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Myeloma update Sobell House

November 2019

Topic

• Myeloma diagnosis & risk stratification

• Bone and Renal issues

• Treatment outcomes Newly diagnosed MM

• Treatment outcomes relapsed MM

• Double refractory MM

• QoL

• Living with myeloma

• Smouldering myeloma/precursor conditions

• Improving outcomes……………………………

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Themes

• Impact of disease-physical/emotional/economic.

• Interventions and outcomes-when to intervene/when not to.

• measuring outcomes…OS/PFS/MRD?

• Survival vs living well.

• Cure?

What is myeloma?

• Incurable plasma cell malignancy

• 2% of all cancers in the UK

• Average age at diagnosis 69 years

• Has a premalignant and early asymptomatic stage

• Remitting relapsing course

• Affects multiple body systems – bone, renal, immunity, bone marrow function

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Myeloma Incidence

• Myeloma is the 19th most common cancer in the UK, accounting for 2% of all new cancer cases (2016).

• In females in the UK it is the 18th most common cancer (1% of all new female cancer cases). In males in the UK, myeloma is the 16th most common cancer (2% of all new male cancer cases).

• 43% of myeloma cases in the UK are in females, and 57% are in males.

Incidence according to age

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Incidence according to age groups over time

Myeloma (C90): 1971-2011 Age-Standardised Five-Year Net Survival, England and Wales

Please include the citation provided in our Frequently Asked Questions when reproducing this chart: http://info.cancerresearchuk.org/cancerstats/faqs/#How Prepared by Cancer Research UK Original data sources: Survival estimates were provided on request by the Cancer Research UK Cancer Survival Group at the London School of Hygiene and Tropical Medicine. http://www.lshtm.ac.uk/eph/ncde/cancersurvival/http://www.lshtm.ac.uk/eph/ncde/cancersurvival/

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Clinical presentation

• Bone disease

• Anaemia

• Impaired kidney function

• Hypercalcaemia

• Recurrent/persistent infections

• Incidental finding?.....

At presentation

• 15% patients have no symptoms

• 38% emergency presentation - Kidney failure

- Spinal cord compression/loss of movement

- Fracture

- High calcium

• Remainder have symptoms, commonly - Backache or bone pain

- Tiredness / anaemia / increased infections

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The normal bone marrow

Plasma Cells in health-protein producing factory

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Ag

Pre-B cell

Naive B cell

Follicular B blast

Centroblast

Centrocyte

Marginal Zone

Memory B-cells

Plasma cell

Extrafollicular B-Immunoblast

Interfollicular area

Immature B-cell

Progenitor B-cell

What are plasma cells?

Follicular area

FDC

Ag

Lymph Node

Germinal Centre

SHM +

class switching

Germs

IgM IgG IgA

B-cell affinity maturation

Normally up to 3% in BM Also present in respiratory and GI tissues

Malignant transformation

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Diagnosing Disease

Too many proteins

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What is an M-protein? SPEP

Polyclonal

smear

M-spike

Normal antibody repertoire

Myeloma antibodies

Serum protein electrophoresis

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Immunofixation

1 normal 2 high level IgG + monoclonal free light chains + immune paresis (pt with MM and renal failure) 3 low level IgA M-protein 4 moderate IgM M-protein

Freelite - serum free light chain immunoassay

Exposed surface Lambda

Kappa

Hidden surface

Light chain

Heavy chain

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FLC (mg/L)

F

LC (

mg

/L)

Blood.2001: 97: 2900-02

Immunoglobulin FLC levels in myeloma

Immunohistochemistry CD138 staining of marrow or biopsy and light chain restriction

CD138

Kappa LC

Images provided by Sue Brown Senior BMS , Royal Berkshire Hospital, UK

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Myeloma(‘pepper(pot(skull’(

i. ii. iii. iv. v.

vi. vii. viii. ix.

