MM: interpreting cytogenetic results for clinical practice

Dr Sally MooreConsultant Haematologist

Royal United Hospital, BathChurchill Hospital, Oxford

This medical education meeting was organised and funded by Janssen-Cilag Ltd. EM-12168 | May 2019

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Disclosures – Dr Sally Moore

Learning objectives

• To understand what CAs are and how they may affect prognosis

• To explore treatment decisions regarding CAs through the use of patient case studies

• To explore factors that might affect future considerations regarding CAs in multiple myeloma

CA: cytogenetic abnormalities

Disease profiling

Landgren O, Morgan GJ. Clin Cancer Res. 2014; 20:804–13.FISH: fluorescence in situ hybridisation;

MGUS: monoclonal gammopathy of undetermined significance; miRNA: micro ribonucleic acid.

Frequency of CAs

Sonneveld P, et al. Blood. 2016; 127:2955–62.

Primary and secondary genetics events that can be identified by FISH

Ig: immunoglobulin; NA: not applicable.

Clinical impact – IgH translocations

• t(4;14) = ↓ PFS/OS1

Bortezomib improves survival vs vincristine2

↑ OS with HDT and tandem ASCT3

• t(14;16) and t(14;20) = predictors of poor outcome4

• t(11;14) associated with CD20 expression and LPL morphology. Reported as favourable in some studies, no impact in others5,6

• In general, t(6;14), t(11;14), gain(5q) and hyperdiploidy do not confer poor prognosis

1. Gertz MA, et al. Blood. 2005; 106:2837–40; 2. Sonneveld P, et al. J Clin Oncol. 2012; 30:2946–55; 3. Moreau P, et al. Leukemia. 2007; 21:2020–4; 4. Boyd KD, et al. Leukemia. 2012; 26:349–55; 5. Fonseca R, et al. Blood. 2002; 99:3735–41; 6. Avet-Loiseau H, et al. Blood. 2007; 109:3489–95.

ASCT: autologous stem cell transplantation;HDT: high-dose therapy; LPL: lymphoplasmacytic lymphoma;

OS: overall survival; PFS: progression-free survival.

Clinical impact – genomic imbalance

General• Due to selection of subclonal disease, the prognostic impact of CA may vary from diagnosis to refractory disease1

Diploidy• Hyperdiploidy (50% of NDMM) = ↑ PFS/OS2. Co-existing hyperdiploidy may not abrogate poor prognosis of adverse CA3

• Hypoploidy is regarded as a poor prognostic CA4

• t(4;14) PFS and OS can be negatively affected by hypodiploidy4

Deletions• Adverse impact of del(13q) is associated with del(17p) and t(4;14). Del(13q) alone does not confer poor survival1,5

• Del(17p) or del(17) has a negative impact on PFS/OS. DelTP53 induces clonal immortalisation and survival of tumour cells6

• What minimum % del(17p) cells = adverse prognosis? Minimums of 20% and 60% have been suggested4,5

• In solitary plasmacytoma or extramedullary disease, del(17p) may occur more frequently7

Gains• >3 copies of 1q = worse outcome (dosage effect)5

• Gain(1q) often associated with del(1p32), which confers poor prognosis8

NDMM: newly diagnosed multiple myeloma.

1. Walker BA, et al. J Clin Oncol. 2015; 33:3911–20; 2. Neben, et al. Haematologica. 2010; 95:1150–7; 3. Pawlyn C, et al. Blood. 2015; 125:831–40; 4. Hebraud, et al. Blood. 2015; 125:2095–100; 5. Boyd KD, et al. Leukemia. 2012; 26:349–55; 6. Teoh PJ, et al. Leukemia. 2014; 28:2066–74; 7. Billecke, et al. Br J Haematol. 2013; 161:87–94; 8. Hebraud B, et al. Leukemia. 2014; 28:675–9.

