Diagnosis and Treatment of High-risk SMM

Institute of Hematology, Peking University Peking University People's Hospital

Lu Jin

In the treatment of other malignancies (breast, colon or prostate cancer), the early intervention is not only appropriate, but also essential for successful treatment and cure.

Treatment concept of early intervention

Curr Opin Oncol. 2014 Nov;26(6):670-6

Early intervention provides a possibility for curing myeloma

Curr Opin Oncol. 2014 Nov;26(6):670-6Haematologica December 2014 99: 1769-1771Clin Cancer Res. 2013 Mar 1;19(5):985-94

The treatment philosophy in multiple myeloma patients has been focused on symptomatic patients.As extrapolated from other medical conditions, including other solid and hematologic malignancies, one may conjecture that early intervention has the potential to provide a path to a cure in myeloma.It can be inferred that in the early (e.g. SMM) stage of the disease fewer genetic changes cause higher cure possibility due to lower disease burden.

Difficulties of SMM treatment advances

Haematologica December 2014 99: 1769-1771

SMM is a heterogeneous plasma cell disease

Clinical Lymphoma Myeloma and Leukemia Volume 10, Issue 4, Pages 248-57

The risk of SMM progressing to active MM

Are there any risk factors predicting progression to active disease?

N Engl J Med 2007;356(25):2582-2590.

Risk Stratification Model

J Clin Oncol. 2015 Jan 1;33(1):115-23

Mayo model is mainly dependent on the serum protein levelsPETHEMA model uses bone marrow cells

Mayo and PETHEMA Risk Stratification Models

Follow-up time (years) Time from the diagnosis (months)

Two risk stratification models currently lack of consistency

A study recently integrated Mayo and PETHEMA risk stratification models .

77 patients with SMM were prospectively risk-stratified based on the two models .There was distinct difference between the two models that only 22/77 patients had the same stratified result (consistency: 28.6%)

Leukemia and Lymphoma 2013 ； 54 (10), pp. 2215-2218

Lancet Oncol. 2014 Nov;15(12):e538-48

Not CRAB but now SLiM CRAB•S (60% increase in plasma cells)•Li (Light chain I/U >100)•M (1 or multiple focal lesions on MRI)•C (Elevated serum calcium)•R (Renal insufficiency)•A (Anemia)•B (Osteopathy)

BMPC≥60% should be considered as MM requiring

treatment

 N Engl J Med 2011;365(5):474-475. Leukemia 2013;27(4):947-953

95% progressed to MM in 2 years

All progressed to MM in 2 years

FLC ratio≥100 should be considered as MM Requiring

treatment

Leukemia (2013) 27, 941–946Leukemia 2013;27(4):947-953

72% progressed to MM in 2 years

98% progressed to MM in 18 months

The predictive value of focal lesion >1 on MRI

J Clin Oncol 2010; 28: 1606–10.  Leukemia2014;28(12):2402-2403

The median time to progression of focal lesion >1 on MRI was 13 monthsThe progression rate of MM in 2 years was 70%

The median time to progression of focal lesion >1 on MRI was 15 monthsThe progression rate of MM in 2 years was 69%

Diagnostic Criteria of MM that may be added in the future

Lancet Oncol. 2014 Nov;15(12):e538-48

The predictive value of cytogenetic abnormalities

JCO VOLUME 31 NUMBER 34 DECEMBER 1 2013

High-risk VS No high-risk cytogenetics 3yearTTP 45% VS 24% (HR, 2.00; P=.001).

The diagnosis of MM will continue to move forward

Blood, 122 (26) , pp. 4172-4181.

Why observe and wait ?

High drug toxicityThe protocol contained alkylating agents (which can cause a second tumor)The enrolled patients were not risk-stratified

Risk stratification and more safe and effective new drugs bring hope for

early intervention

• Selective treatment in high-risk patients.

• The toxic side effects of new drugs are smaller and more effective

QUIREDEX: QUIREDEX: 来那度胺来那度胺 ++地塞米松治疗地塞米松治疗 SMMSMM 的的33期研究期研究

a Spain: 19 sites; Portugal: 3 sites.b DEX (20 mg, D1-4) could be added when the patient had developed to asymptomatic biological progression (M protein increased)D: day; DEX: dexamethasone; LEN: lenalidomide; ORR: overall response rate; OS: overall survival; TTP: time to disease progression.

