Episode 047: Myeloma Series, Pt.8- Myeloma Maintenance Therapy

medicine
Written By TheFellowOnCall HemeOncPodcast

We continue our myeloma series, transitioning our discussion from autologous stem cell transplant to maintenance therapy for myeloma. 

This episode has been sponsored by Primum. To sign up for a free account, check out: tfoc.primum.co.

Why do we use Revlimid (Lenalidomide) maintenance therapy post stem cell transplant?  

  • Improved PFS with revlimid vs. placebo in three individual RCT (CALGB trial in the US, GIMEMA trial in Italy, IFM trial in France)

  • Only CALGB trial showed an OS benefit. Why? These trials were powered for PFS not OS so could be missing a real difference

  • Then combined these three trials in a 2017 meta-analysis which showed an OS benefit of over 10% at 7 years (62% vs. 50%)  

  • Note that Revlimid increases the risk of a second hematologic malignancy and solid tumor malignancy.

    • Hematologic: 6% in revlimid group vs. 3% in placebo group

    • Solid tumor: 7% in revlimid vs. 4% in placebo group

  • You may see that there was no OS benefit in a trial run in the UK called Myeloma XI, but this was due to high rates of crossover to revlimid in the placebo arm

    • https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30687-9/fulltext

What is the maintenance strategy for high-risk patients?

    • Short answer: PI + IMID (two options) or revlimid alone

      • Bortezomib (Velcade) + Revlimid = VR

      • Carfilzomib (Kyprolis) + Revlimid = KR

    • Patients with high-risk cytogenetics have a median PFS of only 2 years with single revlimid maintenance

    • We can get these patients to remission, but it is hard to keep them there

    • We have some weak data to support dual maintenance with PI + IMID in the high-risk patient population which has been largely adopted in the field of myeloma

What is the rationale for adding a PI for high risk?

    • Thalidomide was previously utilized post transplant but…

      • High rates of long term neurotoxicity despite some improvement in PFS

      • Patients in CR did not benefit as much

      • Patients with high risk did not benefit 

    • Then there was a very early transplant trial called HOVON-65 that incorporated the use of velcade with cytotoxic chemotherapy and maintenance 

      • The key with this trial is that maintenance compared single agent velcade and thalidomide

      • Hope was for better efficacy and toxicity with velcade

      • Found that velcade had much better outcomes particularly in high risk patients based on cytogenetics and thalidomide had adverse outcomes in that group

    • At that time, we had single agent velcade as a potential maintenance option which is why you will see this in the NCCN guidelines for high risk patients

      • Weak evidence because induction here was vincristine + doxorubicin + dex vs. velcade + doxorubicin + dex and used thalidomide as comparator not revlimid


What data shows efficacy of doublet maintenance therapy for high-risk patients?

    • Single Institution Emory Experience:

      • Looked at 1000 consecutively treated patients from 2007-2016 treated with RVD induction

      • All patients with high risk cytogenetics got triplet RVD maintenance after transplant

      • Median PFS was 40 months (little over 3 years) and OS 78 months

      • Significant improvement over other trials looking at single agent revlimid which showed median PFS ~2 years in the high risk subgroups

      • Pratically we drop the steroid and use doublet maintenance to spare toxicity from long term use

    • FORTE Trial (Randomized Phase II Trial for Carflizomib):

      • Three different induction triplets using second generation PI carfilzomib 

      • KCyd x 4 + auto vs. KRD x 4 + auto vs. KRD x 4+ KRD x 4 consolidation

      • Then randomized to two different maintenance strategies:

        • KR vs. R

      • KR vs. R maintenance had improved 3 year PFS 75% vs. 65%

      • For high risk subgroup, 3 year PFS ~70% vs. 55% 

        • This includes t(4;14), t(14;16), del(17p), and gain 1q

        • The publication takes out the gain1q patients changing these results slightly 

Here is a deeper dive into the Forte Trial focusing on maintenance randomization portion:

    • First randomization was powered for VGPR prior to maintenance

    • Second randomization was powered for PFS

    • Let’s focus on the maintenance portion for this episode:

      • KR vs. R maintenance had improved 3 year PFS 75% vs. 65%

      • For high risk subgroup, 3 year PFS ~70% vs. 55% 

        • This includes t(4;14), t(14;16), del(17p), and gain 1q

        • The publication takes out the gain1q patients changing these results slightly 

      • Important to note that KR maintenance was superior irrespective of MRD status assessed prior to matinance emphasizing that one time point of MRD isn’t important but sustained MRD is critical 

    • Takeaway:

      • KR vs. R improved PFS which is expected because two drugs should be better than one drug

      • Future trials need to power for OS or PFS2 to really show that this maintenance is warranted!

