Guideline/Pathway for diagnosis, management and treatment of multiple myeloma (MM)

Ausgaben V1: 5/2011, V2: 5/2012, V3: 6/2013, V4: 11/2014, V5(2): 1/2016, V6: 9/2017 (VIII) M.Engelhardt,J.Waldschmidt,H.Reinhardt,S.Dold,S.Müller,C.Kiote-Schmidt,M.Pantic,C.Greil,S.Ajayi,M.Vits,H.Schäfer,J.Neubauer,U.Salzer,A.May,M.Boeker,G.Herget,R.Wäsch

gültig bis 10/2018

Risk stratification model for MGUS

Robert A. Kyle and S. Vincent Rajkumar bjh; 134: 573–589, 2006 Bird J. et al. bjh; 147: 22-42, 2009

Risk factors Risk group Risk of MGUS

progression at 20 years

Follow-up

0 Low-risk (Serum M-protein <15g/l; IgG-Type; Normal FLC ratio)

5% Every 2-3 years

(general practitioner)

1 Low-intermediate-risk (1 risk factor abnormal)

21% Every 12 months

(hematologist) 2

High-intermediate-risk (2 risk factors abnormal)

37%

3 High-risk (all 3 risk factors abnormal)

58% Every 6 months (hematologist)

Predictors of progression of MGUS

to myeloma or related disorders:

• Size of serum M-protein:

Initial Serum M-protein >15g/l

• Abnormal Kappa/Lambda free-light

chain (FLC) ratio

• Type of M-protein:

IgG vs. IgA or IgM MGUS

Risk stratification model for SMM (Mayo clinic)

Mayo Clinic study group

# of risk factors BMPCs ≥10%

M-protein ≥3g/dL

FLC-ratio <0.125 or >8

# of pts (%)

5 year

progression

(%)

1 76 (28) 25

2 115 (42) 51

3 82 (30) 76

Total 273 (100) 51

Initiale Diagnostik Labor mit FLC und 24 Stunden Sammelurin Ganzkörper-CT od. MRT KMP: Zytologie, Histologie, ZM, ZG Risikofaktoren - Hohe Tumorlast: a) PC im KM >60%, b) Involved/uninvolved FLC-ratio >100, c) >1 fokaler MM-Herd Ganzkörper-MRT Bei a),b) u/od.c) mit sensitiver Radiologie-US: consider SMM

als aktives MM und therapiebedürftig

Prognose / PD-Risiko In ersten 5 Jahren nach Diagnosestellung: ~10%/J. (nach 10 J.: 3%, nach 20 J.: 1%/J.) Verlaufsuntersuchungen alle 3-12 M. (Niedrig-Risiko SMM mit 1 RF: 1x/J., 2 RF: alle 6 M., 3 RF: alle 3(-6) M.)

Dispenzieri A, Blood. 2008;111(2):785–789 Rajkumar SV et al. Leukemia. doi: 10.1038/leu, 2013

Rajkumar SV. et al. Lancet Oncol 15: e528, 2014 Rajkumar SV et al. Blood:125(20):3069-75, 2015

Caers J,...Engelhardt. The oncologist 21(3):333-42, 2016

1. Detection of monoclonal immunglobuline/paraprotein

in serum: IgG, IgA, IgD, IgE and/or

in urine: immunglobulin light chains (Bence-Jones-proteinuria)

2. >10 % plasma cells within BM

3. End organ damage (1 criterion sufficient)

[C] Hypercalcemia or

[R] Renal insufficiency (crea >1,4 mg/dl) or

[A] Anemia (Hb <10 g/dl or 2 g/dl < Norm) or

[B] Osteolytic lesion(s)

Diagnosis criteria International Myeloma Working Group

UK Nordic Myeloma Guidelines 2005 Patriaca F.et al. Eur J Haematol 2008

Ludwig et al. Leukemia 2014 Rajkumar V. et al. Lancet Oncol 2014

Caers J,...Engelhardt. The oncologist 2016; 21(3):333-42

or

[I] Clonal BM PCs >60% [II] Invol/uninv. SFLC ratio >100 [III] >1 focal lesion on MRI

4. Revised IMWG criteria (1 criterion sufficient)

5. Potential future biomarkers for diagnosis of active MM (2-y probabilitiy of progression)

Unexplained decrease in creatinine clearance by >25% plus rise in urinary M-protein or serum free light chain levels (tbd)

High BM PC proliferation rate by S-phase assessment on multiparametric flow cytometry (80%)

Abnormal PC immunophenotype >95% plus immunoparesis (50%)

Cytogenetic subtypes: t(4;14) or del17p (50%)

High-levels of circulating PCs (80%)

Evolving type of SMM (65%)

Initial investigation/diagnostics in MM

von de Donk. Haematologica 99:984-96, 2014 Engelhardt M. Haematologica 99:232-42, 2014,2015,2016

NCCN guidelines 3.2016 Krönke J, ....Engelhardt M, .....Langer C.Leukemia. 2017 Jan 20

Screening tests Tests to establish diagnosis

Tests to estimate tumor burden and prognosis/staging

Tests to assess myeloma-related organ impairment (ROTI)

Special tests indicated in some pts

• Individual and family history and physical examination

• Complete blood count (differential; peripheral blood smear) • Serum or plasma electrolytes, urea, creatinine, calcium, albumin and uric acid

• Electrophoresis of serum and concentrated urine

• Quantification of non-isotypic immunoglobulins by nephelometry and densitometry