Clinical impact – multiple abnormalities

• Adverse IgH translocation: 62% have gain(1q) compared with 32.4% in controls1

• Del(17p) frequency is similar in patients without adverse IgH translocations1

• Triple combination of an adverse IgH translocation, gain(1q) and del(17p) had OS of 9.1 months, demonstrating impact of multiple adverse CAs on OS1

• In 110 patients with either t(4;14) or del(17p), 25 had both abnormalities2

• t(4;14): ↓ PFS seen in del(1p32), del(22q), and/or structural changes

↓ OS seen in del(13q14), del(1p32) and higher number of CAs2

• del(17p): ↓ PFS seen in del(6q)

↓ OS seen in del(1p32)2

1. Boyd KD, et al. Leukemia. 2012; 26:349–55; 2. Hebraud B, et al. Blood. 2015; 125:2095–100.

Clinical impact – good and adverse

• Hyperdiploidy: gain5(q31), trisomies 3 and 5 confer a favourable prognosis1,2

• In the Myeloma IX study, 58% had hyperdiploidy. Of these, 61% had ≥1 adverse lesion [t(4;14), t(14;16), t(14;20), gain1q or del(17p)]3

• PFS and OS were shorter in those with hyperdiploidy plus adverse lesion vshyperdiploidy alone (PFS: 23 vs 15.4 months; OS: 60.9 vs 35.7 months)3

• Alternatively, presence of hyperdiploidy did not change the outcome in patients with an adverse lesion3

• Trisomies in patients with t(4;14), t(14;16), t(14;20) or delTP53 reduced their adverse impact4

1. Hebraud B, et al. Blood. 2015; 125:2095–100; 2. Avet-Loiseau H, et al. J Clin Oncol. 2009; 27:4585–90;3. Morgan, et al. Blood. 2012; 119:7–15; 4. Kumar S, et al. Blood. 2012; 119:2100–5.

FISH – what is high risk?

• IMWG 2009 – at least one of: del(17p), t(4;14), t(14;16)1

• IMWG 20162 –

• Mayo Clinic – as above including hypodiploidy and t(14;20)3

• MRC IX – adverse lesions include t(4;14), t(14;16), gain(1q), del(13q) and del(17p)

• FR: absence of genetic lesion

• IR: one adverse CA

• HR: >1 adverse CA

• UHR: ≥3 adverse CAs4

1. Fonseca, et al. Leukemia. 2009; 23:2210–21; 2. Sonneveld P, et al. Blood. 2016; 127:2955–62;3. Stewart, et al. Leukemia. 2007; 21:529–34; 4. Boyd KD, et al. Leukemia. 2012; 26:349–55.

FR: favourable risk; GEP: gene expression profiling; HR: high-risk;IMWG: International Myeloma Working Group; IR: intermediate risk;

MRC: Medical Research Council; UHR: ultra high risk.

FISH cut-off

• IFM1

Percentage of plasma cells with adverse FISH correlates with outcome:

Del(13q) – cut-off 74% OS rate at 41 months 59% vs 80%

Del(17p) – cut-off 60% OS rate at 22.4 months 50% vs 75%

• IMWG R-ISS:2

FISH analyses were performed in a few European laboratories. Despite interlaboratory variability, the analyses of p53 deletion, t(4;14), and t(14;16) were commonly included in each multiple myeloma panel and tested using commercial probes. Of note, however, the cut-off levels were not identical, ranging from 8% to 20% for numerical aberrations and from 10% to 15% for immunoglobulin H translocations

Patients were considered positive for a given CA when it was present in a percentage higher than the cut-off threshold, defined by each local laboratory2

• Eurozone: Spanish 20%, French 60%, UK – number of abnormalities

1. Avet-Loiseau H, et al. Blood. 2007; 109:3489–95; 2. Palumbo A, et al. J Clin Oncol. 2015; 33:2863–9.IFM: Intergroupe Francophone du Myélome; R-ISS: Revised International Staging System.

Double-hit myeloma

Walker BA, et al. Leukemia. 2019;33:159–70. ISS: International Staging System.

