A recently published study may change the goals many myeloma special­ists use to make treatment decisions for newly diagnosed myeloma pa­tients planning on having a stem cell transplant.

The study also has potentially broader implications. Indeed, it may influ­ence ongoing debate on a fundamental controversy about how multiple myeloma, in general, should be treated.

The authors of the new study looked at data for 539 myeloma patients who failed to achieve even a partial response to their initial (induction) treat­ment regimen after diagnosis.

After their initial treatment failed, some of the 539 patients went on to have a stem cell transplant without any additional treatment. The rest of the patients received additional treatment with other myeloma therapies before also going on to a stem cell transplant.

Not surprisingly, the additional therapy received by some of the patients before their transplant meant that those patients had deeper responses before and after their transplant than the patients who went straight from their first treatment to a transplant.

But, when the authors compared the survival of the two groups of patients, they found no difference. The progression-free survival and overall survival for both groups were basically the same.

In other words, among the patients in this study, treating some of them longer and with more treatments to deepen their response did not provide any survival benefit.

These results, the authors of the study conclude, “indicate that transplant-eligible patients who achieve a suboptimal response to initial induction therapy should move on to [their planned transplants] rather than receiving additional … therapy in a quest to deepen the level of response.”

This summary of the study's findings is echoed by Drs. David Vesole and David Siegel of the John Theurer Cancer Center in Hackensack, New Jersey, in a commentary that accompanies the new study. The study, the two myeloma specialists write, makes it clear that “additional hammering of patients with sequential cycles of ‘salvage’ chemotherapy should not be pursued” prior to an initial stem cell transplant.

This approach to the treatment of transplant-bound myeloma patients is different than the one used today by many myeloma specialists, who make pre­transplant treatment decisions based on a goal of achieving a target level of response prior to trans­plan­ta­tion.

Broader Implications Of The Study

There also are potentially broader implications of the new study, because it touches on issues related to a key question that myeloma specialists and patients today face: Should achieving the deepest possible response be a goal when treating multiple myeloma?

Many believe the answer to this question is an unequivocal “Yes”. As evidence in favor of this position, those who support it point to studies that have shown that myeloma patients who achieve a deep response to treatment live longer than patients who do not.

Those who feel the answer to the question is not always “Yes” – or even an outright “No” – argue that the evidence in favor of the “Yes” position is flawed. They believe that, in many cases, the patients who live longer because they achieve a deep response to treatment do so because their disease is less aggressive than the disease found in patients who do not respond as deeply to treatment.

Depth of response, supporters of the “No” position argue, is not the cause of longer survival. Instead, it is a sign of how well a patient’s disease responds to treatment.

The answer to whether or not a deep response should be the goal of myeloma therapy has important im­pli­ca­tions. If it should be the goal, then, for many patients, treat­ment regi­mens probably should include more drugs, and treat­ment should con­tinue longer, than currently is the case. Making these kinds of changes, the argument goes, will lead to more patients achieving a deep response, which will improve overall survival times.

The answer to the depth-of-response-as-target question also influences how one should think about issues such as trans­plan­ta­tion, con­sol­i­da­tion therapy, and maintenance therapy – all of which have deepening of response as a one of their goals.

Of course, a key reason there is controversy about depth of response as a goal for myeloma therapy is because few studies have provided evidence that directly addresses the issue.

Therein lies the potential broader significance of the new study. In a limited – but still important – context, it shows that targeting a deeper response to treatment did not provide an additional survival benefit to patients.

Yes, there are limitations to how much one can conclude based on the new study. It was a retrospective study, so patients received different treatment regimens for different lengths of time. Also, one cannot know for certain why some patients were given additional therapy prior to their transplant, and others were not.

Just as importantly, all the patients in the study received a stem cell transplant. This is one reason why the authors of the study – as well as the authors of a commentary accompanying the journal article – focus on the implications of the study for pre-transplantation treatment.

Nevertheless, despite the study’s scope and the limited claims its authors make about its implications, it is hard to see the study results not providing ammunition for those who argue against depth of response as a universal target during myeloma treatment.

Study Design

The authors of the new study retrieved data for 539 newly diagnosed multiple myeloma patients from the database of the Center for International Blood and Marrow Transplant Research. The patients were seen at more than 80 different treatment centers, of which about 95 percent are in the U.S., according to Dr. Parameswaran Hari of the Medical College of Wisconsin, one of the study’s authors.

