Carfilzomib Triplet in Over-70s With Relapsed Myeloma

Susan Mayor

September 30, 2015

ROME — Adding the newer proteasome inhibitor carfilzomib (Kyprolis, Onyx Pharmaceuticals) to lenalidomide and dexamethasone achieves a similar benefit–risk advantage in patients with relapsed multiple myeloma who are at least 70 years of age and in younger patients, shows a new analysis.

Carfilzomib was approved in 2012 for use in combination with lenalidomide plus dexamethasone in patients with relapsed multiple myeloma on the basis of results from the recently published phase 3 ASPIRE study (N Engl J Med. 2015;372:142-152).

Researchers have reported here at the International Myeloma Workshop 2015 a post hoc subgroup analysis comparing outcome and safety data in patients younger than 70 years with those 70 years and older who enrolled in the ASPIRE study.

"The take-home message is that use of the triplet combination of carfilzomib, lenalidomide, and dexamethasone is safe and effective in patients over the age of 70, with around 100 patients over this age in both arms of the trial," study author Keith Stewart, MB, ChB, consultant in hematology–oncology at the Mayo Clinic in Scottsdale, Arizona, told Medscape Medical News.

"There was still a progression-free survival advantage of 8 months for patients aged over 70 who took triplet therapy. And the side-effect profile really wasn't terribly different, although there was more hypertension and ischemic heart disease in the over-70 population compared to younger patients," he added.

The researchers randomized patients with relapsed multiple myeloma and measurable disease who had received one to three previous lines of therapy to receive treatment with the triplet combination of intravenous carfilzomib 20 mg/m² (on days 1 and 2 for one cycle only), then 27 mg/m² (on days 8, 9, 15, and 16), lenalidomide 25 mg (on days 1 to 21), and dexamethasone 40 mg (on days 1, 8, 15, and 22); or to the control regimen of lenalidomide plus dexamethasone.

Treatment responses and disease progression were assessed centrally on a blinded basis by an independent review committee.

The researchers enrolled and randomized a total of 792 patients from July 2010 to March 2012.

Comparing Over-70s With Younger Patients

The researchers report that 103 (26%) of patients in the carfilzomib group and 115 (29%) in the control group were at least 70 years of age.

Dr Stewart reported that, "at the time, and probably still today, this was the biggest phase 3 trial done in relapsed myeloma, so it's not surprising that we had a relatively large number of patients over the age of 70. But they did have to be in reasonably good health to qualify, with good renal function and no pre-existing heart disease."

Results showed that the addition of carfilzomib to lenalidomide and dexamethasone reduced the risk for disease progression and death significantly in patients 70 years and older compared with the control regimen by a similar degree to that seen in patients younger than 70 years.

In the older patients, median progression-free survival was 8 months longer in the carfilzomib group than in the control group (23.8 vs 16.0 months; hazard ratio [HR], 0.74).

The improvement in progression-free survival in the older age group was similar to that seen in the younger age group, where the carfilzomib triplet achieved an 11-month increase in median progression-free survival, compared with the control regimen (28.6 vs 17.6 months; HR, 0.67).

Table. Progression-Free Survival (PFS) by Age in the Intention-to-Treat Population

Treatment Group by Age Median PFS, Months 95% CI Hazard Ratio 95% CI
Younger        
   Carfilzomib 28.6 24.1–32.3 0.668 0.534–0.836
   Control 17.6 14.5–22.2
Older        
   Carfilzomib 23.8 18.3–29.6 0.739 0.513–1.065
   Control 16.0 14.0–21.3

 

The overall response rate was nearly five times higher with the carfilzomib regimen than with the control regimen in patients 70 years and older (odds ratio [OR], 4.86, 95% confidence interval [CI], 2.26 -10.45), which was even greater than the difference seen in patients younger than 70 years (OR, 3.15; 95% CI 2.07 - 4.78).

In both age groups, more patients in the carfilzomib group than in the control group achieved a complete response or better.

For the older patients, complete response or better was achieved by 38.8% of the carfilzomib group and by 4.3% of the control group. For the younger patients, complete response or better was achieved by 29.4% of the carfilzomib group and by 11.4% of the control group.

No Increased Adverse Events

These improved outcomes were not achieved at the expense of increased adverse events, the researchers note.

Hypophosphatemia was the only adverse event of grade 3 or higher to occur at least 5% more frequently in the carfilzomib group than in the control group (9.0% vs 2.5%). More adverse events fell into this category in the older patients than in the younger patients, including neutropenia (36.9% vs 32.3%), thrombocytopenia (20.4% vs 15.2%), hypokalemia (15.5% vs 6.3%), and cardiac failure (8.7% vs 1.8%).

In the older patients, the rate of discontinuation of any drug in the treatment regimen because of an adverse event was similar in the carfilzomib and control groups (34.0% vs 34.8%). In the younger patients, there were fewer discontinuations in both the carfilzomib and control groups (23.3% vs 20.9%).

"Overall, the risk–benefit profile with the triplet combination of carfilzomib, lenalidomide, and dexamethasone appeared highly acceptable in patients with relapsed multiple myeloma aged 70 years and older, as well in those aged younger than 70. Although I would say that in the very elderly, this would probably not be a regimen that we might choose just because of the convenience factor," concluded Dr Stewart, referring to the fact that carfilzomib needs to be given by intravenously, which necessitates a hospital visit, whereas both lenalidomide and dexamethasone are given orally. "But for people in their 70s who are in reasonably good health, there is no contraindication."

Commenting on the findings to Medscape Medical News, David H. Vesole MD, PhD, cochief of the myeloma division at the John Theurer Cancer Center in Hackensack, New Jersey, said that "the benefit of the triplet of carfilzomib, lenalidomide, and dexamethasone was evident across all age groups, including patients over 70 years of age. Toxicities were only marginally higher in the older age group, including hypertension and ischemic heart disease."

"However," he continued, "it should be noted that patients over 70 were generally fit and not frail. Caution needs to be taken when treating unfit and frail patients. These patients may also benefit at the cost of increased toxicity."

"A frailty index should be evaluated before considering this treatment in the unfit and frail patient population," he advised. Another poster at the same meeting emphasized the need to use a frailty index and not just chronological age when assessing elderly patients with myeloma and deciding on treatment, as reported by Medscape Medical News.

Another expert approached for comment, Charlotte Pawlyn, MB, BCh, from London, United Kingdom, said: "We know from previous studies that triplet therapy tends to be better in patients in general. But the worry was that there might be unmanageable toxicity in the over-70s. The good thing from this analysis is that we see that adding carfilzomib to lenalidomide plus dexamethasone doesn't appear to add significant toxicity compared to lenalidomide and dexamethasone alone."

She added that "myeloma is a disease generally of older people; therefore, it's important we develop therapies applicable to the whole population, including those not eligible for transplant, which we tend to use only in younger, fitter patients."

The ASPIRE study and the post hoc analysis by age group was supported by Onyx Pharmaceuticals. Dr Stewart reports receiving research grant funding and honoraria from Onyx and consulting honoraria from Celgene. Dr Vesole reports receiving honoraria related to speakers' bureau activities from Celgene and Millennium/Takeda. Dr Pawlyn reports receiving conference travel support from Novartis, Celgene, and Janssen.

International Myeloma Workshop (IMW) 2015: Abstract BP-051. Presented September 25, 2015.

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