Diagnosis and Current Standard Treatments for

Multiple Myeloma

Natalie S. Callander, M.D

Professor of Medicine

Goals • Introduce and/or compliment understanding of

plasma cell disorders-MGUS, SMM and

symptomatic MM

• Explain common blood and urine tests- more

with Dr. Wassenaar

• Explain importance of cytogenetics and FISH

testing-prognosis

• Current FDA approved treatments for newly

diagnosed disease

• Autologous stem cell transplantation- more with

Dr. Dhakal

How long has myeloma been around?

Seer Data; Blood 125:410, 2015

Risk Factors

• Associated with Agent Orange exposure, benzene, radiation exposure (Hiroshima experience), 9/11 FR

• Higher incidence in farmers, wood and leather manufacturers

• Small Inherited Risk

• Landgren et al First degree relatives of 4488 Swedish MGUS pts had 3 X increased relative risk of Myeloma, WM, CLL, MGUS

– (Int J Cancer. 2006;118:3095–3098)

• Familial cases exist, 1q and 4q loci regions of interest for germinal genetic mutations; paratarg 7 (Grass et al Blood 2011:118:635)

• Not clear that there are specific polymorphisms, mutations that put pts at risk for development of myeloma

Normal B cell Development

Normally, plasma cells are not found in large numbers inside bone marrow

Normal vs Myeloma

20th Annual Update in

Primary Care

Lots of different types of

whole antibodies

Whole Ab and excess light

chains – and too many of both!

Normal

Myeloma

IgG κ

IgG L

IgA κ

IgA L

IgD κ

IgD L

IgE κ

IgE L

IgM κ

IgM L

IgG κ

IgG κ

IgG L

IgA κ

IgA L

IgD κ

IgD L

IgE κ

IgE L

IgM κ

IgM L

IgG κ

Symptoms:

lytic lesions like these can

fracture….

“LYTIC” BONE LESIONS

Myeloma deposits can exist outside of bone marrow as well

(just like lymphoma): require biopsy to prove plasma cell

origin

Extramedullary deposits

MRI offers ability to see inside of bones, standard of care to

evaluate for spinal cord compression

PET-newer imaging tool for myeloma

• typically using fluorinated glucose to

measure metabolic activity

• About 90% of myeloma pts show uptake-

i.e. some will not have informative PET

• Helpful for pts whose myeloma does not

make protein

• May help predict response

• Likely will become part of initial

evaluation

Laboratory testing:

Interpretation of SPEP (serum protein electrophoresis)

Immunoglobulin molecule

• Immunofixation of

serum or urine (abs

IFE)

• Identifies type of

heavy chain (G, A,

rarely D) and light

chain (kappa or

lambda)of the

monoclonal protein

• ex

Excess protein in urine

Makes “suds”

UPEP- sensitivity to pick up abnormal proteins varies

from lab to lab

NORMAL

Free Light Chain Assay: measures levels of kappa , lambda NOT bound to heavy chains

• Free light assay- designed to detect portions of unbound light chains in serum

• Automated

• Results reported out in mg/L of mg/dl and in κ/λ ratio

• At low concentrations, lower specificity and sensitivity, or if pt has kidney failure

• “significant values > 100mg/L or 10 mg/dL or abnormal ratio (<.015 or >8)

• Levels>100mg/dl now definition of myeloma

• Also ay be used for following amyloidosis pts or confirming CR, or possibly non secretory MM

• REMEMBER: “ normal” value of M protein is 0; but it is normal to have light chains at low levels

In order to definitively diagnose myeloma, a

biopsy must show increase in plasma cells > 10%

Pathologist must prove clonality by IHC staining

Plasma cells can be identified as well by CD 138 expression on flow cytometry

Cytogenetic and Fluorescence In Situ Hybridization

(FISH) are important prognostic tools

27

• Finding small amounts of myeloma cells in bone marrow after treatment may have some importance

What happens to people with MGUS

• Among adults age 50 3% have MGUS, 10% of

80 year old

• The prevalence of MGUS therefore makes

SPEP/UPEP/light chains poor screening tests

• 75% of pts with MGUS will never develop

myeloma

• Times to consider adding these tests to an

evaluation-unexplained renal failure, proteinuria,

osteoporosis in a young person, anemia

SMOLDERING MYELOMA

DEFINITIONS DIFFER

INTERNATIONAL CONCENSUS CRITERIA:

M protein > 3 g/dl

>10% but <60% plasma cells in marrow

no end organ damage

Some use a flow cytometry definition

no renal insufficiency, bone damage (including osteopenia or any lesion found by MRI) , anemia, hypercalcemia, recurrent bacterial infections

• these patients progress much more often to myeloma-

RISK OF PROGRESSION 10%/year

• risk factors for progression include: IgA vs IgG, low

uninvolved immunoglobulins, sheets of plasma cells on

bone marrow biopsy, presence of urinary light chains

• after five years, risk reverts to MGUS risk

• Clinical trials underway to see if early intervention will

prevent most patients from progressing to myeloma

Plasmacytoma-isolated collection of myeloma cells

Isolated plasmacytomas- about 5%

Soft tissue based-sometimes isolated; often cured

with radiation therapy

Bone based-typically progress to myeloma in

several years

Solitary Plasmacytoma

Solitary plasmacytoma (cont)

Long term prognosis

When should you start treatment for

myeloma?