      • Key is that maintenance should change trajectory of disease and improve OS which we don’t know → are we setting up resistant clones at relapse and not improving OS but adding toxicity and infusion time with doublet maintenance?

      • We don’t have the answer to that question but in this trial we do see that dual maintenance seems to benefit high risk patients compared to historical perspective

        • Notable that the single agent R control arm did better than expected with median PFS ~3 years compared to 2 years in prior studies for high risk so may not get this astounding over 3 year PFS benefit but definitely seems better with dual maintenance nonetheless 

What about MRD assessment in the FORTE Trial and how does it emphasize the importance of sustained MRD negativity?

    • MRD rates comparable in KRD + auto vs. KRD + KRD consolidation arm (~5% difference favoring auto arm)

    • However, sustained MRD at 1 year much more different

      • Auto: 47% 

      • KRD consolidation: 35%

    • Went from very similar to a 12% difference and this also translated into better PFS

    • This really highlights the fact that newer combination KRD doesn’t negate the need for transplant and one time point of MRD not as informative as sustained MRD when thinking about using it as a surrogate marker for PFS

What is the role of daratumumab in the maintenance setting?

    • Short answer:

      • IF Dara-VTD induction then dara maintenance not required

      • If Dara-VRD, don’t know but the phase II trial used dara-R maintenance so that is accepted in current practice

      • If Dara-KRD, don’t know but emerging data on risk adaptive MRD approach to consolidation and maintenance post transplant

    • Dara-VTD trial (CASSIOPEIA)

      • Induction randomized Dara-VTD vs. VTD

      • Maintenance randomized daratumumab vs. observation regardless of induction strategy and powered for PFS (not OS or PFS2)

      • Major limitation because revlimid ideally would be control arm as this is current standard of care but revlimid OS meta analysis not published when trial was created

      • Dara improved PFS over placebo in the whole population but there was no benefit for those who got dara at induction

      • This means that observation no different than dara maintenance if used in induction

      • We have no idea how revlimid plays into this and if those who got dara at induction would benefit from R maintenance over observation because of the trial design 


    • Dara-VRD (GRIFFIN Phase II Trial)

      • Everybody got Dara-R maintenance in the Dara-RVD arm and the RVD arm just got R maintenance 

      • Doesn’t answer our question so we continue dara in maintenance


    • Dara-KRD (MASTER Trial)

      • Risk adapted MRD approach to maintenance strategy

      • All patients got Dara-KRD followed by auto

      • They then got more Dara-KRD consolidation if they did not have sustained MRD negativity at two timepoints

      • Those without MRD negativity went on to revlimid maintenance

      • Those who had MRD negativity sustained went on to observation without maintenance therapy

      • Ultimately, results showed that standard risk patients could reasonably undergo a risk adapted MRD approach without the need for maintenance therapy if MRD negative

        • There was a low resurgence of MRD at 1 year off therapy in that trial

    • Key Points:

      • Unclear if dara is required in maintenance if used as quadruplet in induction and would not use if they get dara-VTD but unclear for other quadruplet regimens

      • The future is moving towards a risk adapted approach at least in the standard risk population based on the MASTER trial 

        • Where patients could be observed off treatment with sustained MRD negativity and we may use more quadruplet consolidation rather than indefinite maintenance to get to this goal

References:

This episode has been sponsored by Primum. To sign up for a free account, check out: tfoc.primum.co.

The crew behind the magic:

  • Show outline: Vivek Patel

  • Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath

  • Editing: Vivek Patel

  • Shownotes: Vivek Patel and Madeline Fitzpatrick

  • Graphics, social media management: Ronak Mistry

TheFellowOnCall HemeOncPodcast
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Episode 046: Myeloma Series, Pt.7- Autologous Transplant in Multiple Myeloma