TREATMENT OF RELAPSED DISEASE OUTSIDE CLINICAL TRIALS

Dr. Moshe Gatt

Hadassah Hebrew University Medical Center,

Jerusalem, Israel.

SCOPE OF THE PROBLEM

• Most data for registering

and administering

medications comes from

randomized clinical trials

• Only the minority of patients will enroll to clinical trials.

In the US only 3% of

all cancer patients

participate in clinical

trials

Combest AJ et al, J.

Clin. Oncol. (2013). 31(15 suppl),

e17586

SCOPE OF THE PROBLEM- WHY CLINICAL TRIALS ARE NOT REAL WORLD DATA

https://www.fightcancer.org/policy-resources/clinical-trial-barriers#figures

SCOPE OF THE PROBLEM- WHY CLINICAL TRIALS ARE NOT REAL WORLD DATA

https://www.fightcancer.org/policy-resources/clinical-trial-barriers#figures

SCOPE OF THE PROBLEM

• All data for registering and administering a medication comes from

randomized clinical trials

• Only a minority of patients will enroll to such trials.

• = We treat our patients according to results obtained from an ultra-

selected population.

Evolution of myeloma treatment practices in Europe from 2014 to 2016

Raab et al. British Journal of Haematology, First published: 22 November 2018

SCOPE OF THE PROBLEM

• All data for registering and administering a medication comes from

randomized clinical trials

• Only a minority of patients will enroll to such trials.

• = We treat our patients according to results obtained from an ultra-selected

population.

• Are these results replicable in all populations?

• Are these results replicable in the relatively non-resourceful countries?

• How applicable is the real-world retrospective data?

SCOPE OF THE PROBLEM-EXAMPLE OF A NEW PROTEASOME

INHIBITOR CLINICAL STUDY CRITERIA

• Inclusion criteria:

– Confirmed PD.

(Do we always measure all criteria for PD? Do we have all previous data?);

– Measurable disease.

(advanced stage patients tend to develop non secretory disease);

– ECOG>2

(Elderly and patients with severe skeletal involvement excluded);

– Refractory to IMiD X.

(Easy, but if IMiDY was used or PD recorded after 62 days…=excluded);

– Had at least a PR and DID NOT have PD during treatment of PI

(Not easily found…).

SCOPE OF THE PROBLEM-EXAMPLE OF A NEW PROTEASOME

INHIBITOR CLINICAL STUDY CRITERIA

• Inclusion criteria:

eventually when the compound is authorized, it will be administered to the

average patient who has a high ECOG score, and is resistant to PI’s, as

probably are most pts at this point of their disease

SCOPE OF THE PROBLEM- REAL WORLD DATA

Combined data of GEN501 and Sirius

(Blood. 2016;128(1):37-44)

SCOPE OF THE PROBLEM- REAL WORLD DATA

SCOPE OF THE PROBLEM- REAL WORLD DATA

SCOPE OF THE PROBLEM- REAL WORLD DATA

(Eur J Haematol. 2018;100:494–501)

SCOPE OF THE PROBLEM- REAL WORLD DATA

SCOPE OF THE PROBLEM- REAL WORLD DATA

Combined data of GEN501 and Sirius

(Blood. 2016;128(1):37-44)

(Pick et al, Eur J Haematol. 2018;100:494–501)

“29 of 30 (96.6%) of the heavily pretreated MM patients

progressed or died. Moreover, patients had EM plasmacytomas

and a non-secretory disease”.

SCOPE OF THE PROBLEM- REAL WORLD DATA

• Exclusion criteria:

– Adequate CBC .

(Heavily pretreated and aggressive disease patients will be ineligible);

– CCT of >30.

(20-50% of pts will have renal involvement. 10% require dialysis);

– Diagnosed for another malignancy within 2 years

(5-10% of patients + 3-4% developing new SPM);

– Diagnosis of AL amyloidosis.

(~ 10% of patients);

– Active (sometimes excluding even non active) HBV

(~ 1-8% of the population).