• N=1,273, whole genome and exome data

• HR = ISS III with either bi-allelic TP53 inactivation or ≥4 copies of 1q (6.1% of patients)

100

80

60

40

20

0

0 12 24 36 48 60

OS

(%)

100

80

60

40

20

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0 12 24 36 48 60

Months

PFS

(%

)

Log-rank p-value <0.0001

MonthsDeaths / N 18-month estimate

IMWG: low/standard risk, RP-Risk: Low Risk 21 / 357 96% (94, 98)

IMWG: low/standard risk, RP-Risk: Intermediate Risk 59 / 296 85% (81, 90)

IMWG: low/standard risk, RP-Risk: Double Hit 10 / 24 73% (53, 93)

IMWG: high risk, RP-Risk: Low Risk 6 /30 88% (74, 100)

IMWG: high risk, RP-Risk: Intermediate Risk 6 / 53 94% (86, 100)

IMWG: high risk, RP-Risk: Double Hit 16 / 24 37% (16, 58)

Log-rank p-value <0.0001

Events / N 18-month estimate

IMWG: low/standard risk, RP-Risk: Low Risk 65 / 357 87% (84, 91)

IMWG: low/standard risk, RP-Risk: Intermediate Risk 126 / 296 67% (62, 73)

IMWG: low/standard risk, RP-Risk: Double Hit 15 / 24 44% (23, 65)

IMWG: high risk, RP-Risk: Low Risk 10 /30 69% (51, 88)

IMWG: high risk, RP-Risk: Intermediate Risk 21 / 53 74% (61, 87)

IMWG: high risk, RP-Risk: Double Hit 18 / 24 35% (15, 54)

IMWG Guidelines 2016• Consensus updates: abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20),

non-hyperdiploidy and gain(1q) confer poor prognosis. The prognosis of patients showing

these abnormalities may vary with the choice of therapy

• Treatment strategies have shown promise for HR cytogenetic diseases, such as PI +

lenalidomide combination, pomalidomide, double ASCT + PI, or IT with lenalidomide and

pomalidomide

• Bortezomib and carfilzomib appear to improve CR, PFS and OS for t(4;14) and del(17p)

• Lenalidomide may be associated with improved PFS in t(4;14) and del(17p)

• Patients with multiple adverse CAs do not benefit from these agents

• FISH data are implemented in the R-ISS for risk stratification

Sonneveld P, et al. Blood. 2016; 127:2955–62. CR: complete response; IT: immunotherapy; PI: proteasome inhibitor.

R-ISS 2005–2012

n=3,060 of 4,4451

HR: del(17p) and/or t(4;14)1

Data are generated from 3,060 patients from 11 international trials conducted from 2005 to 2012 that were pooled and analysed by the IMWG.1

1. Palumbo A, et al. J Clin Oncol. 2015; 33:2863–9; 2. Dispenzieri A. Hematology Am Soc Hematol Educ Program. 2016; 2016:485–94.

Figure adapted from Dispenzieri 2016.2

LDH: lactate dehydrogenase; Nml: normal; SR: standard risk.

R-ISS

Palumbo A, et al. J Clin Oncol. 2015; 33:2863–9. CI: confidence interval; F: female; HR: hazard ratio; M: male; NR: not reached.

• 69-year-old lady. PMH of well-controlled asthma; family history of breast cancer

• November 2016: numb lip – mandibular plasmacytoma

• PET-CT: extremely extensive disease. Cauda equina at L2–4

• IgG lambda paraprotein 33 g/l, Hb 76 g/l

• BMT November 2016: 100% plasma cells

• FISH: gain(1q), t(14;16)

• R-ISS III, ISS IIIBMT: bone marrow transplant; CT: computed tomography; Hb: haemoglobin;

PET: positron emission tomography; PMH: previous medical history.

Case study 1

1. CTD

2. Bortezomib-based regimen

3. Myeloma XI

4. CARDAMON trial (KCD)

5. Other

CTD: cyclophosphamide, thalidomide, dexamethasone; KCD: carfilzomib, cyclophosphamide, dexamethasone; Tx: treatment.

Which initial induction Tx?

