Episode 044: Myeloma Series, Pt.5 - Myeloma Treatment

medicine
Written By TheFellowOnCall HemeOncPodcast

In this continuation of our myeloma series, we build on our prior discussion about myeloma pharmacology, this time discussing how to select the optimal regimen for treatment of our patients.

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

What are the phases of multiple myeloma treatment?

  • Induction

    • Goal: Attempting to debulk disease, usually with 4-6 cycles of therapy, ideally M spike is nearly gone (VGPR) and bone marrow plasma percentage is < 10%.

    • We collect stem cells during induction therapy before the bone marrow is too damaged from repeated rounds of chemotherapy.

  • Consolidation

    • Goal: Attempting to deepen the response to treatment

    • In transplant eligible patient: You are trying to do this with high doses of chemotherapy (alkylator), specifically melphalan

    • The toxicity of alkylators is bone marrow suppression which requires us to give them back their own stem cells that we collected earlier (i.e., autologous transplant.)

    • In transplant ineligible patient: We can consolidate with more cycles of our induction therapy or just go on to maintenance.

  • Maintenance

    • Goal: Attempting to maintain response and maximize the patient’s quality of life.

    • Usually, a lower dose of one or more of the components of induction or consolidation therapy.

    • Often -IMIDs, such as lenolidomide used

  • Relapse Refractory

    • Some patients are eligible for a second transplant and will start over with re-induction.

    • Otherwise, patient moves to successive lines of treatment until they have disease progression or intolerable side effects.

How do we determine transplant eligibility?

  • No true age cut-off; more about physiologic reserve

  • Some patients may need reduced doses of melphalan

What does doublet, triplet, and quadruplet therapy mean?

  • Myeloma therapy are multidrug regimens containing either two, three, or four drugs

  • At the time of our recording: triplet is standard of care

  • One of these drugs is always dexamethasone

  • The other drugs are a combination of the following:

    • Proteasome inhibitor → ends in “zomib” (bortezomib, carfilzomib)

    • Immunomodulatory drug (IMID) → ends in “omide” (lenalidomide, thalidomide)

    • CD38 monoclonal antibody (daratumumab)

    • Alkylator → currently cyclophosphamide or historically low dose oral melphalan

Potions 101: Selecting a myeloma treatment regimen.

What characterizes “high risk” myeloma?

  • High-risk cytogenetics:

    • t(4;14)

    • t(14;16)

    • Deletion 17p

    • Amplification 1q (> 3 copies)

  • Circulating plasma cells in the peripheral blood (especially if >20% of total WBCs are plasma cells)

  • Extramedullary plasmacytoma (myeloma cells outside of boney lesions)

  • NOTE: R-ISS is NOT the same as the high risk characteristics noted above when thinking about looking at subgroups in clinical trials

    • You may see elevated LDH in some studies as part of that criteria but always important to look at the methods when interpreting the results

What is the current standard of care for transplant eligible patients?

  • Triplet regimen: IMID + a proteasome inhibitor + dexamethasone

  • In the US, we use VRD (aka RVD): Velcade (bortezomib) + Revlimid (lenalidomide) + Dexamethasone

  • SWOG 0777:

    • Established VRD as standard of care for transplant eligible and ineligible patients compared to doublet therapy (revlimid and dexamethasone)

    • Patients who achieved VGPR at 1 year had improved OS in a landmark analysis

  • In Europe, they use VTD: Velcade + Thalidomide + Dexamethasone

  • Thalidomide is substituted for Revlimid for cost reasons.

  • In the US, we prefer VRD as it has been shown to have deeper responses and less neuropathy in a pivotal integrated analysis from several clinical trials.

  • For high-risk patients, providers may choose induction therapy with KRD: Kyprolis (carfilzomib) + Revlimid + Dexamethasone.

    • FORTE Trial: Data suggested the KRD followed by KR maintenance may be better for high risk patients

    • ENDURANCE Trial: Compared KRD vs. VRD:

      • No difference in overall or progression free survival.

      • KRD had more toxicity and was associated with more treatment related deaths.

      • Note that this trial did not include high risk patients.

Where does “CyBorD” fit in for treatment?

  • CyBorD: Cyclophosphamide + Bortezomib (Velcade) + Dexamethasone

  • Preferred in renal insufficiency.

  • Otherwise, VTD and VRD have been shown to be superior with less toxicity.

When would we consider adding daratumumab (anti-CD38 antibody) for a quadruplet regimen?

  • Trials in the space powered for response rates but no definitive statistical evidence powered for improved PFS or OS

  • If triplets are good, are quadruplets better?

    • GRIFFIN: Dara-VRD better sCR and MRD negative than VRD

    • CASSIOPEIA: Dara-VTD better sCR and MRD negative than VTD, PFS benefit shown but poor post protocol care in the VTD group with many patients not getting dara at relapse

    • MANHATTAN and MASTER: Dara-KRD with high sCR and MRD negative rates

  • High Yield Takeaway Points:

    • Adding daratumumab led to higher CR rates and more MRD negativity with little added toxicity

    • Some myleoma providers prefer this approach for all comers over standard of care VRD with the hope that this will translate into improved PFS, OS, and quality of life

    • Some argue that high risk patients benefit most from quadruplet induction given poor outcomes historically but there is no definitive data that this is true

    • When the patient relapses, we do not know if this translates to an improvement in overall survival because the myeloma cells may now have become resistant to daratumumab

    • Triplet VRD remains the standard of care for all patients but very reasonable to consider quadruplet induction in standard or high risk with the hope that higher MRD negativity will translate in durable, treatment free remissions in the future

  • More research is being done to evaluate this now: Phase 3 PERSEUS trial pending

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: Madeline Fitzpatrick, Ronak Mistry

  • Graphics, social media management: Ronak Mistry

TheFellowOnCall HemeOncPodcast
Previous

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

Episode 043: Myeloma Series, Pt.4 - Myeloma Pharmacology