Continuous TherapyFor Management of RRMM

(continuous versus fixed duration)

Pr Jean Luc HarousseauInstitut de Cancérologie de l’Ouest

France

Initially

This should have been a debate between Paul Richardson (Continuous therapy) and me (Fixed duration)

Initially

This should have been a debate between Paul Richardson (Continuous therapy) and me (Fixed duration)

« what can I say ? »

Multiple Myeloma: Patient Outcomes in Real‐World PracticeTreatment Duration and Treatment‐Free Interval by Line of Therapy*

*Data from 4997 patient charts in Belgium, France, Germany, Italy, Spain, Switzerland, and the UK. The proportion of patients who had received each line are from the cross‐sectional review; data on durations of treatment and treatment‐free intervals are from the retrospective review.1L‐5L = first line‐fifth line treatment; CI = confidence interval; m = month.Yong K, et al. Br J Haematol. 2016;175:252‐264.

End5L

Proportion of patients reachingthis line of therapy (%)

3 m 5 m

1 m 4 m

Treatment‐free interval

Median duration in months shown100% Diagnosis

95%1L

Mean (95% CI): diagnosis, 2 m (1.60, 2.40); 1L, 8 m (7.74, 8.26); 1L maintenance, 9 m (7.78, 10.22)

1 m 6 m6 m

End 1Linduction

Start1L

End 1Lmaintenance

61%2L

Mean (95% CI): interval, 1L‐2L, 16 m (15.0, 17.0); 2L, 9 m (8.64, 9.36)

10 m 7 m

End2L

Start2L

38%3L

Mean (95% CI): interval, 2L‐3L, 11 m (10.22, 11.78); 3L, 8 m (7.63, 8.37)

5 m 6 m

End3L

Start3L

15%4L

Mean (95% CI): interval, 3L‐4L, 7 m (5.9, 8.1); 4L, 6 m (5.5, 6.5)

End4L

Start4L

1%5L

Mean (95% CI): interval, 4L‐5L, 3 m (1.8, 4.2); 5L, 4 m (3.15, 4.85)Start5L

Active treatmentMaintenance treatment

Continuous vs Fixed Duration therapyin RRMM

The question is not relevant in laterelapses (>3prior lines of treatments)

Median PFS are usually

Continuous vs fixed durationtherapy in RRMM

Earlier relapses (1 to 3 previous lines of treatment)

Double combinations

Median PFS or TTP was short APEX (VD): 6.2m MM09‐MM10 (LD): 13.4 m MM03 and Stratus : 4m and 4.6 m (heavilypretreated patients)

Richardson NEJM 2005;16:2487 Dimopoulos Leukemia 2009;23:2147 San Miguel Lancet Oncol 2013;14:1055 Dimopoulos Blood 2016;128:497

Continuous vs Fixed durationThe question is usually irrelevant with BTZ‐based combinations

Since the maximum number of B cycles is 8

Treatment Plannedduration 

Maitenance Effective duration 

Median TTFor PFS

APEX VD vs D 8 cycles  NO 8 cycles in only 29% pts

7m

ENDEAVOR K56D vs VD Untilprogression or SAE

NO Median 39.9w vs 16.8 w

18.7 m vs 9.4 m

PANORAMA 1 Pan VD vs Plac VD

8cycles  4 cycles in both groups

Median 6m vs 6.6 m

12 m vs 8.2 m

CASTOR DaraVD vs VD

8 cycles  Dara onlyUntilprogression or SAE 

57% received 8 cycles VD vs 79% DVD

NR vs 7.2

Continuous therapyLenalidomide‐based combinationsTreatment Planned

duration Maintenance Effective

duration Median PFS (m)

ASPIRE K27d vs Rd 18 cycles Rd in botharms

Median 88 w vs 57 w

26.3 vs 17.6

TOURMALINE1 IRd vs Rd Untilprogression or SAE

Mediannumber of cycles 17 vs 15 (48%vs 43%> 18 cycles

20.6 vs 14.7

ELOQUENT 2

EloRd vs Rd Untilprogression,SAE or consent withdrawal

17m vs 12m 14.9 vs 19.4

POLLUX DaraRd vs Rd Untilprogression, SAE or consent withdrawal

24 m vs 16m

NR (68% at 24 m) vs 17

Lenalidomide‐Dex1 vs ≥vs 2 prior therapies

Stadtmauer E Eur J Haematol 2009;82:426

Treatment of First RelapseLong PFS are achieved with current triplets

Aspire KRd vs Rd    KRD Med PFS 29.6m 

Tourmaline-MM1 Ird vs Rd HR 0.88(0.6 if no prior Tx)

Pollux DaraRd vs Rd   HR 0.44 p

34%

26%

13%10%

6% 3%0

10

20

30

40 DRd (n = 286)

POLLUX: MRD‐Negative Rates and Time to MRD Negativity

• In the total evaluable population, MRD negative rates were more than 3‐fold higher with DRd versus Rd at all sensitivity thresholds• MRD negative patients (identified at the 10–5 sensitivity threshold) accumulated more rapidly with DRd versus Rd

MRD = minimal residual disease.Dimopoulos MA, et al. Presented at European Hematology Association Annual Meeting. June 22‐25, 2017. Madrid, Spain. Abstract P334.

