His findings include:
Dr. Rajkumar presented continuing results of E4A03, a Phase III trial of lenalidomide(REVLIMID®) plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in patients with newly diagnosed multiple myeloma, a trial coordinated by the Eastern Cooperative Oncology Group.
Dr. Rajkumar also presented a landmark analysis of the ongoing results. A landmark analysis begins from a point within a study, so measurements all proceed from a common marker, in this case completion of four cycles of lenalidomide/dexamethasone, the point at which decisions on further treatment had to be made. His findings include:
- 88% two-year overall survival, lenalidomide plus low-dose dexamethasone
- 78% two-year overall survival, lenalidomide plus high-dose dexamethasone
- 93% two-year survival, landmark analysis of patients who continued lenalidomide plus low-dose dexamethasone therapy beyond four cycles
- 93% two-year survival, landmark analysis of patients who went on to transplant beyond four cycles
During the meeting in Chicago, Dr Rajkumar discussed his presentation with the IMF:
DR. RAJKUMAR: I presented an update of the ECOG trial, and we found in the primary trial analysis....The overall survival at one year and two years was in favor of the low-dose arm. We must emphasize that we don’t have long term follow up to know how long these types of differences will last or what eventually we’ll see.
We also presented results of the landmark analysis, where we looked at patients who received lenalidomide and dexamethasone on this trial, and then go on to get transplant as opposed to the patients who did not go to transplant. To do the landmark we took patients who were alive at four months, this is the time point at which decisions were being made, and 431 of the 445 patients were alive at that time point.
255 elected not to go off the study and they stayed on therapy with lenalidomide and dexamethasone, as opposed to the remainder who stopped therapy on the protocol. Of those who stopped therapy on the protocol about half went on to have transplant and the remaining half decided to either just stop therapy or go on to thalidomide/dex or other regimens.
The overall survival in the three groups were compared. If you look at patients who took four cycles and then stopped therapy, they had a two- year survival rate of about 70%. Patients who did four cycles and then went on to transplant had a two-year survival rate of about 93% and patients who took therapy beyond four months, particularly in the lenalidomide low-dose dexamethasone arm did quite well.
In the lenalidomide low-dose dexamethasone arm, those patients who took therapy beyond four cycles had a two year survival rate of 93%.
We compared the groups. The ones who had primary therapy with lenalidomide and low-dose dexamethasone and the people who took four cycles and then went on to transplant and the groups were roughly comparable. In the fact the primary therapy, lenalidomide low-dose dexamethasone arm, as a group had an older age population. They were older,, but they were having good survival.
We then found that even the worst case scenario where we pooled patients who took four cycles and stopped therapy into the primary therapy group, we still found results at two years that were similar to the original intent-to-treat analysis of the trial.
So the original intent-to-treat analysis of the trial said that 88% of the patients taking lenalidomide dexamethasone/low-dose dexamethasone arm were alive at two years, and we were able to show that that number was true across the board whether the patients went to transplant or not.
IMF: Last year here at ASCO you presented one year survival, and you said at the time it was unprecedented. Continuing now for two years, what does that say?
DR. RAJKUMAR: I think survival at one and two years are still at very high levels. At one year the rate (96%) is unprecedented, at two years (88%) it is among the highest people have reported. At MAYO we already have three year results and they’re still very good. We have three years results of 88% in the MAYO trial. And so I’m very confident that we have a good regimen in lenalidomide low-dose dexamethasone.
But as it was pointed out in the meeting, we have to be careful and make sure we do the appropriate trials. And so there are going to be trials looking at this regimen in the context of transplant, as well as trials looking at this in elderly patients as a replacement to MPT (melphalan prednisone thalidomide). So, these future trials will guide us on what the role of this regimen is in long term management.
We are also probably going to have trials trying to improve on this. So you’ve heard Dr. Richardson (Dr. Paul Richardson, Dana Farber Cancer Center Institute, Boston) present data on bortezomib added to this combination. And he was able to show extremely high CR plus VGRP rates. And again, that also needs to be confirmed in randomized trials.
IMF: Patients will hear 93% survival with lenalidomide low-dose dexamethasone, 93% survival with transplant, and say ‘I don’t need a transplant.’
