carfilzomib • High-dose • Ixazomib dexamethasone • Monoclonal Abs • Daratumumab • Elotuzumab

Nookaa,a et al. Blood. 2015;125(20):3085-3099 Treatment related factors: Cardiac disease

• Agents may aggravate cardiac • Agents without major cardiac risk events • Bortezomib • Carfilzomib • Ixazomib • Thalidomide: may be • Lenalidomide • Anthracycline • Pomalidomide • Doxorubicin • Monoclonal Abs • Liposomal doxorubicin • Daratumumab • Elotuzumab

Nookaa,a et al. Blood. 2015;125(20):3085-3099 Patient related factors: Convenience

• Oral agents • Agents requiring frequent • IMIDs hospital visit • Alkylating agents • Proteasome inhibitors • Cyclophosphamide • Bortezomib • Melphalan • Carfilzomib • Dexamethasone • Monoclonal Ab • Daratumumab • Elotuzumab Disease related factors: high risk disease characteristics

• Adverse cytogenetic abnormalities • Aggressive clinical features including • del(17p) • Rapid onset of clinical symptoms • amp(1q21) • Extensive disease at relapse based on • t(4;14) laboratory, pathology, or radiographic findings • Disease-associated organ dysfunction • Extramedullary plasmacytoma • Isotype transformation • Short remission duration after first • Light chain escape treatment • Development of hypo/non-secretory • ISS stage at relapse disease • High LDH levels at relapse

Laubach, et al. IMWG recommendation for RRMM. Leukemia. 2015 Dec 29. [Epub ahead of print] Disease related factors: High risk cytogenetics

Agent showing activity on high risk Agent showing limited activity on high cytogenetics risk cytogenetics

• Bortezomib • Thalidomide • Partly overcomes the adverse effect of t(4;14) and possibly • Lenalidome del(17p) on CR, PFS, and OS • Pomalidomide • Improved PFS and OS in t(4;14) and del(17p) • Combined PIs & IMIDs • VRD • KRD • KPD • Double ASCT plus Bortezomib

Sonneveld , et al. IMWG consensus. Blood. 2016;127(24):2955-2962 Treatment related factors: prior therapies

• PIs or iMIDs naïve • Previous exposure to both PI • Consider treatment with or iMIDs agent patients have never • Carfilzomib received • Pomalidomide • Previous exposure to either • Daratumumab PIs or iMIDs • Avoid regimens that has • Retreat with prior therapy overlapping toxicities • if previously responded and relapsed > 6 months after • Neuropathy prior drug exposure • Myelosuppression • Switching class of novel agents

Laubach, et al. IMWG recommendation for RRMM. Leukemia. 2016 May;30(5):1005-1 Nookaa,a et al. Blood. 2015;125(20):3085-3099 Novel agents approved by Thai FDA for RRMM in patients previously treated with both PI and IMIDs

Carfilzomib Daratumomab Pomalidomide-Dex monotherapy monotherapy

Patients who have Patients who have For patients who have received at least two received at least two received at least three prior therapies including prior therapies including prior lines of therapy lenalidomide and bortezomib and IMIDs including a PI and IMIDs bortezomib and have and have demonstrated demonstrated disease disease progression on progression on the last therapy or within 60 days of completion of the last therapy Novel agents approved by Thai FDA for R/R MM in patients previously treated with both PI and IMIDs

Characteristics Pomalidomide-dex1 Carfilzomib monotherapy2 Daratumumab vs. HiDex (n=351) Vs. low Dex (n=315) monotherapy3 (n=148) Study Phase III Phase III Pooled Phase II

Median prior line of Rx 5 5 5 Including Bor & Len and Including Bor & Len & Thal Including a PI and an IMiD) Refractory to last treatment and Refractory to last or who were double treatment refractory

Both Len & Bor Refractory 73% 62% 86.5%

ORR 31% vs 10% 19% vs 11% 31.1% (p < 0.0001)

PFS 4.0 vs 1.9 months 3.7 vs 3.3 months 4.0 months (p < 0.0001) OS 12.7 vs 8.1 months 10.2 vs 10.0 months 20 months (p = 0.0285) Gr 3-5 AEs Thromboembolic event: Anemia • Anemia: 17.6% • 6% vs 0% • 26% vs 31% • Thrombocytopenia 14.2% Neutropenia: Thrombocytopenia: • Neutropenia 10.1% • 48% vs 16% • 24% vs 22% Infection: ARF: • 34% vs 33% • 8% vs 3% 1.San Miguel JF, et al. Lancet Oncol 2013; 14: 1055–66 Renal failure: 2.Hajek, et al. Leukemia (2017) 31, 107–114; • 5% vs 1%

3. Usmani, et al. Blood. 2016;128(1):37-44 HTN & CHF • 5% vs 1% How to choose treatment when relapse after bortezomib and IMIDs

Carfilzomib Daratumomab Pomalidomide-Dex monotherapy monotherapy

• Underlying peripheral • Underlying peripheral • Renal impairment neuropathy neuropathy • Cytopenia • Avoid in patients with • Renal impairment heart disease, poor controlled HTN • High risk cytogenetics • Avoid in patients with renal impairment • Difficulty in the access to medical service • Cost 300,000/month • Cost 400,000/months • Cost 360,000/month • 3.6 M/month • 2.2 M/year • 1.08 M/year • May have PAP • May have PAP Factors should be considered in R&R treatment

1.patient factors: Age, ECOG 1, toxicity from previous treatment and any comorbidity 2.disease related factors: high risk cytogenetic ??, duration of response from previous treatments No cytogenetics data 3.treatment related factors -previous treatments -Duration of response -Previous toxicity?

