CHICAGO (FRONTLINE MEDICAL NEWS) – Incorporating autologous stem cell transplantation into an extended treatment regimen for patients with newly diagnosed multiple myeloma was associated with a more than twofold increase in the rate of stringent complete responses compared with historical controls, the results of a small study indicate.
Members of the Multiple Myeloma Research Consortium (MMRC) conducted an open-label phase II trial in which autologous stem cell transplantation (ASCT) was performed after four cycles of induction therapy with carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd), followed by KRd consolidation and maintenance, and additional maintenance with lenalidomide.
At the end of eight cycles, the stringent complete response rate (complete response with a normal free light chain ratio in serum and absence of clonal cells in bone marrow on either immunofluorescence or immunohistochemistry) was 71%, compared with 30% for historical controls who underwent KRd induction and consolidation without ASCT.
“The depth of the response improved with the duration of treatment, as we’ve seen in a number of trials,” Dr. Todd M. Zimmerman of the University of Chicago Comprehensive Cancer Center reported at the annual meeting of the American Society of Clinical Oncology.
The stringent complete response rate improved further to 87% after maintenance KRd was completed, and there were high rates of only minimal residual disease at the end of KRd consolidation (85%) and after KRd maintenance (100%), Dr. Zimmerman said.
Although only eight patients had reached the lenalidomide maintenance phase by the time of data cutoff in March of 2015, these early results are encouraging and warrant further exploration of early ASCT in eligible patients in randomized trials, he said.
The combination of four cycles of KRd induction followed by ASCT, four cycles of KRd consolidation, and 10 cycles of KRd maintenance may be the modern equivalent of the chemotherapy- and ASCT-based “Total Therapy” concept introduced by Dr. Bart Barlogie at the University of Arkansas, Little Rock, in 1989, said Dr. Saad Zafar Usmani, director of the division of plasma cell disorders at the Levine Cancer Institute–Carolinas Healthcare System in Charlotte, N.C.
“What we’re seeing with this combination of novel induction, transplant, novel consolidation, and novel maintenance is an unprecedented depth of response, albeit in a small number of patients,” said Dr. Usmani, the invited discussant.
The new data are not sufficient to support changing practice, but support a head-to-head comparison of KRd with lenalidomide, bortezomib (Velcade), and dexamethasone in a modern Total Therapy approach, he added.
In a phase I/II MMRC study , KRd produced an stringent complete response rate of 55% in patients who had newly diagnosed multiple myeloma and were not eligible for immediate transplant or who wished to defer transplant, and was associated with a 3-year progression-free survival rate of 79%. The flip side of that coin, of course, is that 45% of patients did not achieve a stringent complete response, and 21% had disease progression, including relapses, over 3 years, Dr. Zimmerman said.To see whether they could improve on those odds, the researchers conducted the current study, in which 62 transplant-eligible patients with good performance status and adequate bone marrow, cardiac, and renal function initiated therapy.
They received four cycles of KRd induction, followed by stem-cell mobilization with granulocyte-colony stimulating factors with or without plerixafor (Mozobil), transplant, KRd consolidation for an additional four cycles, KRd maintenance for cycles 9-18, and (off protocol) lenalidomide maintenance until progression. Details of the regimen can be found in the study abstract .
At the time of Dr. Zimmerman’s presentation, 47 patients had proceeded to ASCT, 37 had initiated and 24 had completed the consolidation phase, 24 had started the KRd maintenance phase, and 8 had completed KRd maintenance and have gone on to lenalidomide maintenance.
Response rates have improved over the course of treatment, with 85% of 48 patients who completed induction having at least a very good partial response, including 21% with a near complete response, 12% with a complete response, and 8% with a stringent complete response.
Of the 8 patients who had completed KRd therapy, all had at least a near complete response, and 7 had both complete responses and stringent complete responses.At a median follow-up of 11 months, with longest follow-up out to 26 months, all 62 patients were alive, and all but one were free from disease progression.
Adverse events (not including ASCT-related events) included grade 3 or 4 thrombocytopenias in 11.3% of all patients, leukopenias in 9.7%, lymphopenias in 25.8%, and anemias in 6.5%.
The rates and types of adverse events were in the range of historical data with KRd, Dr. Zimmerman said.
The MMRC study was supported in part by Onyx Pharmaceuticals. Dr. Zimmerman disclosed receiving honoraria, consulting, and serving on the speakers bureau for the company.