• Unilateral bone marrow aspirate, trephine biopsy + FISH (e.g. for 17p13, 13q14, t(4;14), t(14;16), t(14;20), 1q + 1p abnormalities) • Immunofixation of serum and urine

• Electrophoresis of serum and concentrated urine

• Plasma viscosity

• Whole body (WB)-CT

• Bone marrow cytogenetics: FISH for 17p13, 13q14, t(4;14), t(14;16), t(14;20), 1q+1p abnormalities

• Quantification of monoclonal protein in serum and urine

• Serum free light chain assay (non- or oligo-secretory and smoldering MM)

• Calcium

• Albumin

• 2-microglobulin

• LDH

• FBC (anemia)

• Serum or plasma urea and creatinine

• (e)GFR (measured or calculated)

• Calcium

• Albumin

• Lactate dehydrogenase (LDH)

• C-reactive protein

• Quantification of non-isotypic immunoglobulins

• WB-CT

• Other organ impairment, e.g. heart: ECHO, proBNP; neurology/PNP

• Bone marrow immunohistology or flow cytometry

• Vitamin B12 and folate assays

• WB-CT • Magnetic resonance imaging (MRI) if EM-MM suspected • (PET-CT)

FBC: full blood count FISH: fluorescence in situ hybridization * The highest number of plasma cells obtained by either procedure is recorded grey color: optional, e.g. with clinical symptoms.

Risk stratification via cytogenetics - review of the literature

Bergsagel L. Blood;121:884-892,2013 Favorable Unfavorable

t(11;14) t(4;14)

t(6;14) t(14:16)

Monosomy 13 t(14;20)

Hyperdiploid non-hyperdiploid

1q gains

17p del

Gain 1q21, del(17p13), t(4;14), t(14;16), t(14;20)

Boyd KD. Leukemia,2012 Standard Intermediate High Risk none of these 5 1 >1

Rajkumar V. Am. J. Hematol,2016

Avet-Loiseau H. JCO,2012

Standard Intermediate High Risk Trisomy t(4;14) del 17p t(11;14) Gain(1q21) t(14;16) t(6;14) t(14;20)

Trisomy + translocation

Standard High Risk

Trisomy del 17p

t(11;14) t(4;14), t(14;16), t(14;20)

all others del 13

Hypodiploidy

1q gain, c-myc

Boyle E. Genes,Chr.&Cancer;54:91-98,2015

High Risk

Age>55, ß2-MG>5.5mg/l; t(4;14), del(17p), 1q gain

1

2

3

5

4

Palumbo A. JCO,2015 High Risk

ISS, HR-CG: del17p, t(4;14) or t(14;16), LDH

5

MM und MGUS: Bildgebende Diagnostik-UKF Allgemein:

• Schnittbildverfahren (CT/MRT/PET) sind "Pariser Schema" überlegen, letzteres wird bei weltweit

durchgeführten Studien z.T. noch gefordert -> muss i.R. des Studienprotokolls dann erfolgen

• Beurteilung Osteodestruktion (Ausmaß/Anzahl Osteolysen) u.Stabilität: Ganzkörper-CT (GK-CT)

• MRT zur Detektion extramedullärer Herde und Weichteilinfiltration GK-CT überlegen

• PET/CT im Einzelfall und Studien erwägen

ED: Nicht-Low-Risk-MGUS, SMM + symptomatisches MM:

• Bei symptomatischem MM mit v.a. Knochenläsionen: in der Regel GK-CT (unter Einschluss

Humeri und Femura

• Bei v.a. extramedulläres MM: zielgerichtetes MRT

SMM, solitäres Plasmozytom und High(er)-risk-MGUS (RF nach Mayo 2+3)

• GK-CT (nach IMWG: MRT1) bei klinischer Indikation

Low-risk MGUS (Mayo-Risikofaktoren: 0-1)

• Radiologische Diagnostik nicht routinemäßig, symptomorientiert

• GK-CT und/oder MRT bei klinischer Indikation, ggf. Röntgen nativ lange Röhrenknochen/WS

1 Rajkumar V. et al. Lancet Oncol 2014 Cavo M et al. Lancet Oncol 2017 (in press)

Soft-tissue mass

Suspected spinal cord compression

MRI2 consider biopsy

Whole body CT1

Urgent MRI scan and appropriate

medical management

Lytic lesions present

At risk for fracture? Systemic therapy

Focal lesions >1 Diffuse pattern

0-1 Focal lesions No diffuse pattern

Observation

Suspected plasmocytoma or MM

Terpos E. et al. Haematologica. 100(10):1254-66, 2015 Rajkumar V. et al. Lancet Oncol 15:e528, 2014

1,2 MM-TB: Prof. Dr. G.Herget, Orthopädie, Dr. J.Neubauer, Radiologie UKF

Algorithm for imaging+bone disease management

1 WB-CT should include humeri/femura (alternatively X-rays in 2 planes). Consider CT of cervical spine in standard-dose (Orthopädie UKF). 2 MRI (Orthopädie, UKF)

Yes

Urgent orthopedic review: consider RTX or operative intervention

Yes

No, but clinical findings?

consider focussed MRI?