• This case • 57 yrs, ECOG 1, prolong DFS (5yrs), relapsed with ISS 3 • No comorbid disease, no serious previous toxicity, never expose to PI 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 bone pain and increase plasma cell in BM in Dec 2011 (2554) Rx: VelCyD 8 cycles end in 8Feb2013; Dec2013 K:L = 12:6.9 plasma cell <5% 62 years-old female, ECOG 1-2 without other comorbidity

ธค.56 มิย 58 สค 59 พค.60 สค 60 28 กย 60 5 มค 61 CBC Mild 3rd Re- anemia treatment Hb8 Since July 2013 (กค58) Plasma <5% VelCyDex 15% 40% cell in BM 8cycles

Kappa 12 1370 End 77 54 386 349 578 มค 59 Lamda 6.9 6.8 --- 9.9 9 14 11.8 8.4 Ratio 1.7 201 --- 7 5.9 27 25.5 65.38 Β2-mGlob 4.3 Spend time ** traveling 62 years-old female, ECOG 1-2 without other comorbidity

5 มค 61 5 เมษา 61 กค. 61 16/10/61 CBC Discuss about using Hb8.5/Hct27 Hb 10.2/ Hct31 other agents Received WBC/Plt OK Plasma 40% Waiting for decision - Lenalidomide (20) Not done yet cell in BM 1*1 (With dexa) Kappa 578 454 36

Lamda 8.4 10 15 **65.38 44.9 2.39 • This patient was also advised to go for SCT. • She is in the process of making decision. Controversy aspects The Who, When, and Why of Treatment https://www.ashclinicalnews.org/features/controversies-myeloma-treatment/

• Recent large trials (including IFM 2009, Myeloma IX, POLLUX, and CASTOR) that have confirmed the prognostic significance of MRD, as MRD negativity is associated with better survival outcomes in both transplant-eligible and -ineligible patients. • “Those study showed that MRD negativity is associated with a better prognosis, [but] should we use MRD testing routinely?” • Double autologous hematopoietic cell transplantation is a good option for transplant-eligible patients (even those with high-risk disease), according to results from the EMN02/HO95 study, followed by consolidation therapy. (U.S. studies have not shown such an advantage to a second transplant.) • The role of maintenance therapy was controversial, with maintenance associated with improved PFS and overall survival (OS) in patients with standard-risk disease, but only PFS for those with high-risk disease. • For transplant-ineligible patients, • Long-fixed duration of carfilzomib, lenalidomide, and dexamethasone (18 cycles) induced high rates of MRD-negativity and long PFS and OS, but the OS benefit of continuous therapy after induction was less clear-cut. • Patients with relapsed or refractory MM had high rates of response and improvement in the quality of response when treated with continued therapy, according to results from the MM09 and MM10 trials. • Role of novel agents vs. cost might be considered THANK YOU for your attention Bisphosphonates in Osteopenic Patients

• Diffuse osteopenia and/or osteolytic lesions afflict ~ 85% of MM patients[1] • Decreases quality of life, PS • Meta-analysis (N = 6692) of 20 trials comparing bisphosphonates to placebo/observation or to other bisphosphonates in MM[2] • Significant reductions in pathologic vertebral fractures, SREs, and pain • No significant increase in hypocalcemia vs no bisphosphonate • No one bisphosphonate clearly superior, except zoledronic acid superior to placebo and etidronate in OS • Note: In perimenopausal patients, OK to use calcium/vitamin D and bisphosphonates, but pay careful attention to risk[3]

1. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2014. 2. Mhaskar R, et al. Cochrane Database Syst Rev. 2012;5:CD003188. 3. Comenzo R. Personal communication. 2013. Bortezomib: SC vs IV Administration

Subcutaneous Intravenous • FDA approved SC in 2012 • FDA approved IV in 2003 • Equivalent efficacy as IV (numerous studies) • Highly effective myeloma therapy • Reduced neuropathy, GI AEs • Neuropathy a notable AE • Consider for patients with preexisting or high-risk PN • 67.8% of patients prefer SC over IV • 54 mins less chair time on average • 46 mins less clinic time on average

For SC administration, Reconstituting For IV administration, add 1.4 mL bortezomib add 3.5 mL 0.9% sodium chloride (3.5 mg vial) 0.9% sodium chloride