Devastating consequences of myeloma bone disease

A 60 year old male with Durie-Salmon IIIA, presenting a multi-focal MRI pattern on saggital T2 sequence with mildly increased signal intensity of FL throughout the vertebral column (A), more intense STIR signal (B). Corresponding PET/CT image shows a high degree of FDG avidity with a multi-focal uptake pattern (C).

Mesguich C, et al. State of the art imaging of multiple myeloma: Comparative review of FDG PET/CT imaging in various clinical settings. Eur J Radiol (2014),

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Increased sensitivity over skeletal survey in detecting lytic lesions.

Finding on WBLDCT not identified on SS. a. Conventional lateral radiograph of the thoracic spine – no focal lytic lesion identifiable. b. WBLDCT sagittal view of the spine showing a focal lytic lesion eroding through the cortex of the anterior wall of the spinal canal at T10 c. WBLDCT axial image showing extension into the canal at high risk of cord compression. The patient was referred for emergency radiotherapy. (Gleeson, T.G. et al 2009 ‘Accuracy of whole-body low-dose multidetector CT (WBLDCT) versus skeletal survey in the detection of myelomatous lesions and correlation of disease with whole body MRI (WBMRI)’

Whole body computerised tomography (WBCT)

Renal complications

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Myeloma Renal Disease

• “Myeloma kidney” • Normal glomerular function

• Concentrated light chains precipitate in tubules

• Monoclonal light chains seen in UPEP with immunofixation

• Glomerular lesions

• Deposits of amyloid or light chain deposition disease

• Nonselective leakage of all serum proteins

• UPEP preponderance of albumin

Cast nephropathy

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Renal Manifestations

Amyloidosis

Light chain Deposition

Pierre Ronco JNEPHROL 2000; 13 (suppl. 3):

Myeloma Kidney Cast Formation

‘Umbrella’ term

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P. Leif Bergsagel et al. Blood 2013;121:884-892

©2013 by American Society of Hematology

15 15

5 10

35

10

40

0

10

20

30

40

50

t(11;14) t(4;14) t(14;16) 17p- 1q+ 1p- 13q-

%

CYTOGENETIC ABNORMALITY

FREQUENCY OF CYTOGENETIC ABNORMALITIES IN MYELOMA AT DIAGNOSIS

Cytogenetic Abnormalities In Myeloma

5 recurrent chromosomal translocations – lead to over expression of an

oncogene

Genomic imbalances – alteration in the number of copies of

chromosomes, or parts of chromosomes (short arm = p arm,

long arm = q arm)

Other Plasma Cell Diagnoses

• MGUS

• Smouldering Myeloma

• IgM Waldenstrom’s Macroglogulinaemia

• AL amyloidosis

• POEMS

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Intact immunoglobulin

Light chain Nonsecretory

AL amyloidosis

MGUS SMM

Multiple myeloma

Monoclonal gammopathies

80% 15 – 20% 1 – 2%

Myeloma vs MGUS vs Smouldering Myeloma

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Diagnosis

CRAB HyperCalcaemia Renal

insufficiency

Anaemia Bone

pain/fractures/osteoporosis

When to Suspect Myeloma?

Unexplained, one or multiple of:

Request a Myeloma Screen (Freelite + SPE)

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Time to MM diagnosis is prolonged

0

30

60

90

120

150

180

Acute myeloidleukemia

Diffuse large B-celllymphoma

Myeloma

Median Time (days)

Adapted from Howell BMC Hematol 2013;13:9

Haematological Malignancy Research Network (2004 to 2011)

Shortest 84

Howell BMC Hematol 2013;13:9

0 300 100 200

Median 163

Longest 306

Time to MM diagnosis is prolonged

Time (days)

Median of 3 or more appointments required for a MM

diagnosis

Lyratzopoulos Lancet 2012;13:353-65

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0 300 100 200

Time (days)