• Unlike lymphomas, stage of myeloma doesn’t tell you what treatment is appropriate or when it should start

• MGUS should not be treated outside of clinical trial

• Symptomatic from myeloma

• Asymptomatic but with CRAB/IWMG criteria

• Smoldering or otherwise asymptomatic can wait with reasonably close follow up

• Patients with renal failure due to myeloma should be treated promptly

What are the clinical trial “phases”?

Phase I Phase II Phase III

Tests Safety Tests how well

treatment works Compares new

treatment to

standard treatment

Limited treatment for myeloma

In the first half of 20th century-

radiation, pain medication

Traditional cancer drugs only work for the short time a cell

actively replicating DNA in order to divide

Myeloma cells grow slowly and don’t spend much time doing this

Modern Age of Myeloma Therapy:

discovery of thalidomide for myeloma

Sold between 1957-1961 to treat morning

sickness

Banned in 1962 in US due to phocomelia

Interest revived in drug after it was reported to be helpful in leprosy in 1965

Suggested as useful in myeloma due to antiangiogenic properties

Kaplan–Meier Estimates of Overall Survival and Event-free Survival.

Singhal S et al. N Engl J Med 1999;341:1565-1571.

Thalidomide/Dexamethasone vs Dexamethasone in

Newly Diagnosed MM

Phase III ECOG E1A00 Study Design

Thalidomide, 200 mg/d orally

Dexamethasone, 40 mg/d*

Days 1–4, 9–12, and 17–20

(n=103)

Stop therapy at Month 4

for stem cell

transplantation or

continue at physician’s

discretion

Stop therapy

Dexamethasone alone, 40 mg/d*

Days 1–4, 9–12, and 17–20

(n=104)

Newly diagnosed,

untreated

symptomatic MM

(n=207)

CR/PR/

stable

Any

progression

4 cycles

*Administered as a monthly cycle

All patients received monthly pamidronate or zoledronic acid

Rajkumar SV et al. Blood. 2004;104(part 1):63a [abstract 205]

NF-kB inhibition by Velcade (Bortezomib)

Multivariate analysis showed that receiving VRD, age <65 associated with

Better disease control and survival

“VRD is the current Standard of Care

How else do you decide appropriate initial

treatment?

1. Availability of clinical trials

2. Host characteristics (age, Performance

Status, comorbidities)

3. Disease aggressiveness-high risk versus

standard risk cytogenetic

4. Intent to transplant

• High Risk Disease

• (75% of pts have what is termed “standard risk” myeloma

(hyperdiploidy, t(11;14), t(6:14) MS->8 yrs

• 15% have high risk (17p, t(14;16), t(14;20) high risk GEP MS-2-3

yrs; high LDH, “plasma cell leukemia”

• triplet therapy (VRD, carfilzomib RD, VDT, CVRD, possibly VRD

plus additional agent

• Extended or indefinite maintenance

• Or Auto stem cell transplant or allogeneic stem cell transplant

followed by maintenance

CLINICAL TRIAL RESULTS PENDING: SWOG S1211: VRD versus

VRD plus elotuzumab

Other combinations under study for newly diagnosed pts

• S0777 has confirmed value of “triplet” therapy

• Not yet considered STANDARD outside of trial

– Carfilzomib, lenalidomide, dex

– Daratumumab, lenalidomide, dex

– Daratumumab, bortezomib, dex

– Daratumumab, lenalidomide, bortezomib, dex

– Elotuzumab, lenalidomide, dexamethasone

– Carfilzomib, daratumumab, lenalidomide, dex

• Special considerations:

• Some patients may be too frail for

intensive therapy, frequent clinic or

hospital visits.

