Controversies in Multiple Myeloma · For SMM New risk classification will (possible) be available •Arjun Lakshman1, S. Vincent Rajkumar1, Francis K. Buadi1, et al. reported in Blood

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

MGUS or smolderingmyeloma

Asymptomatic Symptomatic

ACTIVE MYELOMA

M P

rote

in (g

/L)

20

50

100

1. RELAPSE

2. RELAPSE

REFRACTORY RELAPSE

First-line Rx

Plateau remission

Second-line Rx Third-line Rx

Newly Dx15,000/year in US 45,000/year in US

IMWG Criteria for Diagnosis of Multiple Myeloma

*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.

MGUS§ M protein < 3 g/dL§ Clonal plasma cells in BM

< 10%§ No myeloma defining

events

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

Multiple Myeloma§ Clonal BM plasma cell >

10% or Extramedullaryplasmacytoma

§ AND 1 or more myeloma defining events

§ ≥ 1 CRAB*or

§ SLiM feature

100

80

60

40

20

0

27% will convert in 15 yearsRoughly 2% per year

51% will convert in first 5 yrs~ 10% per yr

0 5 10 15 20 25

Pro

babi

lity

of P

rogr

essi

on (%

)

51

6673

78

4 1016

21

MGUSSmoldering MM

Smoldering Multiple Myeloma

Kyle RA, et al. N Engl J Med. 2007;356:2582-2590. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.

Yrs Since Diagnosis

27% more will convert in remaining 15 yrs~ 2% per yr

For SMM • The Mayo Clinic model (2007-2008) uses

• M-protein (≥3 g/dL),

• BMPC% (≥10%),

• and the ratio of involved to uninvolved serum free light chains (FLCr)

(≥8)

• categorize patients into three risk categories, with a 76% risk of

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.

Smoldering Myeloma 2014

§ M protein ≥ 3 g/dL(serum) or ≥ 500 mg/24 hrs (urine)

§ Clonal plasma cells in BM ≥ 10% to 60%

§ No myeloma defining events

Blood Cancer Journal (2018)8:59.

For SMM New risk classification will (possible) be available

• Arjun Lakshman1, S. Vincent Rajkumar1, Francis K. Buadi1, et al. 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%, M-protein > 2 g/dL, and FLC ratio > 20 at diagnosis

01>2

123

M-protein (≥3 g/dL), BMPC% (≥10%), and the ratio of involved to uninvolved serum free light chains (FLCr) (≥8)

For SMM• Arjun Lakshman1, S. Vincent Rajkumar1, Francis K. Buadi1, et al.

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%, M-protein > 2 g/dL, and FLC ratio > 20 at diagnosis

BMPC% > 10%, M-protein > 3 g/dL, and FLC ratio > 8 at diagnosis

01>2

123

92 (47.8%)

For SMM New risk classification will be available• Arjun Lakshman1, S. Vincent Rajkumar1, Francis K. Buadi1, et al.

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%, M-protein > 2 g/dL, and FLC ratio > 20 at diagnosis can be used to risk stratify patients with SMM.

01>2

123

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

VincristineDoxorubicinDexamethasone

Symptomatic Multiple Myeloma:Frontline Therapy

Initial Approach to Treatment of Myeloma

Nontransplant Candidate (based on age, performance

status, and comorbidities)

Induction treatment

TransplantCandidate

Induction treatment (4-6 cycles)

Stem cell harvest

Stem cell transplantation

Maintenance

Maintenance

Consolidation therapy?

ASCT: EligibilityDespite novel agents, ASCT remains a standard component of MM treatment

Candidates

• Eligibility can depend on transplant center• Factors/considerations:• Age• Cytogenetic abnormalities• Disease status/stage• Type of frontline therapy and

response• Organ function

Treatments

• NCCN Category 1• VD, VTD, PAD (Bor/doxo/dexa)• Lenalidomide/dexamethasone (RD)

• NCCN Category 2A• CyBorD• Bor/len/dex (VRD)• Carfil/len/dex (CRd)

Trial Regimens n ≥ VGPR, % Median PFS, Mos

OS, %After Induction After First ASCT

Harousseau[1] VD VAD

240242

3815

5437

3630

3 yr: 813 yr: 77

Cavo[2] VTDVAD

413414

6228

7958

3 yr: 68%3 yr: 56%

3 yr: 863 yr: 84

Sonneveld[3] PADVAD

413414

4214

7656

358

5 yr: 615 yr: 55

Rosiñol[4] VTDTD

VMBCP/VBAD/B

130127129

602936

NR562836

4 yr: 744 yr: 654 yr: 70

Moreau[5] VTDVD

10099

4936

7458

2630

NR

Rajkumar[6] RDRd

223222

4224

5040

NR 3 yr: 92NR

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.