SCOPE OF THE PROBLEM-EXAMPLE OF A NEW PROTEASOME

INHIBITOR CLINICAL STUDY CRITERIA

• Exclusion criteria:

– Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral neuropathy

(Almost all patients will have some degree of neuropathy at this stage….).

– Treatment with monoclonal antibodies within 5 half-lives days before randomization,

systemic anticancer therapy or radiotherapy within 14 days before randomization

(Excluding patients with the most aggressive disease).

SCOPE OF THE PROBLEM-EXAMPLE OF A NEW PROTEASOME

INHIBITOR CLINICAL STUDY CRITERIA

SCOPE OF THE PROBLEM- WHO IS THE AVERAGE CLINICAL TRIAL PATIENT

• Has sufficient background data, and a measurable disease.

• Must have a good performance status.

• Must not be refractory to all previous lines.

• Neither is he still under the hematologic AE’s of his previous treatment, nor

has myeloma related AE’s such as severe renal failure and BM replacement

by disease.

• Most importantly- his disease must not be too aggressive….

• VD/VCD/VRD/VTD/VMP/

DVD/EVD/VDoxoD/ D-VMP/D-VRD

• CTD/TD/MPT

• RD/KRD/DRD/DVD/ERD/ iRD/CRD/MRd

• Kd/KCD/KTD/KPD

• Pom/CPd/PVd/EPd/ iPD

• Dara/DPd/DKd

• Good old chemotherapy

• Re- ASCT

• More and more and more…

SO – WHAT CAN WE DO WITH THE RELAPSING EVERYDAY PATIENT?

• Treatment according to clinical trials.

SO- WE KNOW WHAT TO DO AND WHAT TO CHOOSE AMONG THE 2ND , 3RD , 4TH LINE

COMBINATIONS

Our real questions start at the point where

there is no data, like:

• What to do with a biochemically

asymptomatic progressing patient?

• What to do with previous resistance (is

there a point in retreatment? Will there be

synergism?)

• What can we do with quadri and penta

resistant patients?????

RRMM- MONEY ALSO MATTERS

• Combining novel agents? Steroids? conventional chemotherapy? All of

these together? Is more better?

• Combine at treatment initiation vs. at NR/PD?

• Use Registered medications (i.e. PI’s, IMiDs, Ab’s, conventional

chemotherapy) vs. Non- registered medications (i.e. venetoclax,

ibrutinib, checkpoint inhibitors etc.)

• At what cost?

(Bortezomib generic but still not trivial at 1500$ per month).

Don’t know the

answer?

Do what I do….

Speak in a foreign

accent until the

customer hangs up

RRMM- DARATUMUMAB AS > 4TH LINE OPTION- ARE COMBINATIONS BETTER?

• Combining novel agents: Daratumumab

(Usmani et al. Blood. 2016;128(1):37-44) (Lakshman et al. Am J Hematol. 2017;92:1146–1155)

DPd, DRd, DVd and other DCT groups. ORR was 47%;

46%, 50%, 57%, and 35%, respectively.

(Pick et al, Eur J Haematol. 2018;100:494–501)

RRMM- DARATUMUMAB AS > 4TH LINE OPTION- ARE COMBINATIONS BETTER?

• Combining novel agents: Daratumumab (4th line in Israel)

(Benyamini et al, ASH 2018; IMS Jerusalem 2019)

No OS difference was

found between those

who stopped

daratumumab at time

of failure and those

who continued it Median OS 5.3 m

Are the responses

for combined agents

– true synergism

or

single second agents

responses?

RRMM- Daratumumab as > 4th line option

THE VALUE OF REFRACTORY AGENTS RE-TREATMENT?

• IMiD-refractory patients with IMiD retreatment ORR was 52% (15/29 patients)

NONE (!) of the 15 responders treated with neither same agent or same dose

nor same regimen (i.e. a third agent combo. Dexa instead of prednisone etc.)….