Engl J Med. 2013;369:438-47

• Primary endpoint: TTP to symptomatic disease• Secondary endpoints: ORR, OS, safety

– Cutoff date for final analysis: October 15, 2012– Median follow-up: 40 months

N = 119a

•SMM

•Stratified by time since diagnosis (≤ 6 vs. > 6 mo)

Early Treatment (n = 57):

LEN: 25 mg, D1-21DEX: 20 mg, D1-4,12-15

Nine 28-day cycles

Observation (n = 62):

(No treatment until progression to

symptomatic MM)

R 1:1

LEN: 10 mg, D1-21b

(Protocol amendment limits total treatment

duration to 2 y)

Maintenance

Eligibility Criteria

BMPC: bone marrow plasma cell; MC: monoclonal component; PC: plasma cell; SMM: smoldering multiple myeloma.

Engl J Med. 2013;369:438-47

• Key inclusion criteria:– Diagnosed with SMM within the past 5 yrs– High-risk of progression to symptomatic disease, defined as:

• BMPC infiltration ≥ 10% and increased monoclonal component (IgG ≥ 3 g/dL, or IgA ≥ 2 g/dL, or Bence-Jones proteinuria > 1 g/24 hours)

OR

• 1 of 2 criteria above and ≥ 95% phenotypically aberrant BMPC with immunoparesis

• Key exclusion criteria:– Presence of CRAB symptoms

• Hypercalcemia • Renal failure (creatinine ≥2 mg/dL)• Anemia (hemoglobin <10 g/dL or 2 g/dL below lower limit of normal) • Bone lesions

Response rate up to 90% for Rd treatment

a 7 patients didn’t receive maintenance treatment: withdrawal of informed consent t (4); Grade 4 pneumonia (1); DEX-related delirium (1); adjudication by investigator (1).

Engl J Med. 2013;369:438-47

• 50 of 57 pts (88%) completed 9 cycles of induction therapy and received LEN maintenance• 12 pts (24%) had an improvement in the quality of response after a median of 15 cycles of LEN

maintenance

Significant prolongation of TTP by Rd treatment

Median TTP

Treatment NR

Observation 21 months

Dx: diagnosis; HR: hazard ratio; NR, not reached; TTP: time to progression; Tx: treatment.Engl J Med. 2013;369:438-47

• Early Tx was associated with significantly longer TTP vs observation– 76% in the observation group developed symptomatic MM requiring Tx initiation vs.

23% in the Tx group– Time between Dx and study entry (≤ 6 mos vs. > 6 mos) did not affect TTP

Significant prolongation of OS by Rd treatment （ since

enrollment）3-year OS rate (%)

Treatment 94

Observation 80

HR: hazard ratio;

• Median follow-up time of 40 months• Compared with observation group, early treatment could significantly increase 3-year survival rate since

enrollment

Engl J Med. 2013;369:438-47

Significant prolongation of OS by Rd treatment （ since

diagnosis）• • Median follow-up time of 46 months• • Compared with observation group, early treatment could siginicanlty increase OS since

diagnosis• • In Rd group, 44% patients with the time from diagnosis to enrollment of ≤6 months, 56% patients

with the time of ＞ 6

a Median follow-up time: 46 months

5-year OS rate (%)

Treatment 94

Observation 78

Engl J Med. 2013;369:438-47

Good Safety- Induction PhaseAE, n (%)

Treatment (n = 62) Observation (n = 63)

Gr 1 Gr 2 Gr 3 Gr 1 Gr 2Hematology

NeutropeniaThrombocytopeniaAnemia

3 (5)6 (10)

11 (18)

8 (13)1 (2)4 (6)

3 (5)1 (2)1 (2)

000

000

Non-hematology Infection a

RashAstheniaConstipationDiarrheaDVT b

19 (31)12 (19)6 (10)4 (6)9 (15)1 (2)

6 (10)6 (10)5 (8)6 (10)4 (6)2 (3)

4 (6)2 (3)4 (6)

01 (2)

0

7 (11)0

5 (8)0

1 (2)0

7 (11)0

1 (2)1 (2)1 (2)

0a 1 patient had Grade 5 infection during the early treatment.b Of the 3 patients, 1 received aspirin (100 mg/day), the second received warfarin with low INR, the third didn’t receive prophylactic treatment.

