Survival Benefit Achieved with Four Drugs plus Maintenance in Myeloma

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An overall survival benefit in newly diagnosed multiple myeloma was attained with a four-drug induction regimen followed by a duet for maintenance in a study from the Italian GIMEMA network. Antonio Palumbo, MD, Chief of the Myeloma Unit at the University of Torino in Italy, reported the findings at the 2012 American Society of Hematology (ASH) Annual Meeting.1

“What we see is that the preclinical synergy observed between bortezomib [Velcade] and an immunodulatory drug may translate into clinical benefit,” Dr. Palumbo said.

The study compared what Dr. Palumbo called the “best experimental therapy” with the “best standard of care.” The four-drug induction regimen was VMPT (bortezomib, melphalan, prednisone, and thalidomide [Thalomid]), which was followed by 2 years of maintenance therapy with VT (bortezomib and thalidomide). This was compared to a control arm receiving induction with three drugs—VMP (bortezomib, melphalan, and prednisone)—without maintenance therapy. Patients received nine 5-week cycles of induction.

The 58-center study included 511 patients older than 65 years and patients ≤ 65 who were not transplant-eligible. The median age was 71.

Risk Reduction

After a median follow-up of 54 months, the risk of progression was reduced by 42% in the experimental arm, and the time to next treatment was reduced by 48%, Dr. Palumbo reported.

Median progression-free survival was 24.8 months with VMP, increasing to 35.3 months with VMPT-VT, and the 5-year progression-free survival rate was 13% vs 29%, respectively (HR = 0.58; P < .0001).

Median time to next treatment was 27.8 vs 46.6 months, respectively.

“We are now able to deliver treatment that can keep disease under control for 4 years, and we can maintain disease in an asymptomatic state,” he commented.

The addition of the immunomodulatory drug to bortezomib during induction clearly points to synergy for this combination, he added. “But more striking is the diverging of the curve that we observe during the maintenance approach. After maintenance, when both groups are off treatment, the curves tend to continue to part.”

“There is evidence that continuous treatment can delay clonal evolution, whereas we see faster clonal evolution and relapse without maintenance,” he explained.

Survival Benefit

Furthermore, an overall survival advantage emerged with the four-drug induction plus maintenance therapy. Five-year overall survival rates were 61% with VMPT-VT, compared with 51% for the control arm, producing a hazard ratio of 0.70 (P = .01). Median overall survival has not been reached in the experimental arm, while it is 60.6 months in the control arm.

“If we look at the landmark analysis, which evaluates survival after induction and from the start of maintenance, the hazard ratio is even better—0.63 (P = .006),” he added. Four-year overall survival from the start of maintenance was 67% with VMPT-VT vs 58% with VMP; median overall survival has not been reached with VMPT-VT and was 54.2 months with VMP. Most of the survival benefit seems to accrue during the maintenance period, he emphasized.

“In the subgroup analysis, we observed that this schema is excellent for patients aged 65 to 75 (HR = 0.60; P = .009), but the benefit is not so evident in those over the age of 75 (HR = 0.76; P = .36),” possibly because the regimen is more toxic, he said. Older patients were more likely to discontinue treatment, and they received a lower dose intensity.

The benefit of the experimental regimen was also more notable among patients with International Staging System (ISS) stages I and II, rather than III, and in patients who obtained a complete response, compared with those with lesser responses.

The study did not show a survival benefit for the novel regimen from the time of first relapse. In those patients, 3-year overall survival rates were about 47% per arm and median overall survival time was 27 months.

In conclusion, Dr. Palumbo suggested that the use of two drugs during maintenance may be more important than the four-drug induction regimen. “A proteasome inhibitor in conjunction with an immumodulatory drug, taking advantage of the synergistic effect, basically doubled the progression-free survival and time to next treatment,” he said, “and more importantly, we were able to keep patients in an asymptomatic condition for up to 4 years.” ■

Disclosure: Dr. Palumbo is a consultant for and has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millennium, and Onyx.


1. Palumbo A, Bringhen S, Rossi D, et al: Overall survival benefit for bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide versus bortezomib-melphalan-prednisone in newly diagnosed multiple myeloma patients. 2012 ASH Annual Meeting. Abstract 200. Presented December 9, 2012.

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