• CTD vs CVAD (up to six cycles) and ASCT

• FISH – 50%

• n=293 adverse CA [t(4;14), t(14;16), t(14;20) gain(1q), del(1p32) del(17p)], n=333 favourable

Morgan GJ, et al. Haematologica. 2012;97:442–50.

PFS = 20 months with adverse interphase FISH vs 34 months with favourable interphase FISH

Transplant-eligible – CTD Myeloma IX

CVAD: cyclophosphamide, vincristine, doxorubicin, dexamethasone.

Transplant-eligible – bortezomib induction

Meta-analysis: n=1,572; four studies

All-comer CR rates 33–55% for bortezomib-based induction vs 20–35% for non-bortezomib-based induction

Sonneveld P, et al. J Clin Oncol. 2013; 31:3279–87.

PFS (intent-to-treat)

Time (years)

PFS OS (%)

All t(4;14) del(17p) All t(4;14) del(17p)

VD1,2

3/4 36/12 28/12 14/12* 81 63 49

VAD1,2 30/12 16/12 NR 77 32 50

VTD3

368% 31% NR 86 NR NR

TD3 56% 63% NR 84 NR NR

*Event-free survival.1. Harousseau JL, et al. J Clin Oncol. 2010; 28:4621–9; 2. Avet-Loiseau H, et al. J Clin Oncol. 2010; 28:4630–4;3. Cavo M, et al. Lancet. 2010; 376:2075–85.

Transplant-eligible – bortezomib induction

NR: not reported; TD: thalidomide, dexamethasone; VAD: vincristine, doxorubicin, dexamethasone;

VD: bortezomib, dexamethasone; VTD: bortezomib, thalidomide, dexamethasone.

Jackson G, et al. Presentation at ASH 2018. Abstract 302 and oral presentation.

Myeloma XI

Bortezomib-based

regimen

No bortezomib-

based regimen

Maximum response

PDSD

MRPR

CRVGPR

R 1:1

R 1:1

R 1:1

• Primary endpoints: PFS and OS for each randomisation

• Median follow-up of 34.5 monthsCRD: cyclophosphamide, lenalidomide, dexamethasone; K: carfilzomib;

MR: minimal response; PD: progressive disease; PR: partial response; R: randomised; SD: stable disease; TE: transplant-eligible; VGPR: very good partial response.

Myeloma XI

Jackson G, et al. Presentation at ASH 2018. Abstract 302 and oral presentation. BM: bone marrow.

Myeloma XI

Jackson G, et al. Presentation at ASH 2018. Abstract 302 and oral presentation.

• SR: absence of any high-risk lesions

• HR: presence of any one of t(4;14), t(14;16), t(14;20), del(17p) or gain(1q)

• UHR: presence of more than one lesion

HR: hazard ratio.

CARDAMON trial• CARDAMON: KCD-ASCT-Kd vs KCD-Kd

• FORTE: n=474

Gay F, et al. Presentation at ASH 2018. Abstract 121 and oral presentation;ClinicalTrials.gov. NCT02315716. Available at: https://clinicaltrials.gov/ct2/show/NCT02315716 [accessed January 2019].

KRd: carfilzomib, lenalidomide, dexamethasone; MRD: minimal residual disease; neg: negative;

sCR: stringent complete response.

Transplant-eligible – ASCT

• RV-MM-EMN-441 (n=127)

• Rd induction – RCD vs ASCT (some tandem) – lenalidomide vs lenalidomide/prednisone

• HR FISH: three-year PFS 43% (ASCT) vs 17% (RCD); three-year OS 78% vs 67%

Dispenzieri A. Hematol Am Soc Hematol Educ Program. 2016; 2016:485–94; Greipp PR, et al. J Clin Oncol. 2005; 23:3412–21; Avet-Loiseau H, et al. Leukemia. 2013; 27:711–7; Palumbo A, et al. J Clin Oncol. 2015; 33:2863–9; Gay F, et al. Lancet Oncol. 2015; 16:1617–29.

RCD: lenalidomide, cyclophosphamide, dexamethasone; Rd: lenalidomide, dexamethasone; R/P: lenalidomide/prednisone.