AE: adverse event; DEX: dexamethasone; DVT: deep vein thrombosis; Gr: grade; LEN: lenalidomide; Ph: phase; pts: patients; SMM: smoldering multiple myeloma.

Engl J Med. 2013;369:438-47

Good Safety-Maintenance Phase

AE: adverse event; DEX: dexamethasone; Gr: grade; LEN: lenalidomide; pts: patients; SMM: smoldering multiple myeloma.

AE, n (%)Treatment (n=50) Observation (n=61)

Gr 1 Gr 2 Gr 1 Gr 2Hematology NeutropeniaThrombocytopeniaAnemia

1 (2)0

4 (8)

3 (6)3 (6)1 (2)

000

000

Non-hematologyAstheniaInfection

06 (12)

2 (4)3 (6)

02 (3)

03 (5)

Engl J Med. 2013;369:438-47

Rd treatment didn’t increase risk of SPM occurence

• 4 patients (6%) in treatment group had second primary tumor a

• Of which, 3 patients had early signs of malignant tumor at enrollment

• 1 patient (2%) in observation group had MDS

• 5-year cumulative incidence of SPM between the two groups was comparable (20% vs.25%; P= 0.42)

aAt the time of the writing of this report, one additional patient in the treatment group had received a diagnosis of concomitant incidental prostate cancer (confirmed by a preplanned biopsy 6 weeks after randomization).

MDS: myelodysplastic syndromes; PSA: prostate-specific antigen; SPM: second primary malignancy; Tx: treatment.

Engl J Med. 2013;369:438-47

Long-term follow-up results provided further evidence of the

efficacy of Rd

Engl J Med. 2013;369:438-47Maria-Victoria Mateos et al. ASH 2014 #3465

Proportion of patients with disease progression to symptomatic disease

Proportion of patients with 5-year survival after progressed to symptomatic MM a

TTP(Months)

OS(Survival rate ，%)

SPM(cases)

Early follow-up results （ median follow-up time of 40 months）

Rd group vs. observation group: 23% vs. 76%

Not reported Rd group vs. observation group: Not reached vs. 21(HR=0.18 P<0.001)

Rd group vs. observation group: 94%vs.80%(HR=0.31 P=0.03)

Rd group vs. observation group: 4 vs. 1

Long-term follow-up results （ median follow-up time of 64 months）

Rd group vs. observation group: 23% vs. 85%

Rd group vs. observation group: 83% vs. 58%

Rd group vs. observation group: Not reached vs. 21 (HR= 6.21, p<0.0001)

Rd group vs. observation group: 93% vs. 67% (HR= 4.35, p=0.008)

Rd group vs. observation group: 4 vs. 1

No new SPM cases

a:>25% of increase in monoclonal component with no symptoms

https://ash.confex.com/ash/2014/webprogram/Paper75696.html

https://ash.confex.com/ash/2014/webprogram/Paper75696.html

Relationship between depth of response and potential curability

Blood. 2015 May 14;125(20):3059-3068

Blood Nov 27, 2014:3380-3388

Blood, 122 (26) , pp. 4172-4181.

SMM: ongoing primary studies

a Trials may include additional objectives not listed in the table.

BORT: bortezomib; BSC: best supportive care; CFZ: carfilzomib; DEX: dexamethasone; DoR: duration of response; ECOG: Eastern Cooperative Oncology Group; ELO: elotuzumab; Gr: grade; IV: intravenous; LEN: lenalidomide; NK: natural killer; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; qd: once daily; QoL: quality of life; SMM: smoldering multiple myeloma; THAL: thalidomide; TTP: time to progression.

http://clinicaltrials.gov/. Accessed Jan 7, 2015

Phase Study Population Planning enrollment Protocol Main purpose a Status

3 ECOG E3A06 (NCT01169337)

High-Risk SMMFLC(< 0.26 or >

1.65） N = 380

Lenalidomide qd for 21 days of 28 day cycles or BSC until

PD

≥ Grde 3 non-heme toxicity, PFS, ORR,

OS, QoL, safetyEnrolling

2 HCI33979(NCT00983346) SMM N = 20

Bortezomib IV (0.7 mg/m2) D1, 8, 15, 22

of 42-day cycles （ 9 cycles）

Bone effects, impact on SMM natural history

Completed

2 12-C-0107(NCT01572480)