Whole body CT1

to complete diagnostics

Multiples Myelom - Stadieneinteilung

Stadien Durie & Salmon International Staging

System (ISS) R-ISS

Stadium I

Alle folgenden Kriterien müssen erfüllt sein - Hb 10 g/dl - Serumkalzium normal ( 12

mg/dl = 2,75 mmo/l) - Bildgebung: maximal eine

solitäre Läsion - IgG 5g/dl; IgA 3 g/dl - Bence-Jones-Proteinurie

4 g/24h

ß2-MG < 3,5mg/ml,

Albumin 3,5 g/dl

ISS I,

Nicht-HR-ZG, wie del17,

t(4;14), t(14;16),

normale LDH

Stadium II - Befunde weder denen in

Stadium I noch III entsprechend

Nicht ISS I und III Nicht R-ISS I und III

Stadium III

Mindestens eines der folgenden Kriterien muss erfüllt sein - Hb 8,5 g/dl - Serumkalzium erhöht

(>12mg/dl = >2,75 mmol/l)

- Bildgebung 2 Osteolysen - IgG >7 g/dl; IgA > 5 g/dl - Bence-Jones-Proteinurie

>12 g/24h

ß2-MG > 5,5mg/ml

ISS III,

HR-ZG

oder/und

erhöhte LDH

Subklassifikation A Serumkreatinin < 2 mg/dl B Serumkreatinin 2 mg/dl

Palumbo A et al. J Clin Oncol 2015;33(26):2863-9 Kommentar: M.Engelhardt. Im Fokus Onkologie 2016;19:1-2

Engelhardt M et al. Haematologica. 2017 Feb 2

AL-Amyloidose-Diagnostik Bei welchen Patienten? • Prinzipiell kann bei jedem MGUS AL-Amyloidose bestehen; bevorzugt bei: - Paraprotein vom Typ Lambda - Zytogenetik t(11;14) - Erhöhten freie Leichtketten im Serum Klinische Symptome? • Makroglossie, periorbitale Einblutungen, Synkopen, Durchfälle, Herzinsuffizienz, Ödeme, Polyneuropathie Welche Diagnostik ist geeignet? • EKG, NT-Pro-BNP,TropT, Albuminurie, S-FLC • Echokardiografie, Neurologische Untersuchung, Oberbauch-Sonographie/

Gamma-GT Diagnostik zum Amyloidosenachweis: • Fat pad*, KMP*, Rekto-/Gastroskopie (tiefe+serielle Biopsie, wenn möglich), * fat pad +

KMP erlauben in 85% der Pat. Amyloidose nachzuweisen; Niere + Herz (letztere erfolgt aufgrund Risiko selten, stattdessen typischer Herzechobefund maßgebend)

• Histopatholog. Nachweis AL-Amyloidose (vs. z.B. ATTR od. senile Amyloidose); Nachweis, dass Amyloid v. Ig-/Paraprotein abstammt obligat; zudem: Serum-/Urin-Paraproteinnachweis vor anti-MM/AL-Amyloidosetherapie

Gertz MA. Am J Hematol 88:416-25, 2013 Müller AM, ....Engelhardt M.Oncologist. 11:824-30, 2006

http://relaunch.amyloid.de/04-ansprechpartner/

Diagnosis of MM (symptomatic MM)

DSMM XVII (once open)

Induction-3-drug regimen

3-4 x V(C)D,VTD,PAD,Kd,

VRD,KRd,R(C)D,KRd,EloRd,IRd

Stem cell harvest (CE protocol)

High-dose melphalan 200 + ASCT

no CR/nCR, HR-MM consider consolidation

• tandem ASCT (IFM: V-Mel-V)

• Bortezomib

• Lenalidomide

Maintenance (SD/MR)

• Lenalidomide

• Thalidomide

• Bortezomib

Recommended initial

treatment (6-9 cycles)

6-9x

V(C)D

VMP

Rd

Alkylator +

steroids + IMIDs:

CTD,MPT,RCD

Additional options:

• Bendamustine/ prednisone

• VMPT-VT

• MPR

Maintenance • Lenalidomide /Thalidomide

• Bortezomib

Engelhardt, Berger, Mertelsmann. The Blue Book. 6. edition. Springer, 2016 Engelhardt M et al. Haematologica 2014, 2016, 2017

Magarotto V et al. 2016, Blood. 127:1102-8 Sonneveld P et al. 2016, Blood. 127:2955-62

Moreau P et al. 2016. Blood. 127: 2569-74 Einsele et al. Leukemia 2017

MM-Pathway Onkolog. Spitzenzentren 2017

Clinical trials

Pembro-Rd

vs. Rd

if eligible

UKF-Pathway: Newly diagnosed MM

eligible for ASCT ?

Assessment: age, comorbidities, ISS, cytogenetics, CRAB criteria. slim-CRAB: BM infiltration ≥60%, FLC ratio ≥100, >1 lesion (MRI)

yes no

MM-TB

Consider ASCT

2nd ASCT if remission > 18-

24 months after 1st ASCT

Use novel agents

IMiD-based (CTD, MPT, RD or Rd) Borte-based (VCD or VD)

Bortezomib-based:

• Borte +/- Dex

• VCD

• VTD

IMiD-based:

• Len/dex

• Thal/dex

• CTD

Consider: clinical trials

PI-based:

VD,VTD,VCD,

Kd,VDD,Pan-

VD

IMiD-based:

RD,Td,CTD,

RCD,RAD,Elo-

Rd

Rajkumar SV et al. 2016, Lancet. 387:1490-2 Engelhardt M et al. Haematologica 2014, 2016, 2017

van de Donk NW et al. 2011, Cancer Treat Rev. 37:266-83 MM-Pathway Onkolog. Spitzenzentren 2017