Lyratzopoulos Lancet 2012;13:353-65

SPE No

urine/urine insensitive

Biopsy

63% with co-morbidities 100% with co-morbidities

Kariyawasan Q J Med 2007;100:635-40 Howell BMC Hematol 2013;13:9

Increasing time to diagnosis = increasing comorbidity development (eg renal impairment)

Median of 3 or more appointments required for a MM

diagnosis

Miss – symptoms not spotted MM Diagnosis Miss – lab investigation negative/incomplete

T=0

SPE = -ve No urine

Development of Comorbidities

SPE = -ve FLC = +ve

Biopsy

Tumour Burden Disease Stage Co-morbidities

Due to delay in seeking help

Due to delay in seeking lab investigation

Due to lab investigation

negative/incomplete

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Delays in Diagnosis

When to Suspect Myeloma?

Myeloma Warning Signs/Symptoms Back Pain

(1st Episode)

Back Pain (2nd

Episode)

Rib Pain Other Bone Pain

Joint Pain Chest Pain

Nose-bleeds

Shortness of Breath

Weight Loss

Nausea Chest Infection

Fracture

As a single symptom

Back pain

HyperCa

Raised Creatinine

Raised MCV

Raised Inflammatory

Markers

Low Platelets

Low Hb

Leukopenia

Suspected Myeloma?: Request SPE+sFLC → Either or both abnormal → Possible Myeloma → Refer to Haematologist → Both normal → Myeloma Unlikely

Positive Predictive Value

for Myeloma

Not Calculated <1% 1-2% 2-3% 3-4%* 4% and above*

Colour key

* NICE recommends all warning signs/symptom (combinations) with a positive predictive value (PPV) >3% should be investigated, those <3% should at least be considered for investigation.

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Too little, too late…..

How many doctors

• Not being heard….

• Multiple presentations

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Psychological impact

• Depression

• Social interaction

Economic impact

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QoL

Assessment of a myeloma patient

• Confirmation of multiple myeloma

• Assessing co morbidities

• Bone disease?

• Renal Impairment?

• Neuropathy?

• Performance status?

• What does the patient want ?

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Natural History

Achieving and Maintaining Disease Control

Symptomatic myeloma

Asymptomatic

1

10

100

Refractory relapse

MGUS or smouldering

myeloma Plateau

remission

Symptomatic

Relapse

M p

rote

in (

g/d

L)

Time

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Treatment

When does treatment start?

• Many patients do not start treatment as soon as they are diagnosed

• No evidence that treating asymptomatic disease will increase survival

• Symptoms or evidence of progression

• Joint decision by doctor and patient

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Aims of treatment

Anti-myeloma treatment

Improve quality of

life and survival

Prevent and treat bone and

tissue damage

Salvage kidney

function

Approach to Treatment of Myeloma

Nontransplant Candidate (based on age, performance status,

and comorbidities)

Induction treatment

Transplant Candidate

Induction treatment (4-6 cycles)

Stem cell harvest

Stem cell transplantation

Relapsed disease – salvage treatment

Monitor disease

Monitor disease

Relapsed disease – salvage treatment

Further relapse – salvage treatment

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Remission – current practice • No treatment, most drugs stopped

• Maintenance treatment – not standard

• Bisphosphonates for at least 2 years

• Minimal effective pain management

20

50

100

1st REMISSION

When do you treat at relapse?

Options

1. Wait till u have a level of paraprotein or light chain load (presentation level)

2. Wait till onset of CRAB

3. At first onset of biochemical relapse

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Aims of treatment at relapse

• Prevent CRAB

• Achieve response

• A response which translates into improved overall survival

• A response that you can maintain?

