Smoldering Myeloma –To Treat or Not to Treat?

NO!

Joseph Mikhael, MD, MEd, FRCPCChief Medical Officer, International Myeloma FoundationProfessor, Translational Genomics Research Institute (TGen) City of Hope Cancer CenterMarch 2020

What if your friend is walking towards a cliff?

• Will you wait until they are falling to rescue them?

• But what if they are really enjoying the walk and the cliff is miles away??

Background

• Remember Myeloma is a unique cancer – defined by the presence of organ damage – not just pathology

• Traditionally we wait until CRAB

• For good reason!!! Many will smolder for years…and may NEVER progress!

• Hence the phrase “Monoclonal Gammopathy of Undetermined Significance”

• HOWEVER….

ConditionMGUS1-4

(Monoclonal Gammopathy of Undetermined

Significance)

SMM1-5,8(Smoldering Multiple

Myeloma)Active Multiple

Myeloma6-8

Clonal plasma cells in bone marrow <10% 10%-60% ≥10%

Presence of Myeloma Defining Events

None None Yes

Likelihood of Progression ~1% per year ~10% per year Not Applicable

Treatment No; observation Possibly for high risk*;No for others Yes

*In clinical trial (preferred) or offer treatment for those likely to progress within 2 years.

1. Kyle et al. N Engl J Med. 2007;356:2582-2590.2. International Myeloma Working Group. Br J Haematol. 2003;121:749-57.3. Jagannath et al. Clin Lymphoma Myeloma Leuk. 2010;10:28-43.4. Kyle et al. Curr Hematol Malig Rep. 2010;5:62-69.5. Mateos et al. Blood 2009;114: abstract 614. 6. Durie and Salmon. Cancer 1975;36:842-854. 7. Durie et al. Leukemia 2006;20:1467-1473.8. Rajkumar et al. Lancet Oncol. 2014;15:e538-e548.

Multiple Myeloma Typically Preceded by Premalignant Conditions

Premalignant Malignant

RAB

alcium elevation

enal complications

nemia

one disease

2014 IMWG Active Myeloma Criteria: Myeloma-Defining Events

C

Clonal bone marrow ≥10% or bony/extramedullary plasmacytoma

AND any one or more Myeloma-Defining Events

Clonal bone marrow ≥60% BM

FLC

MRI

sFLC ratio >100

>1 focal lesion by MRI

BM, bone marrow; FLC, free light chain; MRI, magnetic resonance imaging; sFLC, serum free light chain.Rajkumar et al. Lancet Oncol. 2014;15:e538-e548. Kyle et al. Leukemia 2010;24:1121-1127.

Ultra High Risk SMM = Active Myeloma

Not CRAB but now SLiM CRAB• S (60% Plasmacytosis)• Li (Light chains I/U >100)• M (MRI 1 or more focal lesion)• C (calcium elevation)• R (renal insufficiency)• A (anemia)• B (bone disease)

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

Smoldering Multiple Myeloma

Low-risk SMM5%/year

Ultra-High Risk• >60% BMPC

• FLCr >100

• >1 MRI focal lesions

Intermediate - High-Risk SMM

5-25%/year

7 Reasons NOT to Treat Smoldering Myeloma

1. Above All Do No Harm2. Prevention or just early treatment?3. The heterogeneity of smoldering myeloma4. Major Flaws in Smoldering Trials5. Current interventions are not curative6. The Risk of Resistant Disease7. One day we will eliminate the category of Smoldering Myeloma

1. Primum Non Nocere - Hippocrates

Above all, do no Harm!

• This is more than a catch phrase• So many MM patients live a great quality of life with no therapy• Although our modern drugs are much better than older ones, every drug comes with significant risk

• Recall the first patient treated on the thalidomide SMM trial…

The Incidence of MGUS and SMM is higher than we think!

• At least 3-5% of all adults• MGUS starts earlier than previously thought… maybe even

20s• Earlier intervention – although attractive – must be done

cautiously and with strong evidence

• Iceland Project – screen the WHOLE country for Myeloma• Over 90,000 consented and over 60,000 samples obtained

already!• Discover true incidence of disease, evaluate different

intervention and possibly find driver mutations…

2. Prevention or just early treatment?

• True early intervention in asymptomatic patients should be designed to truly prevent the disease from developing…not just delay progression

• By using the same non curative approaches we use in active disease we should not expect a different outcome (ie cure)

• Currently we do not have available to us interventions that truly have curative or preventative intent

• What we need is to chart a running course that AVOIDS the cliff entirely!