Cfz-based:

KRd

Poma-based

Consider RRMM studies

MK-3475-183

PD-1/

Pom/Dex

MOR03087

CD38ab + Dex

vs. ab-RD vs.

ab-Pom-Dex

BASKET

Dabra+

Trametinib Allo-SCT if chemo-sensitive

disease + within clinical trial

Repeat or change frontline treatment

Switch drug class, especially after:

• short remission (<6 months)

• toxicity concerns from previous line

Re-treatment feasible after:

• Long remission (>6 months)

• No toxicity concerns from

first line treatment

Frontline consisted of:

Frontline treatment with novel agents

yes no

PI+IMiD based:

VMPT,VTD,VRD,

KRd,IRd

Dara: if prior IMiD/ PI

Dara-Rd,

Dara-Vd

Consider

retreatment

if response > 6 months

and no side effects

MM-TB

Dara: if prior IMiD/

PI od.

Dara-Rd/ Dara-VD

Elo-Rd Pan-VD

Individuelle Weiterbehandlung

MM-trials to come

UKF-Pathway: Relapsed/ Refractory MM

new EMN RRMM trial post Cfz-Benda-Dex

(Prof. Gramatzki)

new Selinexor RRMM trials (2)

• Bortezomib-induction w/o ASCT = VMP: inferior to VCD + ASCT

• 242. Sonneveld: consolidation VRD vs. no: PFS prolonged: HR 0.67, p=0.045

• 991. Cavo: 1 vs. 2=tandem Tx: Median PFS: 45 ms vs. n.r., 3y-PFS: 60 vs. 73%, especially in cytogenetically HR pts

M.Cavo. Blood (Suppl) 673, 2016

3-4 VCD+1+2 Tx (n=695)

4x VMP (n=497)

Maintenance Induction

Median follow-upfrom

R1: 26 months VMP

(n=497) Tx

(n=695) HR, p-value

Pt characteristics =

Median PFS (months) 44 n.r. p<0.05

3y PFS 57.1% 65% HR 0.73, p=0.003

PFS benefit in all subgroups

Median OS (months) not mature

R until PD

673. Intensification therapy with VMP vs. ASCT for NDMM: EMN02/HO95 MM trial

R2

Ø consolidation

consolidation: 2 VRD NDMM <65 y

n=1510

R: 2/2011 - 4/2014

R1

LBA-1. ASCT-VRD cons+Len M vs. Tandem-ASCT+Len M vs. ASCT w Len M (BMT CTN 0702 StaMINA trial)

2: Tandem-ASCT

1: 4x VRD cons.

Lenalidomide until PD

Consolidation

Maintenance NDMM <71y

<12 ms of any induc.

n=758, 54 centers

6/2010 - 11/2013

Median follow-up: 38mos 1: ACM (n=254)

2: TAM (n=247)

3: AM (n=257)

p-value

Pt characteristics =

Median age (y) 57 (20-70)

Non-compliance 12% 32% 5% p<0.01

PFS @38ms F-u 57% (50-63) 56% (49-63) 52% (45-59) p>0.05

OS @38ms F-u 86% (80-90) 82% (76-87) 83% (78-88) p>0.05

Cum incidence of disease PD @38ms F-u 42% (36-48) 42% (35-48) 47% (40-54)

SPM (%) 6% (3.4-9.6) 5.9% (3.3-9.6) 4% (1.9-7.2) p>0.05

• Underpowered study, non-compliance: tandem ↑

• Induction influencing PFS/OS results

• Len-maintenance -> approval post Tx -> 2017 EA.Stadtmauer. Blood (Suppl) LBA-1; 2016

3: Ø

R1

Mel200

993. 3.Salvage ASCT / 994. RI+ASCT / 678. Elderly

• 3. Tx feasible w >80% achieving at least PR; if relapse occurs >3yrs post tandem ASCT -> median OS after 3. Tx: >4 years

• HDM w ASCT safe and effective w RI at Tx; significant proportion of pts achieve dialysis independence; improved PFS if moderate RI: w Mel200>140

• Age per se should not be an exclusion criteria for ASCT L.Gardaret 993;; A.Mahindra 994; I.Sanchez-Ortega 678; F.Gay Blood (Suppl) 995;2016

ARARA group:

AARA group: Tandem 3.Tx

3.Tx 1. 2.

993. 3.Tx

<75 yrs

EBMT data

1997-2010

n=1288

n=417

n=72

OS (p=0.602)

PFS (p=0.124)

moderate

moderate

normal

normal

severe

severe

Increase over time of elderly Tx: 2000: 3.4%->2014: 9.8%;

NRM: 4.9%, OS @1+3yrs: 87%+67%

994. Pts w RI

CIBMTR

2008-2013

n=1492

AARA

ARARA

678. Pts >65

EBMT

2000-2014

n=21390

• Despite higher risk population: extended post relapse survival in allo HCT pts

• Reduction in post relapse mortality -> donor immunologic milieu + immune agents: Len, Pom, Dara, Elo, Check point inhibitors

• Post allo transplant immune manipulation can further enhance these benefits.