Phase III Trials: Novel Agent Induction for Transplant-Eligible Patients

P < .001 P < .001

P < .001 P < .001

P < .001 P < .001

P = .05 P = .02

P < .001 P = .04

MM Induction in Transplant-ineligible MM Patients: Triplets vs Doublets• Some comparative efficacy data available[1]

• VTD superior to TD, including in pts with t(4;14)[2]

• VTD superior to VD• CyBorD similar to VTD

• 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.

– MPT superior to MP

– VMP superior to MP

– MPR superior to MP

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

• CRAB symptoms• New extramedullary

plasmacytoma

• Asymptomatic relapse• Significant paraprotein relapse

• Doubling of the paraprotein in 2 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

adjustment• Bortezomib• Carfilzomib

• If elevated serum creatinin not attributed to carfilzomib

• Thalidomide• Pomalidomide• Liposomal doxorubicin• Monoclonal Abs

• Daratumumab• Elotuzumab

• Agents requiring renal dose adjustment• Lenalidomide

• CrCl 30-60 mL/min: 10 mg PO qDay; • CrCl <30 mL/min (not requiring dialysis):

15 mg PO every other day• CrCl <30 mL/min (requiring dialysis): 5

mg PO q Day; on dialysis days

• Ixazomib• Only in ESRD: reduced dose to 3 mg

• Melphalan• CrCl 30-50 mL/min: 50% dose

reduction• Avoid if CrCl < 30 mL/min

• Cyclophosphamide• CrCl < 10 mL/min: 50% dose reduction

Nookaa,a et al. Blood. 2015;125(20):3085-3099; Dimopoulous et al. Blood Adv 2017; 1: 449

When use carfilzomib in renal insufficiency, serum creatinine should be closely monitored

• 35% of patients had a reduction of eGFR >25%

Treatment related factors: Peripheral neuropathy

• Agents may aggravate PN• PIs

• Bortezomib• Carfilzomib: less likely• Ixazomib: less likely

• Thalidomide• Vincristine

• Agents without major neurotoxicity

• Lenalidomide• Pomalidomide• Monoclonal Abs

• Daratumumab• Elotuzumab

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

Treatment related factors: Thrombosis

• Agents may aggravate VTE• IMIDs

• Thalidomide• Lenalidomide• Pomalidomide

• High-dose dexamethasone

• Agents without major VTE risk

• Pis• Bortezomib• Carfilzomib• Ixazomib

• Monoclonal Abs• Daratumumab• Elotuzumab

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

Treatment related factors: Cardiac disease

• Agents may aggravate cardiac events

• Carfilzomib• Thalidomide: may be• Anthracycline

• Doxorubicin• Liposomal doxorubicin

• Agents without major cardiac risk• Bortezomib• Ixazomib• Lenalidomide• Pomalidomide• Monoclonal Abs

• Daratumumab• Elotuzumab

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

Patient related factors: Convenience

• Oral agents• IMIDs• Alkylating agents

• Cyclophosphamide• Melphalan

• Dexamethasone

• Agents requiring frequent hospital visit• Proteasome inhibitors

• Bortezomib• Carfilzomib

• Monoclonal Ab• Daratumumab• Elotuzumab

Disease related factors: high risk disease characteristics

• Adverse cytogenetic abnormalities• del(17p)• amp(1q21)• t(4;14)

• Extramedullary plasmacytoma• Short remission duration after first

treatment • ISS stage at relapse

• Aggressive clinical features including • Rapid onset of clinical symptoms• Extensive disease at relapse based on

laboratory, pathology, or radiographic findings• Disease-associated organ dysfunction

• Isotype transformation • Light chain escape• Development of hypo/non-secretory

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

• Bortezomib• Partly overcomes the adverse

effect of t(4;14) and possibly 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

• Thalidomide• Lenalidome

Agent showing activity on high risk cytogenetics

Agent showing limited activity on high risk cytogenetics

Sonneveld , et al. IMWG consensus. Blood. 2016;127(24):2955-2962

Treatment related factors: prior therapies

• PIs or iMIDs naïve

• Consider treatment with

agent patients have never

received

• Previous exposure to either

PIs or iMIDs

• Retreat with prior therapy

• if previously responded and

relapsed > 6 months after

prior drug exposure

• Switching class of novel

agents

• Previous exposure to both PI

or iMIDs

• Carfilzomib

• Pomalidomide

• Daratumumab

• Avoid regimens that has

overlapping toxicities

• Neuropathy

• Myelosuppression

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

Patients who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on the last therapy

Pomalidomide-DexCarfilzomib

monotherapyDaratumomabmonotherapy

Patients who have received at least two prior therapies including bortezomib and IMIDs and have demonstrated disease progression on or within 60 days of completion of the last therapy

For patients who have received at least three prior lines of therapy including a PI and IMIDs

Novel agents approved by Thai FDA for R/R MM in patients previously treated with both PI and IMIDs

