ROME — Quadruplet therapy that consists of the newer-generation proteasome inhibitor carfilzomib (Kyprolis, Onyx Pharmaceuticals), cyclophosphamide, lenalidomide (Revlimid, Celgene), and dexamethasone, is safe and well tolerated, according to results from the first large trial to assess its use in newly diagnosed myeloma patients who are eligible for transplantation.
The results were reported during a poster session here at the International Myeloma Workshop 2015.
Triplet regimens that include an immunomodulator, such as thalidomide or lenalidomide, or a proteasome inhibitor, typically bortezomib (Velcade, Millennium Pharmaceuticals), or both, are now the standard induction treatment regimens for patients with multiple myeloma who are eligible for autologous stem cell transplantation.
Previous attempts to improve responses with four-drug regimens that contain both bortezomib and lenalidomide have led to increased toxicity without improving patient outcomes.
Newer proteasome inhibitors, such as carfilzomib, have less toxicity, enabling researchers to take another look at quadruplet induction therapy to see if new combinations are better tolerated.
The UK National Cancer Research Institute Myeloma XI trial is the first large phase 3 study to try to answer this question, according to the research group, led by Charlotte Pawlyn, MBBCh, Wellcome Trust Clinical Research Fellow at the Institute of Cancer Research and the Royal Marsden Hospital NHS Foundation Trust in London, United Kingdom.
An experimental group was added to the transplant eligible pathway in that study, of the quadruplet therapy known as KCRD: intravenous carfilzomib 20 mg/m² on days 1 and 2, followed by 36 mg/m² on days 8, 9, 15, and 16; oral cyclophosphamide 500 mg on days 1 and 8; oral lenalidomide 25 mg days 1 to 21; and oral dexamethasone 40 mg on days 1 to 4 and 8, 9, 15, 16
Researchers at centers throughout the United Kingdom randomized patients newly diagnosed with multiple myeloma and who were eligible for stem cell transplantation to induction therapy with either the KCRD quadruplet therapy or with triplet immunomodulator therapy followed by additional proteasome inhibitor triplet therapy in those with suboptimal response.
This was compared with a sequential strategy of triplet immunomodulatory therapy followed by additional proteasome inhibitor therapy with bortezomib in patients with suboptimal response (defined as less than a good partial response based on International Myeloma Working Group response criteria). These treatments were given to either maximal response or unacceptable toxicity.
So far, results for the 337 patients who have commenced KCRD quadruplet therapy have shown that it is well tolerated, with only 5% of patients stopping treatment because of toxic effects, Dr Pawlyn reported.
Most Patients Complete at Least Four Cycles
Most patients (91%) completed at least four cycles of KCRD. Doses of one or more drugs were reduced or omitted in 62% of patients. Doses modifications occurred most frequently for carfilzomib (54% of patients) and lenalidomide (41%).
In patients completing at least one cycle of KCRD, there was a low incidence of grade II to IV neuropathy, thromboembolism, and all-grade infusion reactions.
Table. Toxic Effects Related to KCRD
| Toxic Effects | Percent of Patients |
| Hematologic | |
| Grade III neutropenia | 10 |
| Grade IV neutropenia | 4.9 |
| Grade III anemia | 9.3 |
| Grade III thrombocytopenia | 6.2 |
| Grade IV thrombocytopenia | 2.7 |
| Nonhematologic | |
| Peripheral sensory neuropathy (grade II–IV) | 0.8 |
| Diarrhea | 3.6 |
| Constipation | 0.4 |
| Pulmonary embolism (all grades) | 1.3 |
| Deep vein thrombosis (all grades) | 3.6 |
| Other venous thromboembolism (all grades) | 1.7 |
| Acute kidney injury | 0.8 |
| Hypotension | 0.8 |
| Infusion reaction (all grades) | 4.4 |
Serious adverse events suspected to be related to trial medications were seen in 58.9% of patients receiving KCRD. "This is similar to that previously reported for patients receiving CRD alone (38%)," the researchers report.
The majority of the serious adverse events were related to infection or cytopenias. In terms of cardiac serious adverse events, cardiac failure was reported in one patient (0.3%), pericarditis in one patient (0.3%), arrhythmia/palpitations in seven patients (2.0%), and acute coronary syndrome in one patient (0.3%).
"These results are in keeping with studies of carfilzomib at relapse, and confirm its good tolerability profile," said Dr Pawlyn. "Longer follow-up is awaited to assess the efficacy and tolerability compared with a sequential immunodulator/proteasome inhibitor strategy," she added.
The safety data are encouraging, said Antonio Palumbo MD, chief of the myeloma unit at the University of Turin in Italy. But he agrees that longer follow-up is needed to assess the clinical value of the four-drug combination.
"It is reassuring to see these safety data with carfilzomib at the dose used in this study, but this would be expected based on what would be expected compared with other agents. The dermatologic toxicity with carfilzomib is limited," he told Medscape Medical News.
However, he added, "it's too early to comment on how this four-drug combination might fit into clinical practice. I'm in favor of a three-drug combination because we have more evidence for this." He said it will be interesting to see the efficacy data when they are reported, adding that "we also need to look at toxicity after 12 cycles."
Myeloma XI is funded by the National Cancer Research Institute, a UK-wide partnership between cancer research funders. Dr Pawlyn reports receiving conference travel support from Novartis, Celgene, and Janssen. Dr Palumbo reported acting as an adviser, consultant, or speaker for Celgene, Johnson & Johnson, Millennium, and Onyx.
International Myeloma Workshop (IMW) 2015: Abstract BP-012. Presented September 24, 2015.
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Cite this: Carfilzomib Quadruplet for Myeloma Induction Looks Tolerable - Medscape - Sep 28, 2015.
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