M.Htut. Blood (Suppl) 833, 2016

833. Tandem auto vs. auto-allo-SCT in MM: extended CIBMTR data

5 large prospective trials: lack of OS improvement of auto-allo HCT vs. 3 with benefit

-> OS comparison of tandem-auto (n=404) vs. auto-allo (n=178) HCT from CIBMTR

Auto-allo

Tandem-auto vs. auto-allo (>12 ms) HR=1.55 (1.14-2.11) p=0.0052

Tandem-auto vs. auto-allo (<12 ms) HR=0.72 (0.47-1.09) p=0.1172

- Auto-allo (n=178) - Tandem-auto (n=404)

Tandem-auto

Adjusted Post Relapse Survival Probability %

Years post relapse after 2.Tx

Nooka AK. Blood 2015;125:3085-99 ASH educational 2016

Treatment options for relapsed and refractory MM

New, other options: • Carfilzomib or Ixazomib-combos, e.g.: -Rd or -PomD or -Cyclo-Pred/Dex • Daratumumab mono, Dara-Rd, Dara-VD or Pom-Dex or Pom-Cyclo-Dex • Elotuzumab-Rd, Elo-VD

491. Selinexor + Dex in quad + penta-RRMM (Storm) 977. Selinexor -VD: phase I Stomp trial

973. Selinexor-Cfz-Dex in RRMM

• Exciting new oral treatment option

• May provide deeper responses in otherwise refractory RRMM

• 2 new trials UKF: Sd + SVd vs. Vd DT Vogl Blood (Suppl) 491, NJ Bahlis 977, A Jakubowiak 973; 2016

Oral selective

inhibitor of

Nuclear Export

that binds and

inactivates

Exportin 1

(XPO1)

nuclear accumulation + activation tumor suppressor proteins

inhibition NF-kB

induces

inhibition translation of oncoprotein mRNAs, eg. c-myc+cyclin D potent induction of MM cell apoptosis independent of p53 signaling

Selinexor

Sd=STORM: quad or penta-RRMM: 2x/w S 80mg

n=79 pts: ORR 21%, median OS 9.3ms, median PFS 2.1ms

-> expansion: penta-ref. RRMM

S-Vd=Stomp trial: phase 1b/2

n=22 pts: ORR 77%, n=10 pts >4ms on trial, n=7 >9ms

-> phase III: SVd vs. Vd (Boston)

S-Cfzd=phase I: RRMM>2 prior th., Cfz-refractory

n=18 pts: >MR 75%, >PR 63%, >VGPR 25%

VEN: 300, 600, 900, 1200mg daily -> 1200mg: safety expansion

If PD under VEN -> VEN plus dex

n=66 pts, n=30 in dose escalation, n=36 in safety expansion

Median prior therapies: 5 (1-15)

Median time on VEN; 2.5 ms (0.2-23); 26% +dex for median of 1.4ms (0.1-11)

ORR 21%, median DoR and TTP 9.7 + 2.6 ms

VEN: 50-1200mg daily + Vd

n=66 pts, n=54 in dose escalation, n=12 in safety

expansion at recommended phase 2 dose of 800mg

Median prior therpies: 3 (1-13)

ORR 68%, median DoR and TTP 8.8 + 8.6 ms

VEN cancer cell

488. Venetoclax phase I monotherapy in RRMM 975. Venetoclax -Vd in RRMM

• VEN mono in t(11;14) has clear anti-MM-activity (primarily in t(11;14) w high BCL-2, low BCL-XL and low MCL-1 expression)

S Kumar Blood (Suppl) 488, P Moreau 975; 2016

AZ Badros. Blood (Suppl) 490; 2016

490. Pembrolizumab-Pomalidomide-Dex in RRMM

T-Cell

Tumor-Cell

MPDL3280A

MSB0010718C

Pembrolizumab

Nivolumab PD-1

Phase II study: n=48 RRMM:

Pembrolizumab 200mg i.v. every 2 weeks, Poma 4mg d1-21, Dexa 40mg weekly

Median 3 prior therapies (2-6), 80% double refr.to Len+PI (B n=18, Cfz n=29), 70% ASCT

Median time from diagnosis to study entry: 4 years (1-25)

Median follow-up: 10 ms (2-18): 25 continue, 23 discontinued due to PD (n=15), side

effects (n=7), protocol violation (n=1)

ORR: 56%; median duration of response: 8.8 ms

Autoimmune side effects: pneumonitis (13%), hypothyroidism (10%), transaminitis (6%),

adrenal insufficiency (4%), vitiligo (2%)

SZ Usmani. Blood (Suppl) 1149; 2016 MS Raab. Blood (Suppl) 1152, 2016 AK Nooka. Blood (Suppl) 492, 2016

1149. Phase 1b: s.c.-Daratumumab in RRMM (PAVO)

• SC DARA-PH20: shorter infusion time, well tolerated, serum through concentrations = or ↑ than IV DARA, lower infusion reactions

• Pt- and outpt-convenience ↑ • All upcoming DARA trials -> s.c.

• Median duration of 1., 2. + 3. i.v. Dara: 7 -> 4.2 -> 3.4hrs

• S.c. delivery tested w human hyaluronidase enzyme (PH20) -> systemic absorbtion ↑

• 1200mg + 1800mg: QW for 8 wks, Q2W fr 16 wks, Q4W thereafter.