Characteristics Pomalidomide-dex1

vs. HiDex (n=351) Carfilzomib monotherapy2

Vs. low Dex (n=315)Daratumumab monotherapy3

(n=148)

Study Phase III Phase III Pooled Phase II

Median prior line of Rx 5Including Bor & Len and Refractory to last treatment

5Including Bor & Len & Thaland Refractory to last treatment

5Including a PI and an IMiD) or who were double refractory

Both Len & Bor Refractory 73% 62% 86.5%

ORR 31% vs 10%(p < 0.0001)

19% vs 11% 31.1%

PFS 4.0 vs 1.9 months(p < 0.0001)

3.7 vs 3.3 months 4.0 months

OS 12.7 vs 8.1 months(p = 0.0285)

10.2 vs 10.0 months 20 months

Gr 3-5 AEs Thromboembolic event: • 6% vs 0%Neutropenia: • 48% vs 16% Infection: • 34% vs 33%

Anemia• 26% vs 31% Thrombocytopenia: • 24% vs 22% ARF: • 8% vs 3%Renal failure: • 5% vs 1%HTN & CHF • 5% vs 1%

• Anemia: 17.6%• Thrombocytopenia 14.2%• Neutropenia 10.1%

1.San Miguel JF, et al. Lancet Oncol 2013; 14: 1055–66

2.Hajek, et al. Leukemia (2017) 31, 107–114;

3. Usmani, et al. Blood. 2016;128(1):37-44

How to choose treatment when relapse after bortezomib and IMIDs

• Underlying peripheral

neuropathy

• Renal impairment

• High risk cytogenetics

• Difficulty in the access

to medical service

• Cost 360,000/month

• 1.08 M/year

Pomalidomide-Dex Carfilzomib monotherapy

Daratumomabmonotherapy

• Underlying peripheral neuropathy

• Avoid in patients with heart disease, poor controlled HTN

• Avoid in patients with renal impairment

• Cost 300,000/month• 3.6 M/month• May have PAP

• Renal impairment• Cytopenia

• Cost 400,000/months• 2.2 M/year • 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%

ธค.56 มยิ 58 สค 59 พค.60 สค 60 28 กย 60 5 มค 61

CBC Mild

anemia

Hb8

3rd Re-

treatment

Since July 2013 (กค58)

Plasma

cell in BM

<5% VelCyDex

8cycles

15% 40%

Kappa 12 1370 End มค 59

77 54 386 349 578

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 other agents

Hb8.5/Hct27Received

Lenalidomide (20)1*1

(With dexa)

Hb 10.2/ Hct31WBC/Plt OK

Plasma cell in BM

40% Waiting for decision - Not done yet

Kappa 578 454 36

Lamda 8.4 10 15

**65.38 44.9 2.39

62 years-old female, ECOG 1-2 without other comorbidity

• 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 Treatmenthttps://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• FDA approved SC in 2012

• Equivalent efficacy as IV (numerous studies)

• Reduced neuropathy, GI AEs

• 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

Intravenous• FDA approved IV in 2003

• Highly effective myeloma therapy

• Neuropathy a notable AE

Reconstituting bortezomib (3.5 mg vial)

For SC administration, add 1.4 mL

0.9% sodium chloride

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

For IV administration, add 3.5 mL

0.9% sodium chloride

Barbee MS, et al. ASCO 2012. Abstract E18553. Mateos MV, et al. Ther Adv Hematol. 2012;3:117-124. Bortezomib [package insert].

Administration Route

ORR, % CR, % Median Time to Response,

Mos

Median TTP, Mos

PNAll Grades,

%

PN Grade 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

Moreau P, et al. Lancet Oncol. 2011;12:431-440. Bortezomib [package insert].

Phase III Study: Subcutaneous vs Intravenous Bortezomib in Relapsed MM

• 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

Guidelines for Bortezomib Dose Modification for Management of PN

Severity of PN Signs/Symptoms Modification of Dose and RegimenGrade 1 (paresthesia, weakness, and/or loss of reflexes without pain or loss of function)

Reduce current bortezomib dose by 1 level (1.3 to 1.0 to 0.7 mg/m2). For patients receiving a twice-wkly schedule, change to 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 but interfering with basic activities of daily living)

For patients receiving twice per wk bortezomib, reduce current dose by 1 level or change to a once-per-wk schedule using the 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(limiting self-care and activitiesof daily living), or grade 4

Discontinue bortezomib.

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

Avet-Loiseau H, et al. Leukemia. 2013;27:711-717.

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

Patie

nts

Rem

aini

ng A

live

(%)

Yrs From Treatment Start

100

80

60

40

20

05 10 150

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)

Multiple Myeloma: Risk Categories

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.

Risk Factors Standard Risk(Expected OS: 6-7 Yrs)

High Risk(Expected OS: 2-3 Yrs)

FISH t(11;14)t(6;14)

Hyperdiploidy

Del(17p)Del(1p)

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.

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