Tandem ASCT• Pooled analysis of four trials, n=606, 23% of patients with t(4;14)/del(17p)1

• All received bortezomib induction. Single ASCT n=254, tandem=3521

• <CR post-bortezomib induction resulted in longer PFS and higher OS rate with tandem ASCT vs single ASCT1

• PFS: 42 months vs 21 months; OS: 67 months vs 31.5 months1

1. Cavo M, et al. Blood. 2013; 122: Abstract 767; 2. Cavo M, et al. Blood. 2012; 120:9–19.

• GIMEMA MM-BO20052

• VTD or TD induction, tandem ASCT, consolidation. Patients with t(4;14) on bortezomib-based induction had almost identical PFS as SR patients

PFS for patients with HR cytogenetics and who failed CR after bortezomib-based induction regimens

0.75

0.50

0.25

0.00

Months240 12 36 48

HR=0.41, p=0.006

Single ASCT

Double ASCT

1.00

HR=0.41, p=0.006

Single ASCT

Double ASCT

Months240 12 36 48

0.75

0.50

0.25

0.00

OS for patients with HR cytogenetics and who failed CR after bortezomib-based induction regimens1.00

EMN02/HO95

• Three-year PFS:

• Single ASCT 64%, double ASCT 73%; HR 0.7; p=0.04

• ↑ PFS with double ASCT in all groups including:

• High-risk cytogenetic profile [cyto-3; t(4;14), t(14;16), or del(17p)]:

Hazard ratio 0.42 (95% CI 0.21–0.84; p=0.014)

• Highest-risk cytogenetic profile [(cyto-5; amp(1q), del(1p) and t(4;14),

t(14;16) or del(17p)]:

Hazard ratio 0.65 (95% CI 0.42–1.01; p=0.059)

Cavo M, et al. Presentation at ASH 2017. Abstract 401.

What would you do?

Treatment

DXT: radiotherapy; VTD: bortezomib, thalidomide, dexamethasone.

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IMWG recommendations 2016

• Thalidomide does not abrogate the effect of t(4;14), t(14;16), t(14;20), del(17), del(17p) and gain(1q) in transplant-eligible patients

• Bortezomib partly overcomes the effect of t(4;14) and possibly del(17p) on CR, PFS and OS. There is no effect in t(4;14) and del(17p) in transplant-eligible patients

• Lenalidomide partly improves the adverse effect of t(4;14) and del(17p) on PFS, but not OS, in transplant-eligible patients

• Combining a PI with lenalidomide/dexamethasone greatly reduces the adverse effect of t(4;14) and del(17p) on PFS in NDMM. Carfilzomib/lenalidomide seems effective in patients with HR cytogenetics

• ASCT is standard therapy for transplant-eligible patients with NDMM. It contributes to improved outcomes across prognostic groups

• Double HDT/ASCT combined with a PI may improve PFS in t(4;14) or del(17p), or both. HDT plus double ASCT is recommended for patients with HR cytogenetics

• Allogeneic SCT or tandem auto-allo-SCT may improve PFS in t(4;14) or del(17p)

Sonneveld P, et al. Blood. 2016; 127:2955–62.

Maintenance?

1. None

2. Thalidomide

3. Lenalidomide

4. Carfilzomib

5. Ixazomib

6. Other

Maintenance post-ASCT – thalidomide

MRC-IX

Morgan, et al. Blood. 2012; 119:7–15.

Pat

ien

ts (

%)

Pat

ien

ts (

%)

PFS (months) OS (months)

CTDa: cyclophosphamide, thalidomide, dexamethasone attenuated; ITT: intent-to-treat; MP: melphalan, prednisone.