• DARA-PH20 in 1200mg dose: in 60ml/20' or 1800mg in 90ml/30' + premed

• Part 2: 1800mg s.c. vs. Dara i.v.: 1:1

• n=53 in part 1: 1200mg (n=8) -> 1800mg (n=45); infusion-SAEs: 22%, most G 1/2

• ORR: 1200g: 25%, 1800mg: 38%, median time to response: 4 weeks (4-8)

Promising investigational agents in advanced clinical development

Drug class Drug name Propertiy Phase

PI Ixazomib Marizomib Oprozomib

Rev. boronate PI Irrev.ß-lactone PI Irrev.epoxyketone PI

3 1

1/2

HDACi Ricolinostat HDAC-6 inhibitor 1/2

mAb Elotuzumab Daratumumab Sar650984 + Mor Indatuximab ravtansine J6MO-mcMMAF

anti-SLAMF7 hum mAb anti-CD38 hum mAb -> s.c. anti-CD38 humanized IgG1mAb chimeric anti-CD138 anti-BCMA

3 3 1

1/2 1

Immune

therapies

Pembrolizumab Pidilizumab Nivolumab Anti-BCMA CAR-T cells

anti-PD-1 mAb anti-PD-1 mAb IgG4 anti-PD-1 mAb -> anti-MM T-cell reponse

1/2 1/2 1 1

BM-targeting

therapies

NOX-A12 TH-302

CXCL12 inhib. Hypoxia-activated DNA alkylator

2 1/2

Molecularly

targeted

therapies

Filanesib Selinexor GSK2141795 Dinaciclib GSK525762

KSP inhibitor XPO-1 inhibitor Akt inhibitors CDK1,2,5+9 inhibitor BET small molecule inhibitor

2 2/3 2 2 1

Bianchi G. Blood 2015;126:300-11; ASH 2016, Rosenblatt.NEJM 376;2017 Ludwig H, .... Engelhardt M.Leukemia. 2017 Feb 3

CT offers open Past CT offers at UKF

Blaue Buch-Therapieprotokolle MM/Amyloidose Stan-dard

Integration novel drugs

Mobili-sation

ASCT and allo-SCT

Amy-loidosis

Study protocols

Alexanian

Mel i.v. HD-Dex

Benda-mustin

MP-T, -V, -R Thal/Pred o. Dex

CTD VCD

Benda/Thal/Pred Len/Dex (RD)

Len/Cyclo/D (RCD) Pom/Dex

Pom/Cyclo/Dex Pom-VD

Benda/Bort/Pred (±Thal) Bortezomib (s.c., Erhaltung)

Bort/Dex (VD) Bort/Dex/Len (VRD)

VDD Carfilzomib/Dex

Carf/Len/Dex Carf/Cyclo/Dex Ixazomib-RD

Ixa/Dex, Ixa/Pom/Dex Ixa/Dex/Benda

Elotuzumab-RD, Elo-VD Daratumumab mono Dara-Rd, Dara-VD Panobinostat-VD

Cyclo 2g/m2

(1-4g/m2)

CE

Mel 200 Mel 140 BEAM

BeEAM TEAM

BM Bu/Cy Bu-Mel

Bu mono Bort/Mel 200

all MM protocols

+ Dex/IFN Palladini

VD VCD

PD1-Rd

Morphosys CD38-Ak (Ph I/IIa)

PD1-Pom-Dex (Ph II)

BRF117019: Dabrafenib + Trametinib (Phase II)

Engelhardt, Berger, Mertelsmann, Duyster. Das Blaue Buch. 6.ed., Springer, 2016

4 30 2 10 4 4 total: 54

MM - clinical trials UKF 3/2017

Indi-cation Title Description/content of clinical trial # pts

First-line MK-3475-185 Ph III Elderly, non-SCT eligible pts, PD-1 - RD 2

Re-lapse MK-3475-183 Ph III, PD-1 - Pom/Dex , > 2 prior therapies 1

MOR03087: CD38 Ab Ph I/IIa, > 2 prior therapies: Ab+Dex (8c), Ab+Rd (7e) + Ab-Pom/Dex (7d) 4

Pom/Dex + Elotuzumab Ph II, > 2 prior therapies 1

BRAF V600E -> BRF117019: Dabrafenib+Trametinib

Ph II >2 prior therapies, progressing pts 0

Coming soon

DSMM-XV study Ixa-Pom-Dex+Cyclo -> Len/PI-ref.; 2-4 prior ther. start Q1/17

Storm: Selinexor-Dex Ph II, Penta-refrac.pts to last line therapy (79 pts) start Q1/17

Boston: Selinex.-Vd:Vd Ph III, 1-3 prior lines,, B-naive+-exposed (360 pts) start Q1/17

Re-gister R-MCI Iomedico (Marschner): CARO+Myriam + DSMM

DKH-project -> follow-up grant submitted >2000

MM-center: Profs. Drs. Engelhardt, Wäsch, Waldschmidt, Kiote-Schmidt, Miething, Köhler, Rettig Study team: D. Jakobs, C. Messner, I. Surlan

Lymphoma/MM-center: Herzog, Bürk, Büsch, Tel. 0761 270 71580 od. -71520 MM-tumorboard: each Monday, 16h, kl. Hörsaal pt registration through TOS

https://www.uniklinik-freiburg.de/medizin1/behandlung/zentren-und-sektionen/sektion-klin-forschung-gcp-und-ectu/uebersicht-der-aktuellen-klinischen-studien.html

Type

Infection prophylaxis

Fluconazol (if on corticosteroids) Trimethoprim-sulfamethazole (if on steroids) Acyclovir (all pts irrespective of whether on therapy or not (J.M.,S.S.)

