Examining Toxicity Profiles for Multiple Myeloma Regimens

Though treatment combinations such as melphalan, prednisone, and thalidomide (MPT-T) and melphalan, prednisone, and bortezomib (MPV) have improved survival in patients with multiple myeloma (MM) compared with their predecessors, the potential toxicities of bortezomib and thalidomide may limit the long-term tolerance and thus the success of these regimens – particularly in older patients with MM. There is a need, then, for a therapy combination that offers a similarly high response rate, but minimizes toxicity.

In a phase III trial recently published in Blood, Keith Stewart, MBChB, Mayo Clinic, Arizona, and colleagues compared the safety profile and efficacy of melphalan, prednisone, thalidomide (MPT-T) with melphalan, prednisone, lenalidomide (mPR-R) in patients with untreated MM.

“Lenalidomide is an active agent in MM with high response rates and a modest toxicity profile when used in combination with dexamethasone,” the authors explained. The mPR-R combination could further improve progression-free (PFS) and overall survival (OS) in older MM patients without increasing toxicity, Dr. Stewart and authors hypothesized.

Patients were eligible for study inclusion if they had a confirmed diagnosis of MM, as well as evidence of end-organ damage at the time of diagnosis and had not been previously treated for MM (except for treatment with prednisone or dexamethasone for <4 weeks total dosing, alone or in combination with thalidomide or lenalidomide for <2 weeks total dosing).

A total of 306 patients (median age=75.7 years) were enrolled and randomized to receive either:

  • melphalan 9 mg/m2 and prednisone 100 mg each on days 1-4 with thalidomide 100 mg administered daily (MPT-T arm; n=154)
  • melphalan 5 mg/m2 and prednisone 100 mg each on days 1-4 with lenalidomide 10 mg on days 1-21 (mPR-R arm; n=152)

The lower doses of melphalan in both arms were selected to reduce the myelosuppression that has been seen in other trials, the authors noted. Both therapies were continued for twelve 28-day cycles followed by thalidomide 100 mg or lenalidomide 10 mg daily until progression or unacceptable toxicity.

Mean duration of overall treatment (induction and maintenance therapy) was 15.6 months and 14.9 months, respectively. Of all treated patients, 139 (46.6%) went on to maintenance therapy, with similar proportions between the two study arms. Patients entering the maintenance phase of the study received, on average, 13.5 months of thalidomide and 13.3 months of lenalidomide.

After 12 months of treatment, 56 percent of patients in the MPT-T cohort and 60 percent of patients in the mPR-R cohort had stopped treatment.

At the time of analysis, 222 PFS events had been observed. The study’s primary outcome, defined as a PFS hazard ratio (HR) of MPT-T/mPR-R of 0.82 or lower, was not met: In the MPT-T group, patients had a median PFS of 21 months, compared with 18.7 months for the mPR-R group (HR=0.84; 95% CI 0.64-1.09; p=0.186). Overall survival and per-protocol partial response rates were also higher in the MPT-T group (TABLE).

On the safety side, “neither regimen was particularly well-tolerated,” Dr. Stewart and authors wrote, “with at least 58 percent of mPR-R-treated patients and 73 percent of MPT-T-treated patients experiencing grade 3 toxicity, half the patients discontinuing treatment before finishing 12 months of planned induction therapy, and toxicity being the primary reason (42%) for stopping treatment.”

Toxicity rates were significantly lower in the mPR-R group than in the MPT-T group, though (TABLE 2). Grade ≥3 or higher treatment-related toxicities occurring in at least 5 percent of patients included:

  • hemoglobin <8 g/dL (n=16 in the MPT-T arm; n=11 in the mPR-R arm)
  • leukocytes <2.0 x 109/L (n=29 MPT-T; n=17 mPR-R)
  • lymphopenia <0.5 x 109/L (n=21 MPT-T; n=10 mPR-R)
  • neutrophils <1.0 x 109/L (n=41 MPT-T; n=33 mPR-R)
  • platelets <50.0 x 109/L (n=18 MPT-T; n=13 mPR-R)
  • fatigue (n=16 MPT-T; n=14 mPR-R)
  • constipation (n=8 MPT-T; n=0 mPR-R)
  • dyspnea (n=12 MPT-T; n=6 mPR-R)
  • thrombosis/thrombus/embolism (n=13 MPT-T; n=9 mPR-R)

Quality of life was rated significantly better with the mPR-R regimen, with much of the difference attributable to the lower neuropathy rates with lenalidomide compared with thalidomide.

Quality of life was based on mean change from baseline to follow-up after cycle 12 following induction therapy using the FACT-Ntx Trial Outcome Index, which includes physical, functional, and neurotoxicity scores. The difference in quality-of-life was attributed to lower neuropathy rates among patients using lenalidomide compared with thalidomide.


Reference

Stewart AK, Jacobus S, Fonseca R. Melphalan, prednisone and thalidomide versus melphalan, prednisone and lenalidomide (ECOG: E1A06) in untreated multiple myeloma. Blood. 2015 July 8. [Epub ahead of print]

TABLE. Comparison of Safety and Efficacy Outcomes for MPT-T and mPR-R Regimens
MPT-T (n=154) mPR-R (n=152) p Value
Efficacy
Median progression-free survival, months 21 18.7
Overall survival, months 52.6 47.7 0.476
Per-protocol partial response rate, % 63.6 59.9 0.557
Safety
Grade ≥3 toxicities 73% 58% 0.007
Grade ≥3 hematologic toxicities 59.5% 40% 0.001

 

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