Mieloma Recidivo/Refra5ario: Strategie terapeu;che e An;corpi - - PowerPoint PPT Presentation

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IRCCS CROB Pellegrino Musto Direzione Scien2fica IRCCS-CROB, Centro di Riferimento Oncologico di Basilicata, Rionero in Vulture (Pz) Mieloma Recidivo/Refra5ario: Strategie terapeu;che e An;corpi Monoclonali Pattern of remission and relapse

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IRCCS CROB

Pellegrino Musto

Direzione Scien2fica IRCCS-CROB, Centro di Riferimento Oncologico di Basilicata, Rionero in Vulture (Pz)

Mieloma Recidivo/Refra5ario: Strategie terapeu;che e An;corpi Monoclonali

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Pattern of remission and relapse defines natural course of multiple myeloma

MGUS, monoclonal gammopathy of unknown significance. Figure adapted from Durie BGM. Concise review of the disease and treatment options; Edition 2016. 
 http://myeloma.org/pdfs/ConciseReview.pdf [Accessed July 2016]; Chung DJ, et al. Cancer Immunol Res 2016;4:61-71; 
 Boland E, et al. J Pain Symptom Manage 2013;46:671-80; Bolli N, et al. Nat Commun 2014;5:2997.

ASYMPTOMATIC SYMPTOMATIC

RELAPSING

1st-line

ACTIVE
 MYELOMA

RELAPSED/
 REFRACTORY

FIRST
 RELAPSE Plateau remission Smouldering 
 myeloma 


  • r MGUS

10 50 20

M-protein level (g/L)

Duration of remission decreases with each line of therapy

2nd-line

Time

Bone marrow function Cumulative treatment toxicity Clonal evolution and drug-resistance Median time 3-4 yrs

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Patient outcome in real-word practice

Yong et al. Br J Haematol, 2016

4997 pa;ents diagnosed during 12 months in Belgium, France, Germany, Italy, Spain, Switzerland and the UK

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Expected vs current PFS by treatments and line of therapy at relapse

* Expected

months 3 6 9 12 15 18 21 24 27 30

KPd PanoVD PembrPd CyPd DaraPd KBd VorKRd PanoK KPd DaraPd KPd

First Second Third Fourth Fifth Sixth

DaraRd DaraVd KRd Kd IxaRd KRd EloRd IxaRd Kd PanoVD DaraVd

Relapse

* * * * * *

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Maximize response in depth Prolong survival Delay or prevent disease progression (minimize the risk of relapse) Maximize response in dura;on to maintain disease control Balance efficacy with tolerability and QoL ac;ve (treatments vs pallia;on)

Treatment challenges in patients with RRMM

Prac;cal feasibility (logis;cs, costs)

RRMM pa;ents treatment challenges

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General considerations for salvage therapy selections

Patient characteristics

Age PS/Fitness Co-morbidities Renal Failure Bone Marrow Reserve

Disease characteristics Previous therapy

Alkylants Sequence/Efficacy: Response degree and duration (PFS,TTNT) Toxicities: PN, VTE Cardiovascular Cytopenias Infections Agressiveness: High risk cytogenetics Extramedullary disease PCL Advanced ISS/r-ISS High LDH Clinical vs biochemical relapse MC increase speed PIs IMIDs

Availability of Drugs!

ASCT (eligibility) Maintenance

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Impa5o sul paziente

  • Impegno logistico:

− Accessibilita’ e numero di accessi in ospedale − Impegno del caregiver

  • Effetti collaterali (citopenia,

infezioni, PN, TVP, cuore)

  • Terapie di supporto (profilassi

antitrombotica, antibiotica, antivirale, ecc.)

  • Terapia orale vs i.v.
  • Durata della terapia
  • Qualità della vita
  • Possibilità di continuare a

svolgere le proprie attività

  • Preferenze

Hulin et al. Leukemia Research (2017)

Relapses are associated with a high emotional and physical burden for patients, caregivers and physicians

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Chemotherapy Immunotherapy All causes mortality

  • Median OS provides a measure of when 50% of pa<ents will die, it does not provide a true reflec<on of the

survival <me that may be expected from the pa<ents who are alive aBer the median OS is reached

  • Median OS is considered less suitable for survival curves that are skewed to the right since it does not

differen<ate the propor<on of pa<ents alive or dead aBer 50% of the pa<ents have died

Is the paradigm of survival evalua;on changing also in myeloma?