• Treatment choice that is well tolerated - QoL

Geriatric assessment of MM patients

Blood. 2015 Mar 26;125(13):2068-74

Survival stats for 3 yrs

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Assess fraility

Fit Unfit Frail

Full

go

Slow

go

Very

slow go

2 or 3 drug

regimen

reduce dose

2 (3) drug

regimen

further dose

reduction

MP, CTX-P

VD, Ld

Treatment of patients with multiple myeloma not eligible for transplantation

An approach to treatment

1st Line 2nd Line 3rd Line 4th LineSubsequent

line

Subsequent relapse

3rd Relapse2nd Relapse1st RelapsePresentation

1st Line 2nd Line 3rd Line 4th LineSubsequent

line

Thalidomide Velcade RevlimidClinical

Trials

Clinical

Trials

Clinical

Trials

Disease assessments

“Treatment Palette”

Typical UK approach to treatment

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Immunomodulatory Management

IMiD Structures

Potency Side effects Potency

Renal excretion 80% Renal excretion 20%

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0

10

20

30

40

50

60

70

80

90

100

VAD TD RD PAD VTD RVD CVRD CyBorD CarRD*

Pe

rce

nt

Res

po

nse

Induction Regimen

ORR

VGPR

CR/nCR

Improved Response rates - Its the combinations…..

It’s not just the combinations its also the duration – even in elderly

0

10

20

30

40

50

60

70

80

90

MP TD CTD MPR MPT Rd MPR-R MPV MPVT-VT MPV-VT

PFS

3 Year OS

Mo

nth

s

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RA

ND

OM

ISA

TIO

N 1

:1:1

Arm B

Ld18

Arm C

MPT

LEN + LoDEX: 18 Cycles (72 wks) LENALIDOMIDE 25 mg D1-21/28

LoDEX 40 mg D1,8,15, & 22/28

MEL + PRED + THAL 12 Cycles (72 wks) MELPHALAN 0.25 mg/kg D1-4/42

PREDNISONE 2 mg/kg D1-4/42

THALIDOMIDE 200 mg D1-42/42

PD

, O

S, an

d

Su

bs

eq

ue

nt

an

ti-M

M T

x

PD

or

Un

accep

tab

le T

ox

icit

y

Active Treatment + PFS Follow-up Phase Screening LT Follow-Up

Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL (100 mg D1-42/42); MEL 0.2 mg/kg D1–4

• Stratification: age (≤ 75 y vs. > 75 y), country, and ISS stage (I or II vs. III)

• Thromboprophylaxis was mandatory

FIRST Trial: Study Design

LEN + LoDEX: Continuously LENALIDOMIDE 25 mg D1-21/28

LoDEX 40 mg D1,8,15, & 22/28

Arm A

Continuous Ld

FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; ISS, International Staging

System; Ld, lenalidomide plus low-dose dexamethasone; Ld18, lenalidomide plus low-dose dexamethasone for 18 cycles;

LEN, lenalidomide; LoDEX, low-dose dexamethasone; LT, long-term; MEL, melphalan; MM, multiple myeloma; MPT,

melphalan, prednisone, thalidomide; OS, overall survival; PD, progressive disease; PFS, progression-free survival; Pred,

prednisone; pt, patient; THAL, thalidomide; Tx, treatment. Benboubker L, et al. NEJM. 2014;371:906-17

Median PFS

Ld (n=535) 25.5 mos

Ld18 (n=541) 20.7 mos

MPT (n=547) 21.2 mos

Ld 535 400 319 265 218 168 105 55 19 2 0

Ld18 541 391 319 265 167 108 56 30 7 2 0

MPT 547 380 304 244 170 116 58 28 6 1 0

Hazard ratio

Ld vs. MPT: 0.72 (CI: 0.61-0.85); P < 0.001

Ld vs. Ld18: 0.70 (CI: 0.60-0.82) ; P < 0.001

Ld18 vs. MPT: 1.03 (CI: 0.89-1.20); P = 0.70

Time (months)

Pati

en

ts (

%)

100

80

60

40

20

0 0 6 12 18 24 30 36 42 48 54 60

FIRST Trial: Final Progression-free Survival

23% (Ld18)