• First trial: continuous lenalidomide and

dex based on results of FIRST trial; low

dose VRD or CyBorD possible as well

Lenalidomide and Dex may be very appropriate for some

patients

High Dose Therapy for Myeloma

Lancet 322: 822, 1983

Autologous transplant improves disease control and survival

Attal M et al. NEJM N Engl J Med 1996; 335:91-97

Maintenance Therapy

CALGB 100104:

Post transplant,

Randomization to

Lenalidomide or

Placebo

Treatment given

indefinitely

Holstein S et al In press

3 of 17 identified studies fulfilled criteria[1]

Lenalidomide maintenance intended to be given until progression

– IFM elected to discontinue lenalidomide in 2010 due to second primary malignancy signal, whereas the NCI and GIMEMA chose to continue until progression

Lenalidomide Maintenance After ASCT in

MM: Meta-analysis Studies

Study Treatment Arms Pts, n

CALGB 100104[2] Lenalidomide maintenance

Placebo

231

229

IFM 2005-02[3] Lenalidomide maintenance

Placebo

307

307

GIMEMA[4]

(RV-MM-PI-209)

Lenalidomide maintenance

No maintenance

67

68

1. Attal M, et al. ASCO 2016. Abstract 8001. 2. McCarthy PL, et al. N Engl J

Med. 2012;366:1770-1781. 3. Attal M, et al. N Engl J Med. 2012;366:1782-

1791. 4. Palumbo A , et al. N Engl J Med. 2014;371:895-905. Slide credit: clinicaloptions.com

Lenalidomide Maintenance After ASCT in

MM: Pooled Patient Characteristics

Characteristic Lenalidomide

(n = 605)

Control

(n = 604)

Median age, yrs 58 58

60 yrs of age or older, % 39 38

ISS stage at diagnosis, %

I

II

III

37

31

19

45

28

15

CR/VGPR after ASCT, % 53 56

Prior lenalidomide induction, % 24 24

Adverse risk cytogenetics,* % 15 10

Attal M, et al. ASCO 2016. Abstract 8001.

*t(4;14) or del(17p); from IFM and GIMEMA studies only.

Slide credit: clinicaloptions.com

Lenalidomide Maintenance After ASCT in

MM: Overall Survival

Lenalidomide maintenance significantly improved survival after ASCT from pooled data analysis

– 7-yr OS: 62% vs 50% in the control arm

– Median OS: not estimable* vs 86.0 mos in control arm (median follow-up: 80 mos)

– Overall HR: 0.74 (95% CI: 0.62-0.89; P = .001)

All studies showed lenalidomide benefit, but results were heterogeneous (P = .047)

– CALGB HR: 0.56 (95% CI: 0.42-0.76)

– IFM HR: 0.91 (95% CI: 0.72-1.15)

– GIMEMA HR: 0.66 (95% CI: 0.34-1.26)

Attal M, et al. ASCO 2016. Abstract 8001. Slide credit: clinicaloptions.com

*Median OS for lenalidomide arm extrapolated to be 116 mos based on median of control arm and HR of 0.74.

Summary of frontline therapy.

Philippe Moreau et al. Blood 2015;125:3076-3084

©2015 by American Society of Hematology

Dr. Hari will discuss

Treatments for relapsed disease

SURVIVAL HAS NEVERY BEEN LONGER

Kenneth C. Anderson Clin Cancer Res 2016;22:5419-5427

©2016 by American Association for Cancer Research

Bisphosphonates

Developed in mid 1990s for bone strengthening properties and treatment of hypercalcemia

1996- (Berenson, NEJM) randomized trial of pamidronate vs. placebo in patients with MM for 2 yrs.->40% reduction in skeletal events, pain

Zoledronate, pamidronate used more than alendronate

Higher bioavailability

Less GI toxicity

Same pt after rx, transplant,

Bisphosphonates, 18 mo later

KEY TO BONE HEALTH:

CONTROL MYELOMA!

Study Design

Presented By Noopur Raje at 2017 ASCO Annual Meeting

Results: Exploratory Endpoint

Presented By Noopur Raje at 2017 ASCO Annual Meeting

Only small phase 2 studies of denosumab in relapsed myeloma; no effect on disease progression

(Vij et al Am J Hematol 2009 84:650)

Exercise

• May reduce “inflammation”

• Helps pain, depression

CLINICAL TRIALS UNDERWAY NOW:

THESE ARE THE KEY TO IMPROVING SURVIVAL

• S1211- “high risk” MM

pts will do better with

four drugs (including

an antibody drug)

rather than the three

best drugs

• E1A11-is carfilzomib

better than

bortezomib? Length

of maintenance

• CTN1401- making a

“personalized”

vaccine to give to a

MM pt after a

transplant will help

them repel myeloma,

much like a vaccine

does for shingles, etc.

Conclusions

• Myeloma is a devastating disease

• However, MM patients living longer than ever before; this

is due largely to clinical trials and new drugs that have

incrementally improved survival

• Increasing number of choices for initial treatment

• COST WILL BE HUGE ISSUE NOW AND IN THE

FUTURE—CLINICAL TRIALS CAN SHOW US THE WAY!!!!