MRD

 Negative Ra

te (%

)

P 

PFS Based on MRD Negativity in the ITT POLLUX & CASTOR

PFS was prolonged in patients who achieved MRD negativity

Courtesy Avet Loiseau H

OS Based on MRD Negativity in the ITT POLLUX & CASTOR

OS was prolonged in patients who achieved MRD negativity

PFS Based on Sustained MRD Negativity (10-5; > 12 Months)

PFS was prolonged in patients with sustained MRD negativity 12 months, regardless of treatment arm

OS Based on Sustained MRD Negativity (10-5; 6 Months)

OS was prolonged in patients with sustained MRD negativity 6 months, regardless of treatment arm

IN FIRST RELAPSE

With modern combinations The objective of treatment should now be

to achieve the best possible PFS And to achieve and prolong

It is the same old story

…. AS for Frontline therapy

CONTINUOUS THERAPY

Until progression or SAE One of the causes of the major

improvement in MM outcome observedover the last 20 years

With the objectives of- deepening the response- delaying progression

What would be the interestof fixed (reduced) duration

Decrease the incidence of adverse eventsand improve quality of life

Decrease costs Save effective drugs for later treatments Decrease the risk of resistance ?

Safety in RCT

ASPIRE TOURMALINE 1 ELOQUENT2 POLLUX CASTOR

Treatmentdiscontinuation due to SAE

15.3% 17% 13.5% 6.7% 7.4%

In the past Continuous or maintenance therapyhas always prolonged PFS

in responding patients Chemotherapy

Interferon

Thalidomide

But the key question is OS BENEFIT Adverse events and extra-cost of continuous

therapy are justified only if there is an OS benefit

Chemotherapy: no OS benefit 1 Interferon: 4 to 8 m benefit 2,3 Thalidomide : OS benefit not in all trials

(6 RCT 4 , one meta-analysis 5 )New agents were not always available

EARLY versus LATE Thalidomide

23

1 Belch Br J Cancer 1988;57:94 2 Ludwig H Acto Oncol 2000;39:815 Myeloma trialists Br J Haematol 2001;113:10204 Ludwig H Blood 2012;119:3003 5 Wang Y J Natl Cancer Instit 2016;108;dlv 342

Lenalidomide post ASCTFour randomized trials show a dramatic PFSimprovement

HR 0.57 p

Results are less clear for OS

Significant OS benefit CALGB

MRC XI

No significant OS benefit GIMEMA

IFM

The OS benefit may be delayed due to better salvage treatments

Meta-analysis of the 3 trials (1208 pts, 79.5 mo median f-up) The benefit of a longer duration of first response translates into a longer OS only

after 5 years

Mc Carthy P (JCO 2017 online)

Survival after 1st progression was shorter in the IFM 05-02 with lenalidomide

Patients in the lenalidomide arm responded less wellto HD Len-Dex at relapse

P

Maintenance or continuoustherapy in elderly patients

28

MM‐015: MP 9 cycles vs MPR 9 cycles +/‐ R PFS and OS (459 pts)

• Trend for extended OS with MPR-R vs MP (estimated 3-yr OS: 73% vs 65%; p=0.254)

PFS OS

Palumbo et al. NEJM 2012;366:1759-69

4-year OSMPR-R 69%MPR 61%MP 58%

FIRST trial (1623 pts)MPT 12 cycles vs Rd 12 cycles vs Rd continuous

PFS OS

Benboubker L NEJM 2014;371:906 T Facon Blood 2018;131:301

Rd>MPT (PFS and OS)Rd continuous not >Rd 18m for OS

MRC XI TRIAL Lenalidomide maintenance in the TNE Pathway

PFS med 26 m vs 11 m 3‐yr OS  67% vs 70%

Jackson GH Lancet Oncol 2019;20:57-73

Duration of treatment in First Relapse

Until now no randomized study addressed this question Continuous treatment may be associated with more CR

(KRd parients in the ASPIRE study)

Cumulative ≥ CR rates                PFS according to CR

Dimopoulos M J Haemtol Oncol 2018;11:49

Duration of treatment in First Relapse

Until now no randomized study addressed this question Continuous treatment may be associated with more CR Continuous treatment may be associated with more 

Duration of treatment in First Relapse

Until now no randomized study addressed this question Continuous treatment may be associated with more CR Continuous treatment may be associated with more 

PFS in LEN‐refractory patients

CASTOR 

ENDEAVOR

OPTIMISMM 

Chanan-Khan A ASH 2016 Moreau P Leukemia 2017;31:115 Richardson P Lancet 2019

Double refractory MM

RR to first treatment 12% if Bort or Len

35 % if Pom or Car Med PFS 5m Med OS 15m

80

60

40

20

0Pa

tient

s, %

Overall survival

0 12 24 36 48 60

Duration From Time Zero, months

9Event-free survival 5 (

Kumar S Leukemia 2017

Duration of treatment in First Relapse

Until now no randomized study addressed this question Continuous treatment may be associated with more CR Continuous treatment may be associated with more 

Is it possible to design a trial addressing the question

of treatment duration in First Relapse ? Pharma companies are more interested in trials

testing new drugs or new startegies Should be academic ( ex : IFM trial comparing

DaraRd continuous versus 2y in first relapse) Primary objective ?

- OS too long and non-inferiority design- PS probably in favor of continuous

Based on MRD

Conclusion

In the majority of patients with RRMM treatment should be continued

But in First relapse where a high incidence of long PFS is hoped with new combinations

The question of longer PFS (continued therapy) vs toxicity/quality of life and extra-costs (fixed or result-adapted duration) should addressed