Vaccination

Seasonal influenza Vaccination against Streptococcus pneumoniae + Haemophilus influenzae may be considered, but response may be suboptimal Currently available zoster vaccine contraindicated

Ulcer/gastritis prophylaxis If on steroids, PPI or H2-blocker

DVT ASS, if no history of prior TE phenomena Warfarin, if history of prior VTE or risk of thrombosis LMW heparin (safer alternative than warfarin, particularly in RI)

Regular blood counts + chemistry

At the time of every infusion of B on B-based regimens Initially, every 2 weeks on Len-containing regimens Every 2-4 weeks on Dex- or Thal-containing regimens

Regular clinical evaluation

Every 1-4 weeks to start with based upon regimen Blood pressure and blood sugar monitoring + SPM*

Bone mineralization Bisphosphonates*, Denosumab*, Ca/VitD3, sport activities

Supportives + monitoring on induction or salvage therapy

Mehta J, Cavo M, Singhal S. How I treat elderly patients with myeloma. Blood 116: 2215-23, 2010 Engelhardt. Haematologica 2014

Schnerch,....Engelhardt. IF Onkologie 2014 Engelhardt M. et al. Onkologe 3:217-28, 2014

*Engelhardt, Wäsch, Landgren, Kleber. CLML 14:98-101, 2014 König,...Engelhardt M. Ann hematol 93:479-84, 2014 + König,....Engelhardt CLML 13:671-80; 2013

Link H. Karger Kompass Onkol 4:18-19, 2017

*orale Substitution von mind. 500mg Ca+400 IE Vit D3/d

MM-Bisphosphonat-Therapie

Wer sollte Bisphosphonate erhalten?

• Symptomatisches MM oder solitärem Plasmozytom, nicht MGUS oder AMM

Welches Bisphosphonat?

• Zoledronsäure 4mg als KI (15 min) alle 4 Wochen oder Pamidronsäure 60-90mg als Infusion über 3-4 Stunden alle 4 Wochen (mit normaler Nierenfunktion)

Bisphosphonattherapie bei Niereninsuffizienz (Creatinin-Cl <30ml/min)?

• Ø Pamidronat und Zoledronat, ggf. bei Osteolysen + NI: Pamidronat 30mg/3h

• od. Empfehlung für Clodronat: 50-80CrCL (75% DR), 12-50CrCL (50-75% DR), <12 (50% oder Unterbrechung)

Applikationsdauer der Bisphosphonate?

• Jahr 1 + 2: alle 4 Wochen, ab 3. Jahr gemäß individuellem Remissionsstatus: bei CR 1x jährlich, sonst 1x alle 3 Monate; bei Progress erneut: 1x monatlich

Prophylaxe von Kieferosteonekrosen?

• Vor Beginn und im Verlauf einer BP-Therapie alle 6 Monate: Kontrolluntersuchung beim Zahnarzt.

• Vor Beginn eines zahnärztlichen Eingriffs (Zahn-Extraktion, Wurzelbehandlung,

Kiefer-OP): Unterbrechung BP-Therapie 90d vor + nach Eingriff; prophylaktische Antibiotika-Therapie (z.B. Clindamycin 4 x 300 mg oder Amoxicillin 3x1g über 10 Tage mit Beginn 2 Tage vor dem Eingriff)

Terpos et al. Blood.121:3325-8, 2013 Kortüm, Engelhardt, Rasche, Knop, Einsele. Internist 54:963-77, 2013

Terpos E et al. Expert Rev. Hematol. 7:113-125, 2014 Poxleitner, Engelhardt, Schmelzeisen, Voss. Dtsch Ärztebl Int 2017;114:63-9

Studiendesign: RANKL-AK vs. BP: Nichtunterlegenheitsstudien

Haupt-Einschlusskriterien

•Erwachsene mit Mamma-, Prostata-

karzinom, anderen soliden

Tumoren oder Multiplem Myelom und

≥ 1 Knochenmetastase/Läsion

Haupt-Ausschlusskriterien

•Gegenwärtige oder vorherige

Gabe von i.v.-Bisphosphonaten

•Kreatinin-Clearance <30 ml/min

Tägliche Supplementierung von Calcium (≥500 mg)

und Vitamin D (≥400 E) empfohlen

R A N D O M I S I E R U N G

S T U D I E N E N D E

Denosumab 120 mg s.c. und

Placebo i.v.* alle 4 Wochen

(n=2.862)

Zoledronsäure 4 mg i.v.* und

Placebo s.c. alle 4 Wochen

(n=2.861)

*Gemäß Prüfplan und Zometa®-Fachinformation, i.v.-Dosis angepasst entsprechend der Kreatinin-Clearance zu Studienbeginn und darauffolgende Verabreichungsintervalle festgelegt

entsprechend dem Serumkreatininwert. Es wurde keine Anpassung der s.c.-Dosis aufgrund von erhöhten Serumkreatininwerten vorgenommen.