• PI refractory with PI retreatment ORR was 67% (4/6 patients)

Only 1 of the 4 treated with ~same re-VRD.

Oostvogels et al British Journal of Haematology, 2018, 183, 60–67

THE VALUE OF REAL-WORLD DATA OF IMID+PI REFRACTORY AGENTS SURVIVAL

Risk of progression and survival in

multiple myeloma relapsing after therapy

with IMiDs and bortezomib: A multicenter

international myeloma working group

studyKumar SK et al Leukemia (2012) 26, 149–157.

Natural history of relapsed myeloma, refractory to

immunomodulatory drugs and proteasome

inhibitors: a multicenter IMWG study

Kumar SK et al Leukemia (2017) 31, 2443–2448

PFS= 5 months // OS= 9-15 months

THE VALUE OF REAL-WORLD DATA OF IMID+PI REFRACTORY AGENTS SURVIVAL

Analysis of Real-World Data on Overall Survival in Multiple

Myeloma Patients With ‡3 Prior Lines of Therapy Including a

Proteasome Inhibitor (PI) and an Immunomodulatory Drug

(IMiD), or Double Refractory to a PI and an IMiD

Usmani S et al The Oncologist 2016;21:1355–1361.

THE VALUE OF REAL WORLD DATA

THE VALUE OF REAL WORLD DATA

HERE ARE A FEW CASES TO OUTLINE SOME POINTS OF VIEW

THE VALUE OF SD – MR. A.S.(I .E. CLINICAL BENEFIT RATE (CBR))

• 58 year old male diagnosed 10.2007. Treated with TD (CR)-> Mel 200 -> 6.2010 re

TD. CR until 2013.

• 6.2013 relapse. RD. stopped d/t neuropathy 4.2014.

• 4.2014 relapse. VCD (PR). stopped d/t neuropathy

• 12.2014 = Rd arm of Pollux. (re-neuropathy but controlled)

• 23 months of ongoing SD (11.2016).

• Daratumumab 11.2017. Pom dex ,and guess what?

(2.2019- has ongoing SD)

THE VALUE OF RE- ASCT MR. O.B.D.

• 60 yrs old, diagnosed 2008. Treated with Rd and 3/2009 ASCT.

• 4.2011 relapsed. Enrolled to Rd control arm of the Aspire.

• 7.2012 VCD

• 6.2013 pancytopenia and multiple bone plasmacytomas. BM with 5% PCs and

MDS.

• Radiation + Dex…*

• 11/2013 re- ASCT- 12 months of CR and normal counts.

• 11/2014 relapse (pom, radiation, PD. Death)

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

NCCN 2.2019 guidelines: repeat ASCT

depend on time interval between preceding

SCT and PD < 2 years

*HD solumedrol effective

(Gertz MA et al Leukemia 1995;9(12):2115)

THE VALUE OF CONVENTIONAL CHEMOTHERAPY- MR. A.L.

• 65 yr old. Diagnosed in Russia 2013. Has concurrent AdenoCA of lung (stable). Treated with VCD

gr.4 neuropathy.

• 2014 Active disease. Len based.

• 2015 Pom based.

• 2.2016 Elo+ Cfz. (PR) multiple E.M. relapse +Thalidomide

• 2.2017 Daratumumab CHOP

• 6.2017 I.V. Melphalan 9.2018 (nCR. longest PFS ever).

* Same idea with other alkylators (cyclophosphamide) and Bendamustine

THE VALUE OF METRONOMIC TREATMENT- MR. S.L.

• FOCUS study

Hajek R et al Leukemia (2017) 31, 107-114

• 47 yr old. Diagnosed 10.2007. Treated with MPR.in PR until 5.2010 and then PD= VCD (PR) ASCT 3 months later FLC rising Rd.

• 2.2012 PDVD+/- Perifosine. SD for 5 months and PD.

• 8.2012 metronomic cyclo/dex. CR to the present day (6.5 years!).