Maintenance post-ASCT – lenalidomide

• Meta-analysis, lenalidomide maintenance vs placebo/observation post-ASCT, n=1,2081

• Improved PFS if HR for lenalidomide maintenance vs observation, but no improvement in OS (most patients did not have FISH data)

• Myeloma XI2

• FISH data available: 22.8% lenalidomide maintenance arm, 30.1% observation arm

1. McCarthy PL, et al. J Clin Oncol. 2017; 35:3279–89; 2. Jackson G, et al. Blood. 2016; 128: Abstract 1143.

Maintenance post-ASCT – ixazomib

• TOURMALINE MM3

• Ixazomib maintenance for 26 cycles vs placebo

• Discontinuation rates similar in both arms

• PFS 26.5 months for ixazomib vs 21.3 months for placebo;benefit seen in HR patients and those ISS III

• Maintenance in patients not eligible for transplant pending

Dimopoulos MA, et al. Presentation at ASH 2018. Abstract 301.

Continuous Tx post-ASCT (+/- consolidation) KRD

• KRD x 4 – ASCT – KRD x 4 – KRD reduced dose to C18

• sCR: 20% post-ASCT, 69% post-4 x consolidation, 82% post-KRD maintenance

• MRD-negative: 66% at C8, 71% C18

• Two-year PFS: 97%

• Two-year OS: 99%

• No difference in outcomes with HR and SR

Zimmerman T, et al. Blood. 2016; 128:675. C: cycle.

Allogeneic SCT

• Limited data

• n=73, auto-allo tandem SCT1

• 21.9% had t(4;14)/del(17p); five-year PFS 29% equivalent to non-HR group

• n=143 (1999–2008) retrospective, multicentre analysis2

• HR vs normal: three-year OS 45% (HR) vs 39% (normal)

1. Kröger N, et al. Biol Blood Marrow Transplant. 2013; 19:398–404; 2. Roos-Weil D, et al. Haematologica. 2011; 96:1504–11.

VTD and DXT

HarvestASCT

CD

IRd

Daratumumab

PCd

CD: cyclophosphamide, dexamethasone;IRd: ixazomib, lenalidomide, dexamethasone;

PCd: pomalidomide, cyclophosphamide, dexamethasone.

Progress update

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30/11/2016 01/03/2017 01/06/2017 31/08/2017 29/11/2017 28/02/2018 31/05/2018 30/08/2018

Case study 2

• 70-year-old lady. PMH breast cancer (lumpectomy, DTX, tamoxifen), complex nerve pain, BCC nose and arm, recurrent UTIs

• March 2014: incidental finding, IgG kappa 14 g/l

• SS: NAD, MRI spine: degenerative changes only

• Hb 120, normal U&Es

• ISS I

• BM: 17% plasma cells on aspirate

• FISH: gain(1q), gain(4p) and gain(11q)

BCC: basal cell carcinoma; MRI: magnetic resonance imaging; NAD: no abnormality detected; SS: skeletal survey;

U&E: urea and electrolytes; UTI: urinary tract infection.

Which initial induction Tx?

1. CTD

2. Bortezomib-based regimen

3. Myeloma XI

4. Other

Transplant-ineligible – bortezomib

VISTA1

• VMP vs MP – normalised outcomes with HR

1. Mateos MV, et al. J Clin Oncol. 2010; 28:2259–66. MP: melphalan, prednisone; VTP: bortezomib, thalidomide, prednisone.

Figure adapted from Mateos, et al. 20101

OS in patients treated with VMP

Transplant-ineligible – bortezomib

n=902, HR as per IMWG (27% HR)

VMP plus maintenance vs VMP (GIMEMA-MM-03-05) and MPR vs CPR (EMN01)

Larocca A, et al. Blood. 2017; 130:744.BORT: bortezomib; CPR: cyclophosphamide, prednisone, lenalidomide; HiR: high-risk;

LEN: lenalidomide; MPR: melphalan, prednisone, lenalidomide; PS: performance status; StR: standard-risk.