SMM N = 14Carfilzomib +

lenalidomide + dexamethasone

ORR, PFS, DoR, safety, correlative

studiesEnrolling

2 CA204-011 (NCT01441973)

High-risk SMM（ Mayo criteri

a） N = 40 ELO 10 or 20 mg/kg IV

Change in M-protein and NK

cells, ORR, PFSOngoing

2 UARK 98-036 (NCT00083382) SMM N = 100

Disodium Pamidronate + thalidomide +

Zoledronic acid

ORR, TTP, OS Completed

SMM: ongoing primary studies

a Trials may include additional objectives not listed in the table.BHQ880: Fully Human, Anti-Dickkopf1 (DKK1) Neutralizing Antibody; IV: intravenous; KIR: killer-cell immunoglobulin–like receptor; ORR: overall response rate; PD: progressive disease; PK: pharmacokinetics; q2m: every 2 months; qd: once daily.http://clinicaltrials.gov/. Accessed Jan 7, 2015

Phase Study Population Planning enrollment Protocol Main purpose a Phase

2 11-C-0024(NCT01248455) SMM N = 9 IPH2101 (anti-KIR):

IV q2m for 6 cycles ORR, safety, PK Ongoing

2 IPH2101-203(NCT01222286) SMM N = 30

IPH2101 (anti-KIR) 0.2 or 2 mg/kg IV for

6 cycles

ORR, safety, pharmacodynamics Completed

2 CBHQ880A2204(NCT01302886)

High-risk SMM （ Mayo

Criteria） N = 58 BHQ880AORR, safety, PK, effects on bone

metabolism/densityCompleted

2 2009-015 (NCT01589887)

MGUS and/or SMM N = 17

Polyphenon E 800mg qd for up to

6 × 28-day cycles or until PD

Sustained reduction in M-

proteinOngoing

2 WSU-2009-015 (NCT00942422)

MGUS and/or SMM N = 8

Polyphenon E 800 mg qd for up to

6 × 28-day cycles or until PD

Changes in M-protein levels Ongoing

SMM: ongoing primary studiesPhase Study Population Planning

enrollment Protocol Main purpose a Status

2 NCI-2009-00866(NCT00099047) MGUS /SMM N=36

Celecoxib or PBO;BID for 6 mos until

PD, toxicity

Changes in M-protein, IL-6, β2-microglobulin, IL-1β,

CD4+/CD8+ ratio, COX-2 staining

Ongoing

2 CR100755(NCT01484275)

High-risk SMM （ Mayo criteria） N=100

Siltuximab or PBO;IV q4w until PD,

AE,or study end

1-y PFS rate, PFS, PD, QoL, safety, OS Enrolling

2 12-BI-505-02(NCT01838369) SMM N=10 BI-505 Change in M-protein,

safety, PK Enrolling

1/2City of Hope

04064 b

(NCT00112827)

MM/progressed

SMM requiring treatment

N=86

Tandem SCT+TMI,with lenalidomide for maintenance

treatment

Safety, ORR, PFS, OS Ongoing

1 CR017452(NCT01219010)

MGUS /SMM/indolent MM N=30

Siltuximab 15mg/kgIV q3w for 4 cycles and maint, for 2 y

QTc interval, safety, efficacy, PK,

pharmacodynamics

Completed

a Trials may include additional objectives not listed in the table. b MM pts included.

AE: adverse event; BI-505: Human Anti-Intercellular Adhesion Molecule 1 monoclonal antibody; BID: twice daily; IL: interleukin; IV: intravenous; LEN: lenalidomide; MM: multiple myeloma; ORR: overall response rate; OS: overall survival; QOL: quality of life; PBO: placebo; PD: progressive disease; PFS: progression-free survival; PK: pharmacokinetics; q3w: every 3 weeks; q4w: every 4 weeks; SCT: stem cell transplant; TMI: total marrow irradiation.http://clinicaltrials.gov/. Accessed Jan 7, 2015

Early intervention to high-risk SMM will lead to persistent control or cure of disease

Clinical Cancer Research 17 (6), pp. 1243-1252

Promising treatment prospects of SMM draw much attention from investigators

References to Smoldering Multiple Myeloma

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Peking University Institute of Hematology Peking University

People's HospitalBeijing Key Laboratory of HSCT

Introduction for PUIH