To be included in the study, patients had to have a stem cell transplant between 1995 and 2010, and the transplants must have been carried out within 12 months of the patient’s diagnosis.

In addition – and very importantly – patients could only be included in the study sample if they failed to achieve at least a partial response to their initial myeloma treatment regimen.

The researchers divided the 539 patients in the study into two groups: those who received additional treatment before their transplant (324 patients), and those who did not receive additional treatment and proceeded directly to the transplant (214 patients).

The median age at the time of transplant was 57 years for patients who did not receive additional treatment before transplantation and 56 years for patients who received additional treatment before the transplant. Almost 50 percent of the patients in both groups had stage 3 myeloma at diagnosis.

A majority of the patients received vincristine ^[1] (Oncovin), doxorubicin ^[2] (Adriamycin), and dexa­meth­a­sone ^[3] (Decadron) (VAD) as their initial treatment. More specifically, 60 percent of patients who did not receive additional treatment were treated with VAD as their initial regimen, compared to 47 percent of patients who received additional treatment.

Almost all the patients who did not receive VAD as their initial treatment regimen were treated with a regimen that included a novel myeloma therapy, such as thalidomide ^[4] (Thalidomid), Velcade ^[5] (bortezomib), or Revlimid ^[6] (lenalidomide). This was the case for 32 percent of patients who did not receive additional treatment prior to their transplant, and for 39 percent of patients who received additional treatment.

Among patients who received additional treatment before stem cell transplantation, the majority (76 percent) received one additional line of therapy, 20 percent received two additional lines of therapy, and 4 percent received three or more additional lines of therapy.

More patients who received additional treatment (55 percent) had their transplants in the later period covered by the study (between 2005 and 2010), when more myeloma therapies were available, compared to patients who did not receive additional treatment (35 percent).

Study Results

Given how patients were selected to be included in the study’s analysis, it is automatically the case that none (0 percent) of the patients who went directly to a transplant after their first treatment regimen had achieved either a partial or complete response prior to transplantation.

In contrast, among the patients who received additional treatment after their initial regimen, 68 percent had at least a partial response before their transplant, including 8 percent who achieved a complete response and 60 percent a partial response.

After their transplants, more patients who received additional treatment before transplantation achieved a complete response than those who did not (19 percent versus 9 percent, respectively). The same pattern also held for partial responses (40 percent versus 33 percent, respectively).

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Figure 1
Overall Survival - All Patients
(click on image to view a larger version of it)

However, despite achieving deeper responses before and after transplantation, the patients who received additional treatment before their trans­plant did not have better progression-free survival or overall sur­viv­al than the patients who went straight to trans­plant after their first treat­ment reg­i­men.

The four-year progression-free survival rate was 30 percent for patients who received additional treatment and 31 percent for those who did not. There also was little difference in the overall sur­vival results for the two groups (see Figure 1 to the right).

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Figure 2
Overall Survival - Novel Therapy Patients
(click on image to view a larger version of it)

The researchers also checked if their findings held up when they restricted their analysis to patients in their sample who received novel agents – either thalidomide, Velcade, or Rev­li­mid – as part of their first myeloma treat­ment regimen. This test was done to address potential critics of the study, who might argue that the study’s results are not relevant to current treat­ment decisions, given that novel agents – rather than the older VAD regimen – are now the norm in the initial treatment of multiple myeloma.

Once again, however, there was no sig­nif­i­cant difference in over­all sur­viv­al be­tween the no-additional-treatment and additional-treatment groups of patients. In fact, among the 195 pa­tients who had a novel agent as part of their first treat­ment reg­i­men, there was a (not sta­tis­ti­cal­ly significant) trend toward longer over­all in the 69 pa­tients who re­ceived no ad­di­tion­al treat­ment reg­i­men be­fore their trans­plant (see Figure 2 above).

For more information, please refer to the study by Vij, R. et al., “Impact of Pretransplant Therapy and Depth of Disease Response before Autologous Transplantation for Multiple Myeloma,” in Biology of Blood and Marrow Transplantation, February, 2015 (abstract ^[9]).