Post-Induction CVD Chemotherapy Improves PFS in Patients With Newly Diagnosed Myeloma

For patients with newly diagnosed multiple myeloma (MM) who had a suboptimal response to immunomodulatory drug-based induction therapy, intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) prolonged progression-free survival (PFS), compared with no intensification treatment, according to an analysis of the phase III Myeloma XI trial.

“Our results support the concept that resistance to initial therapy is based on the specific therapy used and can be overcome by switching to a chemotherapy regimen with an alternate mechanism of action,” the authors, led by Graham Jackson, MD, from the Northern Institute for Cancer Research at Newcastle University in the U.K., wrote.

The open-label, randomized Myeloma XI trial included 1,217 adult patients with newly diagnosed MM who had completed their assigned induction therapy (cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, lenalidomide, and dexamethasone) but achieved only a partial response (PR) or minimal response (MR).

In this article, Dr. Jackson and authors report on outcomes of the 583 patients who were included in the intensification arm. Eligible patients were randomized 1:1 to receive either no intensification (n=294) or CVD (n=289). CVD treatment consisted of 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), administered for up to eight 21-day treatment cycles until maximum response or intolerance.

Patients were then stratified by allocated induction treatment, response to induction treatment, and treating center.

Rates of PFS and overall survival (OS), measured from the time of randomization, made up the study’s primary endpoint. Investigators also assessed toxicity and PFS 2 (a combined endpoint, defined as the time from randomization to the date of second progressive disease, start of third antimyeloma treatment, or death from any cause). However, adverse events (AEs) were not monitored for patients randomized to the no-intensification group.

Eighty-four percent of patients randomized to CVD had PR after induction, while 8% had MR. The response was similar in the no-CVD group, with PR and MR rates of 84% and 7%, respectively.

After intensification with CVD, 42.6% improved to at least a very good PR (including a complete response rate of 3.5% and a very good PR rate of 39.1%).

At a median follow-up of 29.7 months (interquartile range = 17.0 −43.5), 131 CVD-treated patients (45%) and 170 from the no-CVD group (58%) experienced disease progression or died. This translated to a significantly longer median PFS with CVD versus no CVD (30 months vs. 20 months; hazard ratio [HR] = 0.60; 95% CI 0.48-0.75; p<0.0001). The benefit was seen across patients who were eligible or ineligible for transplantation.

However, there was no significant difference between the CVD group and the no-CVD group in terms of the three-year OS rate: 77.3% versus 78.5% (HR=0.98; 95% CI 0.67–1.43; p=0.93). According to the authors, the lack of an OS benefit with CVD intensification may have been confounded by therapy use following relapse.

“Resistance to initial therapy … can be overcome by switching to a chemotherapy regimen with an alternate mechanism of action.”

—Graham Jackson, MD

In addition, there was no observed difference with intensification in terms of the median PFS 2 (52 months with CVD vs. 48 months with no CVD; HR=0.83; 95% CI 0.61-1.22; p=0.22).

Overall, patients received a median of 4 cycles of CVD (range = 3-5). Approximately two-thirds of patients (n=187/289) stopped treatment due to achieving maximum response, while 34 (12%) stopped due to unacceptable toxicity.

The most frequently reported AEs in patients randomized to CVD included:

  • anemia (73%)
  • peripheral sensory neuropathy (60%)
  • thrombocytopenia (47%)
  • constipation (36%)
  • neutropenia (27%)
  • diarrhea (21%)

Most events were mild or moderate in severity, with small numbers of grade ≥3 AEs. The most common treatment-related serious AE was infection, accounting for 42 of the 71 serious AEs (59%) reported in the CVD group.

According to this analysis, switching to a proteasome inhibitor–based combination improved response and PFS. “Taken together, our data suggest that if agents of several different classes are available and can be tolerated in combination, they should be used together upfront, as is now the standard of care in the U.K.,” the authors concluded. “If not, agent class should be switched rapidly in the absence of a deep response with the aim of response intensification to prolong PFS.”

However, the implications of this analysis are limited by the large proportion, nearly half, of Myeloma XI participants who discontinued the trial prior to intensification randomization and were not included in this analysis. The researchers explained that this could have been attributable to “investigator and patient discomfort with delivering intensification to patients with responses very close to very good PRs but not quite meeting it or, conversely, not delivering intensification to patients with a response of only MR to initial induction.”

The authors report relationships with Celgene, Amgen, and Merck, which collaborated on the trial.

Reference

Jackson GH, Davies FE, Pawlyn C, et al. Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Haematol. 2019 21;6:e616-29.