23% (MPT)

42% (Ld)

CI, confidence interval; mos, months; FIRST, Frontline Investigation of Revlimid and Dexamethasone

versus Standard Thalidomide; Ld, lenalidomide plus low-dose dexamethasone; Ld18, lenalidomide plus

low-dose dexamethasone for 18 cycles; MPT, melphalan, prednisolone, thalidomide; mos, months; PFS,

progression-free survival; wks, weeks

Benboubker L, et al. NEJM. 2014;371:906-17

Facon T, et al: EHA 2014; Oral Presentation and Abstract S643

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FIRST Trial: Overall Survival Interim Analysis

574 deaths (35% of ITT)

FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; Ld, lenalidomide plus low-dose dexamethasone; Ld18, lenalidomide plus low-dose dexamethasone for 18 cycles; MPT, melphalan, prednisone, thalidomide; OS, overall survival

Pa

tie

nts

(%

)

Ld

Ld18

MPT

535

541

547

488

505

484

457

465

448

433

425

418

403

393

375

338

324

312

224

209

205

121

124

106

43

44

30

5

6

3

0

0

0

4-year OS

Ld (n= 535) 59%

Ld18 (n= 541) 56%

MPT (n= 547) 51%

Overall survival (months)

100

80

60

40

20

0 0 6 12 18 24 30 36 42 48 54 60

Hazard ratio

Ld vs. MPT: 0.78 (CI: 0.64-0.96); P = 0.02

Ld vs. Ld18: 0.90; P = 0.31

Ld18 vs. MPT: 0.88; P = 0.18

Benboubker L, et al. NEJM. 2014;371:906-17

Monoclonal antibodies in Myeloma

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Daratumumab: Mechanism of Action

• Human CD38 IgGκ monoclonal antibody

• Direct and indirect anti-myeloma activity1-5

• Depletes CD38+ immunosuppressive regulatory cells5

• Promotes T-cell expansion and activation5

1. Lammerts van Bueren J, et al. Blood. 2014;124:Abstract 3474.

2. Jansen JMH, et al. Blood. 2012;120:Abstract 2974.

3. de Weers M, et al. J Immunol. 2011;186:1840-8.

4. Overdijk MB, et al. MAbs. 2015;7:311-21.

5. Krejcik J, et al. Blood. 2016. Epub ahead of print. 72

Progression-free Survival

73

Pro

port

ion s

urv

ivin

g w

ithout p

rog

ressio

n

0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21

283

286

249

266

206

248

179

232

139

189

36

55

5

8

0

0

Rd

DRd

No. at risk Months

73

Rd

DRd

63% reduction in the risk of disease progression or death for DRd vs Rd

12-month PFS*

*KM estimate; HR, hazard ratio.

83%

60%

18-month PFS*

78%

52%

HR: 0.37 (95% CI, 0.27-0.52; P <0.0001)

Median PFS: 18.4 months

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CAR-T

Crossroads

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Continuous treatment

Consolidation/maintenance

Remission induction Initial treatment to kill myeloma cells

Consolidation

Short period of treatment aimed at maximising response from

previous treatment

Maintenance

Longer term treatment aimed at

long term disease control

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Patient journey and the value of extended remission

Hulin C, et al. Leukaemia Research 2016. Manuscript under review.

Hulin C, et al. EHA 2014:abstract P635. Poster presentation.

Emotional journey. Illustration from a UK patient diagnosed with MM 9 years ago,

who had experienced 2 relapses (according to physician records). Note: this

diagram was re-drawn by the interviewer during the discussion. Illustration

reproduced using computer software.

Effects of relapsed disease on the patient

Hulin C, et al. Leukaemia Research 2016. Manuscript under review.

Hulin C, et al. EHA 2014:abstract P635. Poster presentation.

