Episode 045: Myeloma Series, Pt.6- Myeloma Treatment in Transplant Ineligible Patients

medicine
Written By TheFellowOnCall HemeOncPodcast

In this episode, we start with a little bit of story time about the history of myeloma treatments and how we got to the present day. We then finish off the episode with how this information helped us treat transplant ineligible patients.

A Historical Perspective: 

  • 1960s-1970s:

    • MP, that is, Low dose oral Melphalan (an alkylating agent) and Prednisone was the standard of therapy for Multiple Myeloma.

    • Progression free survival with MP was 15 months, overall survival very poor. 

  • 1980s: 

    • High dose IV Melphalan + dexamethasone followed by stem cell transplant (as high dose melphalan resulted in bone marrow failure).

    • For relapse refractory disease after MP, high dose dexamethasone alone was given.

    • The efficacy of dexamethasone in myeloma treatment has been known for a long time. (This is why high dose dex is still included in all myeloma regimens today!)

  • Late 1990s: 

    • MP was still the standard of care.

    • Thalidomide was used for relapse/refractory disease for its anti-angiogenic properties. 

      • It was removed from the market due to its teratogenic properties (severe limb hypoplasia in fetus) when given to pregnant women. Later, it was approved for myeloma treatment. 

      • Newer generations are now used including Lenalidomide (Revlimid) and Pomalidomide, which have lesser toxicity but are more expensive.

      • Thalidomide is still used around the world, especially in Europe, but newer agents are more popular in the US. 

    • Around the same time, Bortezomib was introduced.

      • It is a dipeptide which has boronic acid component (hence the name “Bor” tezomib). Also known as Velcade. It was the first ever proteasome inhibitor used for Myeloma treatment.

      • Original studies looked at Velcade vs dex in relapsed/refractory settings, getting its approval. 

    • Cytotoxic chemotherapy was also used as induction therapy prior to transplant. Commonly a combination of vincristine + doxorubicin (aka Adriamycin) + dexamethasone (VAD). Studies in the relapsed/refractory setting suggested that dexamethasone was doing the heavy lifting in these regimens.

    • As a result, later studies found doublets velcade + dexamethasone and thalidomide + dex to be more efficacious than the cytotoxic regimens. 

      • IFM 2005-01 Phase III Trial compared Velcade + dexamethasone to vincristine + doxorubicin + dexamethasone and found velcade + dexamethasone had better VGPR rates and less toxicity.

  • 2000s:

    • Numerous trials looked at a variety of doublet and triplet combinations.

    • There was emergence of a lot of phase 2 trials showing the triplet combination was better! After that, phase 3 trials also showed survival benefit. An example is the SWOG 007 trial, discussed last week. 

How has the treatment evolved in transplant ineligible patients?

  • In patients who are are not candidate for high dose melphalan + transplant: 

    • In the late 90s, velcade + melphalan + prednisone (VMP) became the treatment of choice in older transplant ineligible patients. 

    • Thalidomide+MP (TMP) also worked but this combination caused many toxicities (neuropathy from thalidomide and cytopenias from melphalan). 

    • Revlimid+dex (RD) was compared to TMP, RD was found to be superior.

    • So at that point, we had VMP and RD as options for the transplant ineligible population until SWOG 0777 trial

    • VMP and RD formed the control arm for 2 modern trials that  used Daratumumab in these older patients who are transplant ineligible

  • Right now, the Standard of treatment in transplant ineligible patients is Triplet therapy (VRD or Dara-RD), but some people are also steering towards Quadruplet therapy. 

Why is Triplet regimen the standard of care in transplant ineligible patients? 

  • Recall that SWOG 0777 Trial showed that Bortezomib + Revlimid + Dexamethasone (VRD) improved progression free and overall survival when compared to RD.

    • How do we know this works? 31% in the SWOG trial were transplant ineligible.

    • They got 8 cycles of VRD followed by RD maintenance.

    • There is an overall survival benefit with VRD. 

What is the trial that led to Quadruplet therapy? 

  • ALCYONE trial

  • Compared Daratumumab-velcade+melphalan+predinsone (Dara-VMP) to VMP: 

    • Patients were given 9 cycles of quadruplet therapy and then were put on Dara indefinitely.

    • 3 year overall survival was 78% (this is 10% improvement in standard VMP arm in the trial). 

    • 10% improvement in MRD (minimal residual disease) negative rates:

      •  14% of patients who got Dara VMP were MRD negative, that sustained for >1 year. The control arm only had 3% MRD negative.

    • The caveat of ALCYONE trial is that only 10% of the control arm got Dara when they progressed.

      • It would have been ieal for control arm to get daratumumab on progression.

      • Post protocol care is critical when looking at studies moving an effective later line option to the front line.

      • It does not tell us whether sequential treatment is better than giving Dara upfront. 

What is the MAIA trial?

  • Compared Dara-RD vs RD alone. 

  • Dara RD improved both progression free and overall survival and improved MRD negative rates for >1 year at 11% in Dara-RD vs 2% in RD alone. 

    • Like in ALCYONE trial, MAIA trial also had only 21% patients in the control arm who got Dara in relapse/refractory settings. You could argue that poor post protocol care can harm the control arm so it is important to always think “what did the patient get after progression when thinking about overall survival benefit”.

  • In the US, we use the MAIA trial: indefinite Dara-RD until progression. 

Why did the MAIA trial use RD as control arm instead of VRD? 

  • All the updated analyses from SWOG trial were not available and the older subgroup did not show a statistically significant OS difference. 

  • There was known high grade 3 Neurotoxicity and GI toxicity in older population who got VRD followed by RD maintenance.

Should we give Dara upfront or as sequential treatment in relapse/refractory disease? 

  • Both ALCYONE and MAIA trials failed to answer this question.

  • CASTOR trial:

    • Compared Dara combination therapy vs no-Dara: Control arm got Dara on the back end and it still showed survival benefit.

  • Dara changed the trajectory of the disease in this trial, but we don’t know if that’s the case in the up front setting. Most argue that this will likely be the case but the caveat is that we don’t have good trial data for this thought given poor post protocol care.

TL:DR: In transplant ineligible patients, Dara-RD or VRD remain the standard of care.

  • VRD can be used in patients who can tolerate toxicity.

References:

The crew behind the magic:

  • Show outline: Vivek Patel

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

  • Editing: Vivek Patel

  • Shownotes: Maria Khan, Ronak Mistry

  • Graphics, social media management: Ronak Mistry

TheFellowOnCall HemeOncPodcast
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Episode 046: Myeloma Series, Pt.7- Autologous Transplant in Multiple Myeloma
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Episode 044: Myeloma Series, Pt.5 - Myeloma Treatment