Hydration: a key nursing consideration, especially in patients with renal compromise

Barbee MS, et al. ASCO 2012. Abstract E18553. Mateos MV, et al. Ther Adv Hematol. 2012;3:117-124. Bortezomib [package insert]. Phase III Study: Subcutaneous vs Intravenous Bortezomib in Relapsed MM

Administration ORR, % CR, % Median Time to Median PN PN Route Response, TTP, Mos All Grades, Grade Mos % 3/4, % IV (n = 73) 42 8 1.4 9.4 53 16 SC (n = 145) 42 6 1.4 10.4 38 6 P value .387 .044 .026

• SC administration of bortezomib noninferior to IV (P = .002) • Improved safety profile with bortezomib SC vs IV • Recommended for pts with preexisting PN or at high risk of PN

Moreau P, et al. Lancet Oncol. 2011;12:431-440. Bortezomib [package insert]. Guidelines for Bortezomib Dose Modification for Management of PN

Severity of PN Signs/Symptoms Modification of Dose and Regimen Grade 1 (paresthesia, weakness, Reduce current bortezomib dose by 1 level (1.3 to 1.0 to 0.7 and/or loss of reflexes without pain or mg/m2). For patients receiving a twice-wkly schedule, change to loss of function) a once-per-wk schedule using the same dose. For patients with previous PN, consider starting with 1.3 mg/m2 once per wk. Alternatively, for patients with preexisting PN or at high risk of PN, consider subcutaneous administration. Grade 1 with pain or grade 2 (no pain For patients receiving twice per wk bortezomib, reduce current but interfering with basic activities of dose by 1 level or change to a once-per-wk schedule using the daily living) same dose. For patients receiving bortezomib on a once-per-wk schedule, reduce current dose by 1 level or consider temporary discontinuation; upon resolution (grade ≤ 1), restart once-per-wk dosing at lower dose level in cases of favorable benefit-to-risk ratio.

Grade 2 with pain, grade 3 Discontinue bortezomib. (limiting self-care and activities of daily living), or grade 4

Richardson PG, et al. Leukemia. 2012;26:595-608. Bortezomib [package insert]. 2012. Effect of t(4;14), FISH Status, ISS Staging, and Age on OS in Multiple Myeloma

100

80

60 A vs B: P < .0001 40 C vs D: P < .03 E vs F: P < .05 20

0 Patients Remaining Alive (%) Alive Remaining Patients 0 5 10 15 Yrs From Treatment Start Events, n/N Estimated 4-Yr OS, % (Range) A. ISS I/II & -FISH & aged < 65 yrs 270/935 75 (72-78) B. ISS I/II & -FISH & aged ≥ 65 yrs 159/409 62 (56-67) C. ISS/II/III & -FISH or ISS I & + FISH & aged < 65 yrs 278/526 48 (44-53) D. ISS II/III & -FISH or ISS I +FISH & aged ≥ 65 yrs 136/230 38 (31-45) E. ISS II/III & +FISH & aged < 65 yrs 241/378 37 (32-43) F. ISS II/III & +FISH & aged ≥ 65 yrs 113/160 24 (16-32) Avet-Loiseau H, et al. Leukemia. 2013;27:711-717. Multiple Myeloma: Risk Categories

Risk Factors Standard Risk High Risk (Expected OS: 6-7 Yrs) (Expected OS: 2-3 Yrs) FISH t(11;14) Del(17p) t(6;14) Del(1p) Hyperdiploidy Gain(1q) t(4;14)* t(14;16) Hypodiploidy

β2-M* Low (< 3.5 mg/L) High (≥ 5.5 mg/L) Isotype -- IgA Gene expression profile Good risk High risk

*Patients with t(4;14), β2-M < 4 mg/L, and Hb ≥ 10 g/dL may have intermediate-risk disease. Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Fonseca R, et al. Leukemia. 2009;23:2210-21. Kyle RA, et al. Clin Lymphoma Myeloma. 2009;9:278-288. Munshi N, et al. Blood. 2011;117:4696-4700. Gene Expression Profiling (GEP) in MM

• NCCN: GEPs have potential to refine risk stratification in MM[1] • qPCR is a potential surrogate for GEP arrays[2]

• High β2-M, low CDKN1A, and high SLC19A1 gene expression predict short TTP • High ISS stage, low CDKN2B, and high TBRG4 gene expression predict poor OS • GEP assay available in MM[3,4] • Provides risk-stratification data • Identifies genomic aberrations that may influence treatment

1. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2014. 2. Sarasquete ME, et al. Br J Haematol. 2013;[E-pub ahead of print]. 3. Broyl A, et al. Blood. 2010;116:2543-2553. 4. Zhou Y, et al. Blood. 2012;119:e148-e150. Frontline Therapy: Conclusions

• All combination therapies provide high response rates during induction; the optimal choice depends on patient characteristics, patient and physician preference, and toxicity profiles • Doublets or triplets are appropriate induction for transplant-ineligible patients • Cytogenetics have the strongest prognostic significance Maintenance