PFS

Months Months

OS

OverallSex

FemaleMale

Age≤75 years>75 years

FISHStRHiRMissing

ISSIIIIII

Karnofsky PS90–10070–8950–69

LDH≤450>450Missing

Hazard ratio (95% CI) Interaction-p

0.76 (0.66–0.88)

0.78 (0.64–0.95)0.74 (0.61–0.90)

0.74 (0.63–0.88)0.81 (0.62–1.06)

0.87 (0.72–1.05)0.54 (0.41–0.72)0.78 (0.59–1.04)

0.85 (0.65–1.12)0.74 (0.60–0.91)0.71 (0.54–0.94)

0.69 (0.56–0.84)0.83 (0.67–1.02)0.87 (0.56–1.34)

0.78 (0.67–0.92)0.68 (0.44–1.05)0.69 (0.48–0.98)

0.66

0.55

0.01

0.62

0.34

0.71

0.41 1 1.34

Transplant-ineligible – lenalidomide

• Lenalidomide/dexamethasone – does not normalise HR FISH1,2

• FIRST3

• MPT vs lenalidomide/dexamethasone

• Lenalidomide/dexamethasone confers no advantage with HR FISH

• Myeloma XI4

1. Kapoor, et al. Blood. 2009; 114:518–21; 2. Jacobus, et al. Br J Haematol. 2011; 153:340–8; 3. Avet-Loiseau. Blood. 2015; 126: Abstract 730; 4. Jackson G, et al. Blood. 2018; 128: Abstract 1143. MPT: melphalan, prednisone, thalidomide.

Progress update

Complicated by pseudo-obstruction, urosepsis, D and V, AKI

Hb 78, WCC 6.1, neuts 4.3, plts 243BM 30% plasma cells

What would you do?

Par

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AKI: acute kidney injury; D and V: diarrhoea and vomiting; neuts: neutrophils; plts: platelets; WCC: white cell count.

01/06/2015 30/11/2015 01/06/2016

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Cyclophosphamide omitted for last two cycles Vomiting, pneumococcal sepsis

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What would you do?

01/06/2015 30/11/2015 01/06/20160

30/11/2016 02/06/2017 01/12/2017

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VMP x8

CDTa

IRD (PAS)

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PAS: patient access scheme.

Progress update

Case study 3

• 58-year-old nurse consultant. PMH Addison’s disease, idiopathic urticaria, lichen sclerosis, osteopenia

• June 2015: lytic lesion R femoral diaphysis ‘thigh pain’

• SS:

• Hb 126, Cr 103, Ca 2.54

• Paraprotein IgA lambda 19 g/l

• ISS I

• BM 60% plasma cells

• FISH t(4;14), gain(1q)

CA: calcium; Cr: creatinine.

Initial treatment

IgA levels

What would you do?

25

20

15

10

5

0

01/06/2015 30/11/2015

Which re-induction Tx?

1. Induction with CTD and second ASCT

2. ACCORD trial with plan for second ASCT

3. PI-based regimen

4. Other

Myeloma X

Cook G, et al. Lancet Oncol. 2014; 15:874–85.

Myeloma X

Included: • Progression ≥12/12

Exclusion criteria:• Tx for relapsed disease

• ECOG PS 3–4

• Grade 2 peripheral neuropathy

• Comorbidity precluding ASCT

1. Cook G, et al. Lancet Oncol. 2014; 15:874–85. ECOG: Eastern Cooperative Oncology Group; TTP: time to progression.

Table adapted from Cook, et al. 20141

Myeloma X

Patients missing from the table received no treatment; *Includes both sCR and CR.†Early death after induction was defined as death between registration and up to and including 21 days after the final cycle commenced; early death after randomised treated was defined as death between randomisation and up to and including 100 days after randomisation.Cook G, et al. Lancet Oncol. 2014; 15:874–85.

Best response in all registered patients after induction and in all randomly assigned patients after randomised treatment

Response after induction (n=297)

Myeloma X

OS 67 vs 52/12

Cook G, et al. Lancet Oncol. 2014; 15:874–85.

Subgroup analysis of TTPOS in the intent-to-treat population

Myeloma XII – ACCoRd

• RRMM post-ASCT relapse: • ITD-ASCT vs ITD-ASCT(augmented)

• Ixazomib vs observation post-ASCT maintenance

• 68.2% SR, 24.2% HR, 6.1% UHR at relapse

• ORR did not differ by genetic risk (SR/HR: ORR 57.8% vs 50.0%, p=0.55)

• Previous PI exposure important (exposed vs naïve: ORR 57.8% vs 75.9%, p=0.03)

• PD more commonly seen in PI-exposed (18.6%) and HR (18.8%) vs overall population (11.9%)

Cook G, et al. Presentation at ASH 2018. Abstract 255.ITD: ixazomib, thalidomide, dexamethasone;

ORR: overall response rate; RRMM: relapsed/refractory multiple myeloma.