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Possibile algoritmo rimborsato da O5obre 2017 nel paziente elegibile al trapianto

1°linea 2°linea 3°linea VTD 90%

TE 100%

Other with R 10% KRd Rd EloRd Kd Kd Poma o Dara mono EloR d Poma o Dara mono

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Possibile algoritmo rimborsato da O5obre 2017 nel paziente inelegibile al trapianto

1°linea 2°linea 3°linea VMP 70%

TI 100%

Rd 30% KRd Rd EloRd Kd Kd Poma o Dara mono EloR d Poma o Dara mono

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Including ASCT

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Second transplant, Allo-RIC * Doxil, bendamustine

*

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Second transplant, Allo-RIC

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Second transplant, Allo-RIC

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Dara-Rd vs Lenalidomide-based Studies

POLLUX DRd vs Rd

PFS HR (95% CI) 0.37 (0.27-0.52) ORR 93% ≥VGPR 76% ≥CR 43% Duration of response, mo NE OS HR (95% CI) 0.64 (0.40-1.01)

  • 1. Stewart AK, et al. N Engl J Med. 2015;372(2):142-152.
  • 2. Lonial S, et al. N Engl J Med. 2015;373(7):621-631.
  • 3. Dimopoulos MA, et al. Blood. 2015;126(23):Abstract 28.
  • 4. Moreau P, et al. N Engl J Med. 2016;374(17):1621-1634.

ASPIRE KRd vs Rd1 ELOQUENT-2 ERd vs Rd2,3 TOURMALINE-MM1 IRd vs Rd4

0.69 (0.57-0.83) 0.73 (0.60-0.89) 0.74 (0.59-0.94) 87% 79% 78% 70% 33% 48% 32% 4% 14% 28.6 20.7 20.5 0.79 (0.63-0.99) 0.77 (0.61-0.97) NE

K, carfilzomib; E, elotuzumab; N, ixazomib. Dimopoulos er al. N Engl J Med 2016;375:1319-31

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Dara-Vd vs PI-based Studies

Daratumumab DVd vs Vd PFS HR (95% CI) 0.39 (0.28-0.53) PFS, median mo NE ≥VGPR 59% ≥CR 19% Duration of response, mo NE OS HR (95% CI) 0.77 (0.47-1.26)

  • 1. Dimopoulos MA, et al. Lancet Oncol. 2016;17(1):27-38.
  • 2. San-Miguel JF, et al. Lancet Oncol. 2014;15(11):1195-1206.
  • 3. San-Miguel JF, et al. Blood. 2015;126(23):Abstract 3026.
  • 4. Jakubowiak A, et al. Blood. 2016. Epub ahead of print.

Carfilzomib Kd vs Vd1 Panobinostat PVd vs Vd2,3 Elotuzumab EVd vs Vd4 0.53 (0.44-0.65) 0.63 (0.52-0.76) 0.72 (0.59-0.88) 18.7 12.0 9.7 54% 28% 36% 13% 11% 4% 21.3 13.1 11.4 0.79 (0.58-1.08) 0.94 (0.78-1.14) 0.61 (0.32-1.15)

Palumbo et al. N Engl J Med 2016;375:754-66

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  • Triplets/second generation: no increase in treatment discontinuation or toxicity
  • Different treatment emergent AEs
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Overall Survival

Subgroup analysis in all patients

Age ISS Stage Frailty

Patients (%)

Fit defined as: score=0 Frail defined as: score>2 HR Fish: presence of t(4;14) or t(14;16) or del 17q13 >75yr vs <75yr, HR=1.72 p=0.001

3-yr OS < 75yr 79% > 75yr 68% 3-yr OS ISS 1 89% ISS 2 70% ISS 3 65% 3-yr OS Fit 84% Frail 57%

Frail vs Fit, HR=3.53 p<0.001

Palumbo A et al, Blood 25(13):2068-74, 2015

0.00 0.25 0.50 0.75 1.00 5 10 15 20 25 30

Months

35 0.00 0.25 0.50 0.75 1.00 5 10 15 20 25 30 35

Months

0.00 0.25 0.50 0.75 1.00 5 10 15 20 25 30 35

Months

ISS3 vs ISS1, HR=1.94 p<0.001

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  • Triplets/second generation always better than old standards
  • All effective over 65
  • Few data over 75
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First infusion Second infusion Subsequent infusions

Daratumumab infusion

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Prevention of IRRs

  • Administer pre-medica;on to reduce the risk of IRRs (approximately 1 hour prior to every

daratumumab infusion)

  • intravenous cor<costeroid (methylprednisolone 100 mg or equivalent)
  • oral an<pyre<c (paracetamol at 650-1000 mg)
  • oral or intravenous an<histamine (diphenhydramide 25-50 mg or equivalent)
  • Post-medica;on cor<costeroids on 1st and 2nd day aBer all infusions
  • In case of occurrence of IRRs
  • React early to mild signs of symptoms and immediately stop the infusion
  • Manage symptoms appropriately, consider e.g. an<histamines, cor<costeroids
  • Once symptoms have resolved, treatment resumed at half the infusion rate
  • In case of grade 4 IRRs permanently discon<nue treatment.

