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Total Therapy Demystified (Part Two)

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Total Therapy Demystified (Part Two)

Today Nick break’s Total Therapy (TT) down into distinct segements; induction, transplants, consolidation and maintenance.

Total Therapy Demystified (Part Two)

Multiple myeloma survivor and Total Therapy Patient Nick van Dyk

PHASE ONE:  INDUCTION

In traditional conservative treatment approaches, induction refers to the use of one or more agents to reduce disease burden before a transplant.  Now that more conservative centers are embracing the use of novel agents, induction usually consists of some combination of an immunomodulator (Revlimid or Thalidomide, increasingly the former) and a steroid (usually dexamethasone, though the less potent prednisone is still used in some places), potentially with a protease inhibitor (typically Velcade).  In traditional conservative treatment, induction continues indefinitely until complete response / complete remission occurs, or until the disease plateaus and further improvement is unlikely, after which a transplant may or may not be undertaken.

In Total Therapy, induction is approached differently.  It is given in one or two cycles (depending on the lite or standard arm) and its intent is to destroy tumors through multiple pathways.  Each cycle is 30 days and the protocol consists of:

Velcade – 1 mg/m2 on days 1, 4, 7 and 11
*Thalidomide – I think 200mg daily for days 1-21 but I cannot recall clearly
Dexamethasone – 40mg days 1-4
Platin / Cisplatin, a potent chemotherapy drug – continuous low-dose IV drip over 4 days
Adriamycin / Doxyrubicin, another potent chemo – same method of administration
Cyclophosphomide / Cytoxin, another potent chemo – same method
Etoposide, another potent chemo – same

*Thalidomide is used because Revlimid, per UAMS, inhibits platelet recovery and also makes stem cell collection more difficult.  Revlimid is therefore used post-transplant after platelet recovery is no longer an issue.

In addition to the above-mentioned drugs, the patient is given a small test dose of Melphalan, which is another strong chemo drug, on the first day.  This is because even this small dose will cause changes in the marrow which can be measured and used to help predict the outcome of therapy.

Patients can expect MRI, PET/CT and Bone Marrow Biopsy before and after each cycle of induction.  Again, TT4 lite involves one cycle of this induction treatment, and TT4 standard involves two.

After induction, stem cells are collected.  UAMS typically collects enough for as many as 6 transplants.

PHASE TWO:  TRANSPLANT

After induction is finished, the patient typically has 2 weeks to recover before the first of two transplants.

Your readers will likely know that transplants consists of a high dose of chemotherapy designed to destroy the cancerous cells in the marrow, followed by an infusion of either one’s own blood stem cells (an autologous transplant) or the stem cells of a matched donor (an allogeneic transplant).  It is UAMS’ contention that allogeneic transplants are too risky, and they elect to do two autologous transplants back to back.

As is the case with induction, transplants are viewed differently by UAMS than by traditional disease-control approaches.  In the latter, a transplant is generally used to “lock in the gains” achieved by induction and to increase the length of remission or response.  Typically, a single transplant is done and then the patient waits 100 days or so after which the patient is tested to determine the efficacy of the transplant.

In Total Therapy, the transplants are considered interim steps in active therapy, and two are performed in order to increase the amount of melphalan that is administered without causing it to be such a high dose that it would kill a patient.

In the “Lite” arm, one is given 400mg of melphalan over four days (so 100mg/day).  In the “Standard” arm, one is given 200mg daily for two days.  The “Standard” arm is the same protocol as is typically done with single autologous transplants elsewhere.  The “Lite” arm spreads out the dose in an effort to reduce side effects.

Again, the patient receives BMBs, MRIs and PET/CT before each transplant. Rather than waiting 100 days to determine the impact of the first transplant, after a 4-6 week recovery period, the patient immediately proceeds with the second transplant.  Because of the rapid procession of treatment, patients are generally in consolidation or even maintenance before they even see the impact of the first transplant, let alone the second.  The theory is that a continued, unabated multi-pathway assault on the myeloma cells will kill the greatest number of cells including progenitor cells which may include multiple clones.

In between the transplants, the patient is on thalidomide and dex in order to make sure that even during that 4-6 week recovery time frame, the myeloma doesn’t have a chance to recover.

PHASE III:  CONSOLIDATION

In a step that is generally not part of more conservative therapy, after the transplants, Total Therapy includes another round (TT4 Lite) or two (TT4 Standard) of “consolidation” therapy that mirrors the induction therapy.  This is administered following a 4-8 week recovery period from the transplants.

In TT4 Standard, the patient has two 30-day cycles of the VTD-PACE regiment.

In TT4 Lite, the patient has one cycle, and the PACE agents are dose-reduced by 25%.

PHASE IV:  MAINTENANCE

TT4 calls for three years of maintenance with VRD.  Velcade is given weekly, Revlimid is 15mg for days 1-21 of a 28 day cycle and Dex is given in doses ranging from 8-20mg per week in one dose on the same day as the Velcade administration.  The patient is usually weaned off the Dex over the three year period.

I would like to thank Nick for taking the time to outline Total Therapy for us here at MMB.  I am already receiving correspondence from TT “haters” that attack TT at every turn.  A reasonable person might ask, “Why?”

A perplexing question.  Thousands of patients have made the decision to undergo therapy hell in order to try and make their myeloma disappear.  Does Total Therapy do that?  The data is mixed.  But I know dozens of TT patients that are doing fabulously well years after completing this protocol.

Yes, time may that TT chemotherapy carpet bombing techniques were overkill.  OR investigators may discover that hitting a newly diagnosed myeloma patient with everything available up-front was–as promised– able to stop this cancer dead-in-its-tracks.

TT may not be perfect.  But the concept of hitting myeloma hard up-front is gaining momentum.  The only question is how hard?  And do our myeloma specialists have the right combination of therapies at their disposal to do that yet.

Here’s my guess:  In a matter of a few years, TT style therapies may be the gateway to a chronic cure.  However, I’m hoping that therapy advances will allow doctors to achieve the same or better results using lower doses and combinations of less toxic therapy agents.

Love it or hate it, Total Therapy is no picnic!  But clinicians that practice it–and the brave patients that chose to undergo it–deserve our unconditional support.  Choosing a doctor and therapy direction is an intensely personal decision.  One we all should respect.

I questioned the validity of Total Therapy early-on.  Nick and I got into some downright drag-out write-offs a few years ago behind the scenes!  But he was always respectful and introspective, and we have become close friends over the years.

I see the mainstream myeloma therapy world adopting treatment philosophies used in TT.  Likewise, Nick outlines how “TT Lite” is attempting to help improve their patient’s quality of life.

Moreover, I have kept a close eye on Total Therapy’s numbers over the years.  And trust them or not, the overall survival stats coming out of UAMS are the best around.  They are so good I personally feel they can no longer be dismissed out-of-hand, based on unsubstantiated innuendo.  We all fear things we don’t understand.  Demystifying Total Therapy–like Nick helped do today–should go a long way toward clearing some of this up.

But one thing I’m absolutely sure of; this won’t be the last word on the subject!  So “play nice” out there, boys and girls, as you debate the validity of one myeloma therapy over another.  Remember that at this point, even our best and brightest myeloma specialists are still just guessing.

Feel good and keep smiling!  Pat