DR. RAJKUMAR: That’s probably not the right thing to do because this was not a randomized result. When a patient is at the four cycle time point, I think the trial showed that patients who were responding extraordinarily well to therapy were the ones who would say let me just stay on this drug. So they’re inherently a biased population.
The ones who went to transplant were those whose response rate at four cycles was slightly lower. So unless we do a randomized comparison, this gives us a hypothesis we can test.
I’m afraid that a lot of patients want to do that. If they really do that then we have to collect stem cells for a transplant and freeze them.
IMF: So they can have the option later on.
DR. RAJKUMAR: Yes, they should never give up the option of a transplant. At present a transplant is still the standard of care whether it’s done early or late. At some point, for eligible patients, transplant should be included in the standard of care.
IMF: Nevertheless, those figures were surprising that they came out so close?
DR. RAJKUMAR: The fact that lenalidomide with low dose dexamethasone as primary therapy was giving us results in the same range as transplant was very surprising and very encouraging at the same time.
IMF: Let’s talk about the use of Complete Response, CR. In KOS (the11th International Myeloma Workshop in Greece) I heard you say the best indication of survival is survival. Yet a lot of people still look at CR. If you’re getting a complete response, why isn’t that an indication of survival?
DR. RAJKUMAR: Because CR is not a consistent predictor of eventual overall survival. There have been trials in which the arm that had the higher CR rate went on to be the arm that showed the better survival. But there have also been trials in which the arm that had the better CR rate did not turn out to be the arm that had a better survival. So it’s not a perfect surrogate. And when you want to chose a surrogate instead of the actual end point, you want to pick one that’s always predicting the winner, not something that can go wrong, because a lot rides on these decisions of what we do.
Having said that, CR is a good prognostic marker. If patients achieve CR they probably are going to do well compared to patients who don’t achieve CR. That’s probably true. On the other hand, where the fallacy happens is interpreting that to mean, therefore I’m going to do everything within my power to get to that CR. It is not a proven strategy.
There are many patients with myeloma who can get into a minimal residual disease state, very good partial response state or plateau state, and do just fine. They may go into a sort of MGUS-like stage, and we find that trying to get an M spike that is very low at zero point two down to zero is where you get into trouble sometimes.
It happens, fine. But trying to make it happen is a strategy that hasn’t been validated. That’s something that’s worth testing, but has not been proven.
Dr Barlogie (Dr. Bart Barlogie, University of Arkansas for Medical Sciences [UAMS]) has shown that if you take all myeloma patients there is a high risk group, which is a small group, about 15%, that benefits from getting a CR. And the vast majority of patients, 85%, seem to do the same whether they are in CR or not. So that also needs to be kept in mind.
And finally, it’s not just achievement of CR; it’s the duration of CR that must also be taken into consideration for the ones who reach it.
When you have a CR, how long you live doesn’t depend on just on the regimen you took to get the CR. It can depend on all things that happen from the CR on....New drugs happen, complications happen, so there are a lot of events that can change what was a primary result into an interim result.
IMF: So what happens? Is it the toxicity that’s required to achieve a CR that gets in the way?
DR. RAJKUMAR: Yes. If it were as easy as giving an aspirin to get the CR we would do it. The problem with the strategy of—we are going to intensify our therapy trying to get a CR—is a double-edged sword. Because we are going to add toxicity, cost, prolonged therapy affecting quality of life, all those side effects associated with therapy to the mix, and it’s not clear you want to do that unless you have a real, proven approach that suggests that, yes, getting a CR at all costs improves survival.
IMF: If a patient is diagnosed with myeloma, there are all these choice, all these options, not all proven yet, what do they do? How do they make a decision?
DR. RAJKUMAR: Well, it is hard because a lot of the choices are dependent on the physician and institutional preference and philosophy....My suggestion is as far as possible try and see if there is a clinical trial that they are eligible for that they can join, which is available in many, many centers – we have many good trials that are open. In MAYO we have a strategy called the SMART protocol, which is constantly updated depending on outcome results of various trials. Anyone can access it at mSMART.org, and it basically provides the algorithm that we think we would do for ourselves.