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Patient perceptions at relapse

Patients were asked to indicate the extent of change, if any, since the most recent time

they felt their disease was stable, until their latest relapse/disease progression, based on

a 7-point scale where 1 = very much improved and 7 = very much worse. Mean score

does not include respondents who selected ‘not applicable’ or ‘don’t know’.

Hulin C, et al. Leukaemia Research 2016.

Manuscript under review.

Effect of relapse on the haematologist

Hulin C, et al. Leukaemia Research 2016. Manuscript under review.

Hansen T, et al. EHA 2014:abstract P633. Poster presentation.

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QoL instruments

CIPN, chemotherapy-induced peripheral neuropathy; FACT-G, FACT-General; MID, minimally

important difference; QoL, quality of life. Sonneveld P, et al Leukemia. 2013;27:1959-69.

Instrument Description Validation

QLQ-C30 30-item, self-administered HRQoL patient

questionnaire

Designed for use in cancer patients

QLQ-MY24

and

QLQ-MY20

QLQ-MY24 was developed as an addition to

QLQ-C30 for specific use in MM. The QLQ-MY24

was refined to 20 items (QLQ-MY20)

The psychometrics, including reliability and validity

of QLQ-MY20, in MM have been published

QLQ-CIPN20 20-item QLQ-CIPN20 instrument for patient-

reported CIPN

The reliability, validity and responsiveness of this

instrument is currently being investigated in a wide

range of oncology patient populations

FACT-Multiple

Myeloma

14-item disease-specific FACT-MM HRQoL

measure

Acceptable psychometric properties

FACIT-

Fatigue

Bolt-on module to the base FACT-G HRQoL

questionnaire; a 27-item instrument measuring

well being (Physical, Social/Family, Emotional

and Functional), with a recall period of 1 week

No reliability, validity or other psychometric

properties specific to MM have been described

FACT-NTx Another FACT-G bolt-on module with additional

neurotoxicity parameters

Good psychometric properties in women with ovarian

cancer; however, it has only been used in a limited

number of MM studies, similarly to FACIT-Fatigue

EQ-5D Standardised generic HRQoL questionnaire that

can be converted into a ‘health utility’ score

questionnaire used to measure health outcomes

The MID reported in MM patients

What concerns patients most?

• Is this chemotherapy?

• How is it given and what are the side effects?

• What are my chances on this?

• How long is the treatment given?

• Can I continue to do things as normal at home?

• Do I get admitted, how frequently do I have to come to hospital?

• When will you know that I am getting better?

• Am I getting better?

• Can I travel/work during treatment?

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Individualised treatment approach

• Listen to patient/patient preference

• Discuss treatment goals e.g. symptom relief, going on holiday, getting back to work

• Explain how side effects can be minimised

• Offer flexibility in appointments

• Communicate MM treatment updates

• Perform holistic needs assessment

• Be open to using web-based tools so that patient can take control

Long-term therapy requires considerable support

Agree clear treatment goals with patients and review

at appropriate intervals; keep your patient well informed.

Build a team

around the patients, e.g. nurse specialist,

pain team, psychologist

Ensure QoL is taken into account

Manage side effects expectantly and

encourage discussion with support group

Successful long-term treatment

delivery

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Cure?

Myeloma is clonally heterogenous

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Clonal tides….

Slide Courtesy of Dr Rafael Fonseca

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Treating Myeloma earlier?

• Treating smouldering/asymptomatic myeloma

• Targeting MGUS?

• Treating well patients with toxic treatments……

• Delaying progression vs toxicities

• Measurement of QoL imperative.

• No outcomes to change practice yet.

Themes

• Impact of disease-physical/emotional/economic.

• Survival vs living well.

• Interventions and outcomes-when to intervene/when not to/measuring outcomes…

• Cure?

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Thank you.

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Future

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Stem Cell Transplant

Coping with treament

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Future Treatments

New drugs on the way?....

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BCMA/BiTE

Improved Survival

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Toxicities/Patient Related Outcomes

Quality of Life?