3. The heterogeneity of smoldering myeloma

This is an inordinately complex and diverse disease –aptly named “multiple” myeloma

Until we better define higher risk SMM it is inevitable that we will be overtreating a large number of stable smoldering patients…

Identification of high-risk SMMà 50% of progression risk at 2y

• Mayo Clinic: ≥10% clonal plasma cell bone marrow infiltration, and ≥30g/L of serum M-protein, andserum-free light ratio >0.125 or <8

• Spanish: ≥95% of aberrrant plasma cells measured by flow plus >25% decrease in one or bothuninvolved immunoglogulins

• Heidelberg: Tumor mass defined by Mayo risk model plus t(4;14)/del17p/gains of 1q/• Japanese: Beta 2-microglobulin ≥ 2.5 mg/L plus M-protein increment rate > 1 mg/dL/day

• SWOG: serum M-protein ≥2 g/dL plus involved free light chain >25 and GEP >-0.26 (71% of risk progression at 2 yrs)

• PENN: ≥ 40% clonal PCBM infiltration plus sFLC ratio ≥ 50 plus Albumin � 3.5 mg/dL (81% of risk at 2 yrs

• Czech & Heidelberg: immunoparesis plus serum M-protein ≥ 2.3 g/dL plus involved/uninvolvedsFLC > 30 (81% of risk at 2 yrs)

• Barcelona: evolving pattern plus serum M-protein ≥ 3 g/dL plus immunoparesis (80% of riskat 2 yrs)

Which patient population are truly high risk SMM? SO many scoring systems!

4. Major Flaws in Smoldering Trials

• Inclusion criteria• Intervention• Adverse Events and Drop Outs• Outcomes – PFS and OS• Inability to capture “PFS2”

Smoldering Multiple Myeloma: Management

AgentsORR

(%)TTP OS Reference

Early MP* vs Deferred MP

5255

No benefit

No benefit

Hjorth M, et al. Eur J Haematol. 1993Grignani G, et al. Br J Cancer. 1996 Riccardi A, et al. Br J Cancer. 2000

Thal+Zol vsZol**

370

No benefit

No benefit

Witzig TE, et al. Leukemia 2013

Bisphosphonates*** vs observation 0 No

benefitNo

benefitMartin A, et al. Br J Haematol. 2002 D’arena et al. Leuk Lymphoma. 2011Musto P, et al. Cancer. 2008

*Abandon: No differences in survival and potential risk of secondary leukemias**Low efficacy&high rates of discontinuation due to PN***Skeletal related events lower in the bisphosphonate groups (39% vs 73% and 55% vs 78%)

Mateos NEJM 2013;369:438-47.

Len-dex for high-risk smoldering MM

8% @ 2 yr

50% @ 2 yr

70% @ 3 yr

20% @ 3 yr

Freedom from progression Overall survival

Mateos Lancet Oncol 17(8): 1127-1136.

BUT WHAT DOES A POPULATION OF ALL COMERS SMM LOOK LIKE?

What are the end points that are clinically relevant?

• Progression-free survival (progression to myeloma or death)• Progression to myeloma (CRAB and MDE criteria)• Response: depth of response

MUST BE OVERALL SURVIVAL

E3A06: Randomized phase III trial of lenalidomide versus observation

Lenalidomide Observation*

1 year 2% 11%2 years 7% 24%3 years 9% 34%

*ASCO abstract #8001

A study for intermediate and high-risk SMM*

BUT 51% of Patients Dropped out of the study due to AEs!!!!

5. Current interventions are not curative

• Do you really believe single agent lenalidomide will prevent or completely delay the progression to myeloma??

• We talk about TRIPLETS being the standard of care and yet we are willing to ½ treat myeloma at earlier stages??