• Primärer Endpunkt: Zeit bis 1. skelettbezogene Komplikation (SRE; Nichtunterlegenheit)

• Sekundärer Endpunkt: Zeit bis zum ersten SRE während der Studie (Überlegenheit), Zeit bis

zum ersten und folgenden SRE während der Studie (Überlegenheit)

I

Nach Lipton A, Fizazi K, Stopeck AT, et al. Eur J Cancer 2012;48:3082-3092

II Phase III, n=1718 MM pts: DEN vs. ZOL Non-inferiority: +, HR 0.98 (95%CI: 0.85-1.14)

Superiority DEN vs. ZOL: not met

OS DEN vs. ZOL: HR 0.9 (95%CI: 0.7-1.16)

Primärer Endpunkt: Zeit bis zur ersten Knochenkomplikation (SRE)

während der Studie

Denosumab Denosumab

ZOL

ZOL

Time to first SRE: pts w/o Time to 1.+subsequent SRE: # of SRE

I

Lipton A, Fizazi K, Stopeck AT, et al. Eur J Cancer 2012;48:3082-3092

Amgen Press release 10/2016

Rü Prof. La Rosee, Villingen-Schwenningen 2017 zu MM-Pathway 2017/2018

Link H Karger Kompass Onkol 2017;4:18-19

II Phase III, n=1718 MM pts: DEN vs. ZOL Non-inferiority: +, HR 0.98 (95%CI: 0.85-1.14)

Superiority DEN vs. ZOL: not met

OS DEN vs. ZOL: HR 0.9 (95%CI: 0.7-1.16)

Verlaufsdiagnostik nach MM-Therapie (außerhalb von Studien)

• Anamnese: Karnofsky-Index, Infektionen und Begleiterkrankungen

• Körperlicher Untersuchungsbefund inklusive Größe und Gewicht: Polyneuropathien?, Infektionen? und Schmerzlokalisation?

• Laboruntersuchungen (Blut): Blutbild mit Differentialblutbild, Gesamtprotein, Albumin, Kreatinin, Harnstoff, Natrium, Calcium, Kalium, GOT, GPT, g-GT, Bilirubin, LDH, AP, Harnsäure, CRP, ß2-MG, Serum-Elektrophorese mit Immunfixation, freier Leichtkettentest (SFLC), eGFR (MDRD), quantitative Immunglobulin-Bestimmung, Immunfixation

• Knochenmark-Diagnostik: bei initialer KMP, keine direkte Verlaufskontrolle nach Therapie (außerhalb von Studien) bei Bestimmbarkeit Paraprotein + damit Remissionsstand wichtig aber zur Remissionsfestlegung vor auto- (+ allo-) SZT

• Bildgebung: im Verlauf bei klinischer Indikation

Engelhardt. Haematologica 2014 van de Donk. Haematologica 2014

Schnerch,....Engelhardt. IF Onkologie 2014 Engelhardt M. et al. Onkologe 3:217-28, 2014+2015

Response criteria EBMT/IBMTR/ABMTR*

Response category

Response criteria

Complete response No M-protein detected in serum or urine by immunofixation for a minimum of 6 weeks and fewer than 5% plasma cells in bone marrow

Partial response >50% reduction in serum M-protein level and/or 90% reduction in urine free light chain excretion or reduction to <200mg/24h for 6 weeks‡

Minimal response 25-49% reduction in serum M-protein level and/or 50-89% reduction in urine free light chain excretion which still exceeds 200mg/24h for 6 weeks

No change Plateau

Not meeting the criteria of either minimal response or progressive disease No evidence of continuing myeloma-related organ or tissue damage <25% change M-protein levels and light chain excretion for 3 months

Progressive disease

Myeloma-related organ or tissue damage continuing despite therapy or its re-appearance in plateau phase >25% increase in serum M-protein level (>5%g/l) and/or >25% increase in urine M-protein level (>200mg/24h) and/or >25% increase in bone marrow plasma cells (at least 10% in absolute terms)†

Relapse Reappearance of disease in patients previously in CR, including detection of paraprotein by immunofixation

* EBMT: European Group for Blood and Marrow transplantation; IBMTR: International Bone Marrow Transplant Registry; ABMTR: Autologous Blood and Marrow Transplant Registry. † For patients with non-secretory myeloma only, reduction of plasma cells in the bone marrow by >50% of initial number (partly response) or 25-49% of initial number (minimal response) is required. ‡ In non-secretory myeloma, bone marrow plasma cells should increase by >25% and at least 10% in absolute terms; MRI examination may be helpful in selected patients

Rajkumar SV. et al. Blood 117: 4696-4700, 2011 Lonial S & Anderson KC. Leukemia 28:258-68, 2014

Response criteria International myeloma working group (IMWG)

Response category

Response criteria

Stringent CR (sCR) CR as defined below plus: Normal FLC-ratio, no clonal BM PCs by immunohistochemistry or Flow cytometry

CR Serum/urine IF-, ≤5% BM PCs, no soft tissue plasmocytomas

VGPR Serum/urine IF+, not via electrophoresis or >90% serum M-protein reduction plus urine M-protein level <100mg/24h

PR

≥50% reduction of serum M-protein and reduction in 24h urinary M-protein by ≥90% or to <200mg/24h If serum and urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels required If serum and urine M-protein are unmeasurable, and SFLC assay is also unmeasurable, ≥50% reduction in PCs reqiured, provided baseline BM PCs were ≥30% If present at baseline, ≥50% reduction in soft tissue plasmocytomas

SD Not meeting criteria for CR, VGPR, PR or PD

PD

Increase of ≥25% from baseline in: • Serum M-component and/or • Urine M-component and/or • only in pts w/o measurable serum and urine M-protein: difference between involved and uninvolved FLC levels: absolute increase ≥10mg/dl • BM PCs ≥10% • New bone lesions or soft tissue plasmocytomas or increase of existing bone lesions or soft tissue plasmocytomas • hypercalcemia (corrected serum calcium >11.5mg/dl), attributed solely to MM

Rajkumar SV. et al. Blood 117: 4696-4700, 2011 Lonial S & Anderson KC. Leukemia 28:258-68, 2014