Fourth Drug’s the Charm? Comparing Combination Therapies in the Myeloma XI Trial

Triplet combinations of anti-myeloma induction therapies lead to deeper, longer remissions than doublet combinations. Results from the U.K. National Cancer Research Institute’s Myeloma XI trial presented at the 22nd Congress of the European Hematology Association suggest that adding a fourth drug to the combination (the proteasome inhibitor carfilzomib) could further improve clinical outcomes.

“[Triplet combinations] containing an immunomodulatory agent, a proteasome inhibitor, or both are the current standard of care in Europe and the United States,” explained lead author Charlotte Pawlyn, MB BChir, PhD, from the Institute of Cancer Research in London, and colleagues. “Potential approaches to further improve outcomes include response-adapted induction, treating suboptimal responders with sequential treatment using an agent with a different mechanism of action, or intensifying induction for all patients by the use of quadruplet combinations upfront.”

In the phase III Myeloma XI trial, researchers randomized 2,568 transplant-eligible patients with newly diagnosed myeloma (median age = 59 years; range not provided) who were enrolled from more than 100 centers to receive either a four-drug induction regimen or sequential treatment with a three-drug regimen. Patients with asymptomatic myeloma or previous or concurrent active malignancies were excluded from the trial.

Patients in the quadruplet arm (n=526) received induction therapy in 28-day cycles, consisting of:

  • carfilzomib 36 mg/m2 intravenously on days 1, 2, 8, 9, 15, and 16
  • cyclophosphamide 500 mg orally on days 1 and 8
  • lenalidomide 25 mg orally on days 1-21
  • dexamethasone 40 mg orally on days 1-4, 8, 9, 15, and 16

Patients in the triplet arm (n=2,042) received 28-day cycles of:

  • cyclophosphamide 500 mg orally on days 1 and 8
  • lenalidomide 25 mg orally (n=1,021) or thalidomide 100-200 mg orally (n=1,021) daily on days 1-21
  • dexamethasone 40 mg orally on days 1-4 and 12-15

Patients in the triplet arm who experienced a very good partial response (VGPR) or complete response proceeded directly to autologous hematopoietic cell transplantation (AHCT). Suboptimal responders (patients who achieved partial response or minimal response or had stable or progressive disease) received additional, sequential, pre-transplant consolidation therapy with cyclophosphamide (500 mg on days 1, 8, and 15), bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11), and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12).

All patients in the analysis received a minimum of four cycles of initial induction therapy and continued therapy until maximum response. At 100 days post-AHCT, patients were randomized to maintenance therapy with either lenalidomide or observation.

At the time of data cutoff, all enrolled patients had completed induction therapy and more than half of the patients in each treatment arm had follow-up data through 100 days after AHCT (TABLE).

Overall, patients received a median of five treatment cycles (ranges not provided) in all treatment groups.

“Grade ≥3 hematologic toxicities differed between the groups,” the authors reported, although p values were not provided. Rates of grade ≥3 neutropenia appeared to be highest in the lenalidomide triplet group (22%), compared with the thalidomide triplet and quadruplet groups (12% and 16%, respectively).

Grade ≥3 thrombocytopenia and anemia appeared to be more common adverse events in the quadruplet group (8.1% and 10%, respectively) than in the triplet groups (3.4% and 6.7% for thalidomide triplet; 4.5% and 9.6% for lenalidomide triplet). But, the authors added, “there was no statistically significant difference in rates of investigator-reported, all-grade, thromboembolic events between regimens (11.8% for thalidomide triplet, 11.1% for lenalidomide triplet, and 14.7% for quadruplet).”

Grade ≥2 neurologic toxicity was greater with the thalidomide-containing regimen (9.5%), compared with the lenalidomide triplet (3.4%) and the quadruplet (2.3%) regimens (p values not provided).

Follow-up data indicated that patients in the quadruplet arm experienced deeper responses than the triplet arm, “with an impressive response rate (VGPR or better) of 92 percent [at 100 days post-transplant],” compared with 77 percent and 82 percent in the triplet groups, the authors reported (TABLE). This was evident at the end of first induction regimen and persisted through 100 days after AHCT (p<0.0001 for both). “These differences were observed despite the use of randomized pre-transplant consolidation for suboptimal responders to triplet immunomodulatory therapy,” they added.

Longer-term follow-up is needed to confirm the durability of response and survival outcomes, as well as the effect of maintenance therapy. Variations among the participating centers may have limited the study’s findings.

Dr. Pawlyn reports financial relationships with Celgene and Takeda Oncology.


Reference

Pawlyn C, Davies F, Cairns D, et al. Quadruplet vs sequential triplet induction therapy for myeloma patients: results of the Myeloma XI study. Abstract #S407. Presented at the 22nd Congress of the European Hematology Association, June 24, 2017; Madrid, Spain.

TABLE. Responses Observed in the Myeloma XI Trial According to Treatment Arm
Response at end of first induction therapy

Cyclophosphamide, thalidomide, dexamethasone (n=1,021)

Cyclophosphamide, lenalidomide, dexamethasone (n=1,021)

Carfilzomib, cyclophosphamide, lenalidomide, dexamethasone (n=526)

Complete response (CR)

6.1%

8.4%

18.1%

Very good partial
response (VGPR)

46.8%

52.2%

60.6%

Partial response (PR)

29.7%

25.6%

7.6%

Response at day 100 after AHCT
Number completing AHCT to date

647

672

332

CR

20.9%

23.7%

34.9%

VGPR

56.1%

58.5%

57.5%

PR

16.1%

14.4%

4.8%

AHCT = autologous hematopoietic cell transplantation

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