Curative Estrategia Smouldering Alto Riesgo (CESAR trial)

Induction 6 cycles of KRd

ASCT (melphalan 200)

Maintenance (Len-dex for 2yrs)

Consolidation (2 cycles of KRd)

Objective To evaluate the proportion of pts in sustained immunophenotypic response at 5 years

Hypothesis: At least 50% of patients will achieve the objective

20 centers

MRD

MRD

MRD

MRD

CURATIVE STRATEGY (GEM-CESAR) FOR HIGH-RISK SMOLDERING MYELOMA

100%

50%

1 2 3

90%

OS = 98%

PFS = 94%

At 30 months

*EHA abstract

CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE (KRD) AS INDUCTION FOLLOWED BY HDT-ASCT, CONSOLIDATION WITH KRD AND MAINTENANCE WITH RD*

Aggressive Smoldering Curative Approach EvaluatingNovel Therapies and Transplant (ASCENT)

6. The Risk of Resistant Disease

We have come to appreciate the poor prognosis associated with lenalidomide resistanceALL patients half treated with lenalidomide only as SMM will now be lenalidomide resistant at diagnosis of MM

7. One day we will eliminate the category of Smoldering Myeloma

MGUS HR SMM MM

Low risk MGUS High risk MGUSLow risk SMM New HR SMM

2/20/20

Ultra high risk

MDE CRAB

Monitor Treat as MM

What is my alternative? When would I treat SMM??

• We have a new risk stratification for SMM from the International Myeloma Working Group (IMWG)…

Risk Factor CoefficientOdds Ratio

(95% CI) P-value ScoreFLC Ratio

0-10 (reference) - - - 0

>10-25 0.69 1.99 (1.15, 3.45) 0.014 2

>25-40 0.96 2.61 (1.36, 4.99) 0.004 3

>40 1.56 4.73 (2.88, 7.77) <0.0001 5

M protein (g/dL)

0-1.5 (reference) - - - 0

>1.5-3 0.95 2.59 (1.56, 4.31) 0.0002 3

>3 1.30 3.65 (2.02, 6.61) <0.0001 4

BMPC%

0-15 (reference) - - - 0

>15-20 0.57 1.77 (1.03, 3.06) 0.04 2

>20-30 1.01 2.74 (1.6, 4.68) 0.0002 3

>30-40 1.57 4.82 (2.5, 9.28) <0.0001 5

>40 2.00 7.42 (3.23, 17.02) <0.0001 6

FiSH abnormality 0.83 2.28 (1.53, 3.42) <0.0001 2

*689 of the original 2286 had complete data for all risk factors. Logistic regression analyses performed. Principal investigators: Mateos; Kumar; San Miguel; Durie. ASCO abstract #8000; also EHA abstract.

Total Risk score Predicted risk at 2-years % of sample

0 3.2 11.6

2 6.2 8.1

3 8.5 11.0

4 11.6 4.2

5 15.7 14.4

6 20.8 6.8

7 27 8.4

8 34.3 8.7

9 42.5 5.1

10 51 6.2

11 59.5 4.9

12 67.5 3.1

13 74.6 2.3

14 80.5 2.0

15 85.4 1.7

16+ 89.2 1.3

34.9%

26.6%

Low

High

IMWG Project: New SMM Risk Score Tool*

Risk Stratification

Groups

Hazard Ratio (95% CI)Versus Low-risk group

(censored 2 year)

0-4 Reference

5-8 7.56 (3.77 to 15.2)

9-12 17.3 (8.63 to 34.8)

>12 31.9 (15.4 to 66.3)

Total Risk score 2 year progression n (%)

0-4 9 / 241 (3.7%)5-8 67 / 264 (25.4%)9-12 65 / 133 (48.9%)>12 37 / 51 (72.6%)0-4

5-8

9-12

>12

241 238 229 213 194 175 153 117 100 76 63

264 256 229 197 174 145 118 91 73 53 44

133 119 98 73 59 47 33 26 20 14 13

51 41 29 21 14 9 7 5 2 2 2

# at Risk

High-risk group >12

Intermediate-risk group (9-12)

Low-risk group (0-4)

Low-intermediate-risk Group (5-8)

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60

Months

% w

ith p

rogr

essi

on

For LOW-RISK: 96% prediction of non-progression at 2 years

72.6%

Risk of Progression at 2 years

THANK YOU!

Joseph Mikhael, MD, MEd, FRCPC

Chief Medical Officer, International Myeloma Foundation

Professor, Translational Genomics Research Institute (TGen) City of Hope Cancer Center

Director of Myeloma Research and Consultant Hematologist, HonorHealth Research Institute

jmikhael@myeloma.org