THE VALUE OF METRONOMIC TREATMENT- MR. H.H.

• The Arkansas metronomic VDT-PACE • 63 yr old Diagnosed 10.2010 with PCL

and stage IV cardiac AL amyloidsis. Treated with VCD (CR)+ V maintenance.

• 10.2014 relapse with E.M. plasmacytomas. DCEP x 2 and ASCT Len maintenance CR for 2 years but now has pancytopenia.= MDS.

• 8.2017 relapse. Daratumumab+Pd(NR) Cyclo+ Kd (NR) Low dose CHOP (NR). metronomic Cyclo/dex(NR) .

• 6.2018= E.O.L. talk

• 6.2018 metronomic melphalan. PR to the present day, continuously declining FLC.

+ GCSF/ blood and plt support for the MDS

Papanikolaou X et al . Haematologica (2013); 98(7). 1147

BIOCHEMICAL RELAPSE – TO TREAT OF NOT TO TREAT?

Katodritou et al Annals of Hematology (2018) 97:1671–1682 Sidana et al Leukemia (2018) Oct 15

(No OS benefit)

EARLIER ADDITION OF CYCLOPHOSPHAMIDE TO LENALIDOMIDE

REFRACTORY PATIENTS

Nijhof I et al. Blood 2016;128:2297-2306

67 pts.

ORR 67%

PFS 12.1 months

OS 29.0 months

Cecini L et al. Eur J Haematol 2018;101:160-164

31 pts.

ORR 29%

PFS 13.1 months

OS 17.7 months

THE VALUE OF CLARITHROMYCIN’S ADDITION TO IMIDS (BIRD) – MR. M.S.

• 60 yr old. Diagnosed 2.2013 treated with VCD 2 cycles NR.

• VDT-PACE – nPRlow CD34 SC collection ASCT MEL200

• 2 months post ASCT BM w/20% PCs and FLC rising. Pancytopenia

• Thalidomide Dex PD

• Clarithromycin added.PR. Dex stopped.

• Thal replaced by Lenalidomide after 1 year.

• PFS 12/2013-5/2017 on 5 mg Len+ clarithromycin.

THE VALUE OF CLARITHROMYCIN’S ADDITION TO IMIDS

Ghosh N et al.Am J Hematol. 2014 Aug;89(8):E116-20.

24 pts.

ORR 41.7%

PFS 4 months

OS 25.0 months

Shaulov A. et al. Am J Hematol. 2017 Feb; 92(2):131-135.

31 pts.

ORR 48.0%

PFS 5.2 months

OS 25.2 months

COMPASSIONATE USE OF MEDICATIONS OR WHEN THE PATIENT HAS FINANCIAL

RESOURCES

• Venetoclax for t11:14 or w/ bortezomib for all)

(ORR 65% and w/bortezomib-97%)

• Selinexor (with dex or w/ bortezomib)

(ORR 20% and w/bortezomib 63% and even 43% for PI resistant)

• Ibrutinib (with dex)

(ORR 11% but CBR 34% and PFS 4 months)

• Panobinostat (with bortezomib dex)

(PFS benefit of 7.8 months with PAN-BTZ-Dex)

• CAR-T (not readily available. China?)

CONCLUSIONSTREATMENT OF RELAPSED DISEASE OUTSIDE

CLINICAL TRIALS

• Only a minority of pts are enrolled in clinical trials so our every day patient most of the time cannot be really compared.

• Real world data is almost always inferior to that described in clinical trials

• A stable disease is NOT necessarily treatment failure

• Re- usage of agents in refractory patients may not be additive if really refractory to it.

• We should consider the value of treating at a biochemical relapse

• Conventional chemotherapy is an option, especially if the patient was hardly exposed to it

• Metronomic therapy may surprise you

• Clarithromycin addition to IMiDs may surprise you

• New novel agents and therapies are close by… so there’s hope even for advanced patients

• Enroll your patients on clinical trials!

• Continue reporting REAL world data

THANK YOU FOR LISTENING