Largest Trial of Transplants in Myeloma: No Need for Extras

Roxanne Nelson, BSN, RN

December 15, 2016

SAN DIEGO — In the largest trial to date of autologous hematopoietic cell transplant (autoHCT) in patients with multiple myeloma, all three approaches that were tested yielded similar results.

Maintenance therapy with lenalidomide (Revlimid, Celgene) after autoHCT has been shown to improve both progression-free and overall survival and is considered the standard of care; the new results suggest that this regimen may be all that most patients need.

Patients who received additional interventions, such as tandem autoHCT or triple therapy with bortezomib (Velcade, Millennium), lenalidomide, and dexamethasone (RVD) for consolidation, did not show significantly better outcomes, the new results indicate.

The findings come from the StaMINA trial and were presented here at the American Society of Hematology (ASH) 2016 Annual Meeting (abstract LBA-1).

"In the era of thalidomide analogues and proteasome inhibitors used in initial therapy for myeloma, and the use of prolonged maintenance therapy with lenalidomide, post transplant consolidation or a second transplant do not produce incremental PFS [progression-free survial] benefit," said lead author Edward A. Stadtmauer, MD, of the Abramson Cancer Center, University of Pennsylvania, in Philadelphia, who presented the findings.

He reported that 38-month estimated probabilities showed no difference between the treatment groups with respect to progression-free survival (the primary endpoint) or overall survival (a secondary endpoint).

"Progression-free survival ranged from about 52% to 56% in the three arms," he said. "Even more clear is overall survival — there is no difference at 38 months, with a rate of about 82% to 85% of patients in the three arms."

Less Seems to Be More

"Transplant is standard of care in multiple myeloma," commented Joseph Mikhael, MD, professor of medicine and consultant hematologist, Mayo Clinic, Phoenix, Arizona. "Patients receive induction therapy, they receive a transplant, and we are quite convinced, based on a number of trials and a meta-analysis, that lenalidomide as maintenance therapy is also the standard of care.

"So the question being addressed here is, Is that sufficient, or should we add a second transplant? Or should we add more consolidation with more chemotherapy?" he said.

In an interview with Medscape Medical News, he emphasized that this study is very important because it has really looked for that answer. "It didn't matter that much what patients received for their induction, as long as they didn't relapse," he said. "It didn't look at what happened after maintenance. From the outset, it was very well designed, with enough patients to answer a very important clinical question."

I believe that we are going to be seeing fewer second transplants as a result of this study. Dr Joseph Mikhael

The clinical implications of this study are quite significant, he noted. "Even though a second transplant is not as common in the US as in Europe, there has been some conflicting evidence as to the benefit of a second transplant. But I believe that we are going to be seeing fewer second transplants as a result of this study.

"This is really important for patients," Dr Mikhael emphasized, "because transplants are exhausting, and they are costly."

The second implication is that utilizing more consolidation therapy would not be necessary if the outcomes remain the same. "I don't think it completely shuts the door, because a European trial showed that there may be some benefits," he added. "But for right now, I think clinicians can be very comfortable telling their patients after transplant that they can go right to lenalidomide maintenance. This is where the study will be will be very influential."

No Difference in Endpoints

This phase 3 randomized trial was conducted in 758 patients with symptomatic disease who were eligible for transplant; 24% of patients were classified as high risk. Inclusion criteria required that these patients be younger than 71 years; the median age was 57 years (range, 20 to 70 years).

All patients received maintenance therapy with melphalan 200 mg/m2 autoHCT and lenalidomide.

However, one group received a tandem transplant, and another group received in addition four cycles of RVD consolidation therapy (lenalidomide 15 mg daily on days 1-14, dexamethasone 40 mg on days 1, 8, and 15, and bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 every 21 days).

All arms included maintenance with lenalidomide at the maximum tolerated dose of 5 to 15 mg orally daily until progression, with dose modifications for toxicities.

The cohort was evenly divided among the three groups.

The median available follow-up from randomization was 38 months. Dr Stadtmauer explained that follow-up will continue through January 2017.

The 38-month estimated probabilities for progression-free survial were 57% for the patients who received additional RVD consolidation, 56% for the patients who received trandem transplants, and 52% for the third group, who received only lenalidomide maintenance therapy. The differences were not statistically significant.

The corresponding probabilities of overall survival were 86%, 82% and 83%. Dr Stadtmauer noted that median overall survival has not yet been reached.

The cumulative incidences of disease progression at 38 months were 42%, 42%, and 47% for the three groups.

"For high-risk patients, the progression-free survival was somewhere between 40% to 48% at 38 months, and no difference in overall survival," said Dr Stadtmauer. "I think its an impressive result that 77% to 79% of high-risk patients are still alive.

"There was also no difference in treatment-related mortality, which, fortunately, was very low," he noted.

A total of 39 cases of second primary malignancies were reported in 36 patients. The cumulative incidences were 6.0% for patients who received consolidation therapy, 5.9% for patients who received tandem transplants, and 4.0% for the patients who received only lenalidomide maintenance therapy. "This is consistent with what has previously been reported," said Dr Stadtmauer.

To fully understand the impact of the results, many important future evaluations of this study are needed, he concluded. A long-term follow-up trial to track outcomes in these patients is ongoing.

Consolidation With Novel Drugs

Another expert reiterated the point that this is a long-awaited and very important study of the impact of double transplant in a three-arm trial.

Brian G. M. Durie, MD, chairman of the International Myeloma Foundation, noted that it may be possible that with longer follow-up, a benefit from double transplant will be seen in a subset of patients.

PULL QUOTE "The bottom line is that the benefit of double transplant is marginal at best."

The bottom line is that the benefit of double transplant is marginal at best. Dr Brian Durie

"But the bottom line is that the benefit of double transplant is marginal at best, and with all of the new novel therapies, I get the sense that people are turning away from double transplant," he told Medscape Medical News. "I sense there will be significant trend in that direction ― there has been hesitation among patients, and doctors have not been pushing double transplantation.

"Maybe what we should be looking at is a single transplant and some consolidation with novel combinations," Dr Durie said. "We have had such tremendous results, and they have achieved such a deep response."

The study was funded by the National Heart, Lung, and Blood Institute. In addition, Takeda and Celgene provided grants. Dr Stadtmauer has served as a consultant for Amgen, Takeda, Celgene, Novartis, and Janssen. Several coauthors have reported relationships with industry, as noted in the abstract. Dr Mikhael has disclosed relationships with AbbVie, Celgene, Onyx, and Sanofi.

American Society of Hematology (ASH) 2016 Annual Meeting. Abstract LBA-1, presented December 6, 2016.


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