What is Important to Myeloma Patients? Progression Free Survival, Overall Survival or MRD Negative Status?

What matters most to myeloma patients when it comes to assessing outcomes after mutliple myeloma treatment? And what should patients be watching the most when clinical data is presented from myeloma studies?

With clinical trials currently measuring Progression Free Survival (how long you go until you relapse), Overall Survial (how long you live in total) and now MRD negative status (if there is no measurable myeloma after treatment), patients want treatment options to take all these markers into account - they want it all. 

A very interesting paper was presented at the most recent ASH (American Society of Hematology) forum that compared the outcomes of a study in newly diagnosed, transplant eligible, myeloma patients of two different induction treatments. The study in question included a large group of patients (about 660) that were evenly divided in two groups:

• Group 1 was dosed with a regimen many of us will be familiar with: Revlimid-Velcade-dexamethasone (RVd).
• Group 2 was dosed with the same RVd but to that was also added the monoclonal antibody Sarclisa (isatuxemab) or (isa-RVd).
• The induction regimen was divided over three six-week cycles (with five weeks of treatment followed by one week ‘off’). The specifics of the dosing of the different drugs are detailed in the link provided above, but with respect to the RVd portion there is nothing there that most of us are not already familiar with from our very own induction experience (though we may have had shorter treatment cycles, such as e.g., 2 weeks ‘on’ and 1 week ‘off’, administered over 4 or more cycles).

The ’primary endpoint’ [the end result of what the study was trying to show] of the study was to see how the addition of isatuxemab would impact Minimal Residual Disease Negativity (MRD-) compared to the current standard of care, RVd. And here it is:

• 35% of the patients in the RVd group reached MRD- (to a level of less than 1 cancerous cell can be found in 100,000 cells evaluated)
• 50% of the patients in the isa-RVd group reached MRD negativity
• Complete responses (CR) were the same for both groups
• Very good partial responses or better (such as CR or stringent complete responses [sCR]) were 60% in the RVd group and 77% in the isa-RVd group

The question now is which of these two treatment options is best?

What we do know is the following:

• MRD is prognostic and patients who achieve MRD negativity tend to do better than patients who stay MRD positive.
• BUT “… historically in the past, additional interventions to deepen responses in myeloma -- deepen responses, get more MRD negativity -- have not always translated to an improved survival if that intervention is given later.” [See reference]
• The addition of the fourth drug to induction MAY give a longer Progression Free Survival (PFS), but these data are not (yet) available from this trial. All that was reported is that the trial met its objective in proving that adding isatuxemab to RVd results in more patients achieving MRD-.
• The addition of the fourth drug to RVd will increase the toxicity of the ‘cocktail’ to the patient. [Personally, I do not have fond memories of my own 4-cycle induction with RVd. It was a twelve-week period that, I think, was tougher than my first transplant. And this regimen adds another six weeks with a fourth drug. But, hey, that is just my own personal experience, that obviously cannot be extrapolated to the rest of my fellow myeloma patients.]
• And then there is the cost of treatment. The addition of a CD-38 monoclonal antibody to a treatment program is significant, especially since the Revlimid-Velcade portion of the rest of the regimen is already expensive. [Though the actual treatment expense to the patient is very dependent on the terms of the patient’s health insurance plan.]

And here we need to shift to a broader discussion. I used the clinical trial referenced above as an example to set the stage for getting to a hot discussion topic within the myeloma medical community. Key opinion leaders are pushing hard to make MRD one of the endpoints of clinical studies. And this makes sense since the achievement of MRD- confers a higher likelihood of a longer-term better response for the patient.

The pharmaceutical industry is also pushing hard to make MRD the endpoint of their studies, as opposed to PFS and OS. And this can also be readily understood because MRD is reached earlier in time than either PFS and/or OS. 

If the US Food and Drug Administration would be willing to accept MRD data as a substitute for disease progression and/or survival (something that they have not yet agreed to) then clinical trials can be wrapped up sooner, products can be approved faster, and revenues/profits from sales can also start sooner. Economics matter.

We patients, however, cannot be left out in the cold. We want it all. We want to know which drug (and/or drug combinations) and/or sequences of different drug regimens will give us the best chances to achieve MRD negativity, will give us the better quality of life for a given PFS and OS, what will give us the better PFS and OS, and what will give us a life where our family’s financial health is not adversely impacted.

The problem, however, is that between the key opinion leaders and the pharma industry there is very little discussion with regard to the design of clinical trials that would generate all of these patient-focused data, which would be ideal for us to know and understand. We are becoming increasingly attuned to reading the outcomes of trials where the initial treatment is shifting from triplets to quadruplets and pretty much all we see and hear is MRD negativity as the ‘holy grail’.

There is a very interesting read, that I highly recommend, that captures the discussion between three myeloma specialists regarding the isa-RVd vs. RVd trial. Let me quote a few snippets from this discussion to whet your appetite for the full discussion transcript:

“And MRD negativity of a single timepoint is not cure. That's been shown from other studies that have MRD negativity of a single timepoint, it's fickle. It can go away; in a few months they may not even hold. So is this curing more people? Is this making people live longer?” 

“…  am I going to get the studies that I want in the newly diagnosed setting? And I don't think I will, because even if the FDA doesn't approve of MRD as a surrogate for OS [overall survival], I think the field has moved on. The field doesn't care. The field is already making MRD a primary endpoint in itself.” 

“So, we're not even going to get studies in the future that look at PFS for newly diagnosed myeloma, let alone overall survival. So, like, if we wait for PFS too, or if you wait for OS, we're gonna be waiting a really, really, really long time to get our answers on whether four drugs is better than three drugs.” 

“.. if we wait for a trial that tests the right strategy of giving all the drugs upfront versus optimal sequence of drugs, we'll be "Waiting for Godot," we'll be waiting forever.” 

“My question is always, is the global health-related quality of life for your cancer journey, is that better or is your survival better? And I think I agree with Manni, that we're not going to see those trials in our lifetime, because it has been hijacked, I think, by the industry and by KOLs [key opinion leaders] and that they have their own agenda. They're in love with MRD.”

Remember that patients want it all! We want to achieve MRD negativity, have excellent Progression Free Survival, see outstanding Overall Survival, maintain good quality of life and receive treatment at an affordable cost After all, WE are the PATIENTS and not just some randomized bunch of people put into a clinical trial.

We look forward to the medical community balancing all measurements to identify the right treatment at the right time for the right patient and the best possible therapy for us all.