ReLApsE – ASH 2018• n=282

• Arm A: Rd continuous, Arm B: Rd x3 – ASCT #2 – R maintenance

• Arm B: 29.5% did not receive planned ASCT

• HR FISH: A: 31.6%; B: 42.9%

• ORR at LM analysis (post C5): A: 69.6%; B: 82.3%

• Multivariate LM analysis: superior PFS (hazard ratio 0.6, p=0.01) and OS (hazard ratio 0.39, p=0.006)

• LR FISH and R-ISS I demonstrated superior OS with B over A. Benefit not seen with HR FISH or R-ISS II/III

Arm A Arm B

ORR 74.6% 77.9%

≥VGPR 47.1% 49.3%

PFS 18.8 months 20.7 months

OS NR 62.7 months

LM analysis Arm A Arm B p-value

PFS 20.1 months 23.3 months 0.09

OS NR 57 months 0.046

Goldschmidt H, et al. Presentation at ASH 2018. Abstract 253 and 254. LM: landmark; LR: low risk; R: lenalidomide.

Progress update

VTD

ASCT

ITD (Myeloma XII) DT-PACE

Rd

40

30

20

10

001/06/2015 30/11/2015 01/06/2016 30/11/2016 02/06/2017 01/12/2017 03/06/2018 02/12/2018 04/06/2019

25

20

10

001/06/2015 30/11/2015 01/06/2016 30/11/2016 02/06/2017 01/12/2017 03/06/2018 02/12/2018 04/06/2019

15

5

What would you do?

Progress update

VTD

ASCT

ITD (Myeloma XII) DT-PACE

RD

40

30

20

10

001/06/2015 30/11/2015 01/06/2016 30/11/2016 02/06/2017 01/12/2017 03/06/2018 02/12/2018 04/06/2019

25

20

10

001/06/2015 30/11/2015 01/06/2016 30/11/2016 02/06/2017 01/12/2017 03/06/2018 02/12/2018 04/06/2019

15

5

DT-PACE: dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide.

Which subsequent Tx?

1. RD

2. IRD

3. Daratumumab

4. Pomalidomide-based triplet

5. Pomalidomide (+/- clarithromycin)

6. Pomalidomide (+/- cyclophosphamide)

7. Bortezomib-based regimen

Principles of treating HR disease

• Accurately identifying patients

• Rapid disease control

• Scheduling

• Tailoring treatment to disease biology

• Avoid alkylating agents

• Aim to achieve outcomes similar or ‘less than expected’ difference to SR disease

Dr Sally Moore, personal communication.

CA considerations

• Most labs only test FISH according to R-ISS

• Sample quality is essential

• Much unknown re. confounding factors

• Role of repeat FISH at relapse – clonal evolution

• Limited by Tx algorithm/NICE appraisals

• Role of clinical trials

• Balance of toxicity with response

• Elderly add in third drug to doublet if issues with tolerability?

Dr Sally Moore, personal communication.

2018 updated guidelines on diagnosis, risk stratification and management

Rajkumar SV, et al. Am J Hematol. 2018; 93:1091–110.

Non-transplant-eligible

mSMART risk stratification

Bortezomib-based regimen

Bortezomib-based regimen x 3–4 cycles

PI-based maintenance

Bortezomib-based regimen

Risk groupPercentage of newly diagnosed patients with the abnormality

SR 75%

Trisomies

t(11;14)

t(6;14)

IR 10%

t(4;14)

Gain(1q)

HR 15%

t(14:16)

t(14;20)

del(17p)

Transplant-eligible

PI-based maintenance

PI-based maintenance

Thank yousallymoore5@nhs.net