Adapted from: Protocol for: Lokhorst et al. N Engl J Med 2015 Aug 26 [Epub] EMA SmPC Nov 2016

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Costello C, Ther Adv Hematol 2017

Daratumumab in specific popula;ons

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Efficacy of Daratumumab as single agent: Combined Analysis

18% 10%

1%

2%

5 10 15 20 25 30 35 16 mg/kg ORR, %

PR VGPR CR sCR

ORR = 31%

16 mg/kg (N = 148) n (%) 95% CI ORR (sCR+CR+VGPR+PR) 46 (31) 23.7-39.2 Best response sCR CR VGPR PR MR SD PD NE 3 (2) 2 (1) 14 (10) 27 (18) 9 (6) 68 (46) 18 (12) 7 (5) 0.4-5.8 0.2-4.8 5.3-15.4 12.4-25.4 2.8-11.2 37.7-54.3 7.4-18.5 1.9-9.5 VGPR or better (sCR+CR+VGPR) 19 (13) 7.9-19.3 CR or better (sCR+CR) 5 (3) 1.1-7.7

  • ORR = 31%
  • CBR = 83% à OS benefit observed also in SD/MR pts
  • Median (range) TTR: 0.95 (0.5-5.6) months
  • Median DOR = 7.6 (95% CI, 5.6-NE) months; responses deepened with continued

treatment (7/10 PR à VGPR; 3 PR à CR - 1 patient - sCR - 2 patients)

Usmani, SZ. Blood. 2016. hfp://dx.doi.org/10.1182/blood-2016-03-705210.

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Usmani, SZ. Blood. 2016. hfp://dx.doi.org/10.1182/blood-2016-03-705210.

Daratumumab Monotherapy – PFS/OS

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OS

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PFS PFS PFS PFS TTNT OS

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How to improve long term outcome in double refractory: the case of Pomalidomide-based triplets in RRMM Pom Dex

ORR 50%, Shah Blood 2015 ORR 64%, Bringhen ASH 2016 ORR 48%, Krishnan A, ASH 2016 ORR 55%, Nooka, ASH 2016 ORR 62%, Chari, IMW 2017 ORR 86%, Paludo Blood 2017 ORR 65%, Richardson, EHA 2016 ORR 48%, Krishnan A, ASH 2016 Ongoing, San Miguel

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Secondo Trapianto in salvataggio

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Treatment Strategy: general principles

Multifactorial decision process Benefit of three drug regimens in early phases of the disease

  • Many combo available
  • Possibility to choose the most suitable mainly (but not
  • nly!) according to pt fitness and previous treatments

At present, no triplets available in late phases of the disease

  • In late phases, tolerability can become even more relevant

than in early phases Generally better to switch to a different class of agent

  • At least one drug from a non-refractory class

But consider re-treatment in specific cases

  • Duration of previous remission
  • Clinical presentation defines agressiveness

Aggre ssiven ess

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Survival es;mates of matched MM pa;ents and controls

Fonseca R, Leukemia 2017

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  • Thirteen clinical trials with 2,402 pa;ents par;cipa;ng.
  • ORR was 57% (95% confidence interval [CI]: 38-76%).
  • VGPR was 32% (95% CI: 19- 46%).
  • mAb-based regimens prolonged PFS ( hazard ra;o: 0.52, 95% CI: 0.36-0.75) compared to non-mAb-

based regimens.

  • The efficacy of triplet regimens was superior to that of single or doublet regimens for both

daratumumab and elotuzumab, with acceptable toxicity

  • The most common grade 3/4 adverse events: anemia, neutropenia, lymphopenia,

thrombocytopenia, leukopenia, pneumonia, and fa;gue.

  • Elotuzumab and daratumumab improved the ORR, at least VGPR, and PFS compared to non-mAb-

based regimens.

  • Daratumumab triplet therapy (daratumumab, lenalidomide, and dexamethasone) was superior to
  • ther triplet regimens.
  • Daratumumab monotherapy was more effec;ve than either single agent.
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Fonseca R, Leukemia 2017