NEW ORLEANS—Development of novel agents for multiple myeloma in recent years is bearing fruit, as treatment regimens move away from alkylating agents and toward immunomodulatory drugs and proteasome inhibitors.
Case in point: A plenary session report here at the American Society of Hematology Annual Meeting of the open-label Phase III “FIRST” (Frontline Investigations of Revlimid+Dexamethasone Versus Standard Thalidomide) trial (MM-020/IFM 07 01) showed lenalidomide plus low-dose dexamethasone to be superior in progression-free survival compared with the long-time standard of melphalan-prednisone-thalidomide (MPT), when given as front-line treatment for patients with newly diagnosed, transplant-ineligible myeloma.
Thierry Facon, MD, Professor of Hematology at Centre Hospitalier Régional Universitaire de Lille in France, reported that the oral regimen of lenalidomide plus low-dose dexamethasone (Rd) given in continuous 28-day cycles reduced the risk of disease progression byere 28 percent in newly diagnosed patients ineligible for transplant, compared with the same regimen given for 18 28-day cycles, and compared as well with the current standard of 18 cycles of MPT (Abstract 2).
Three-year progression-free survival with the all-oral continuous Rd regimen was 42 vs. 23 percent for patients taking either the Ld18 regimen but for only 18 cycles (72 weeks), or MPT for 72 weeks.
“In newly diagnosed myeloma patients who are transplant ineligible, the FIRST trial establishes continuous Rd as a new standard of care,” Facon said.
The study was sponsored by Celgene and designed and conducted in partnership with the IFM, the cooperative group for myeloma in France and Belgium.
At a news conference highlighting important studies at the meeting, the moderator, Joseph R. Mikhael, MD, Associate Professor of Medicine at Mayo College of Medicine in Phoenix, Ariz., said the study is confirmatory for current practice in the United States: “This comparison of a globally accepted standard with a novel combination is important because, although lenalidomide-dexamethasone already is used considerably in the U.S., that has been mainly in patients prior to transplant. It is not used as prolifically in older patients or in patients not going to autologous transplant, and that is the target population of this study.
“This study has implications for helping us convert multiple myeloma from an incurable condition to a more chronic, stable condition, especially in older patients.”
After the presentation, speaking from the audience, Kanti Rai, MD, Professor of Medicine at Hofstra NorthShore-LIJ School of Medicine, pointed out that the progression-free survival curves for the three study arms were almost overlapping until 18 months, at which point the Ld arm started to level off, but the Ld18 and MPT arm curves continued declining—“That will make a case for a paradigm shift in treatment,” Rai said.
Enrolled Sickest Patients
Facon noted that the FIRST study population was older and sicker, based on age and renal function, which mirrored real-life myeloma patients. “Patients with renal insufficiency have never been enrolled in clinical trials in myeloma before,” he said.
The study, conducted in 246 centers around the world, enrolled 1,623 patients. Median age was 73 (range of 40 to 92); 35 percent were 75 or older; and 41 percent had ISS stage 3 disease. Patients were randomized to one of three arms:
* Arm A “Ld,” 535 patients: Lenalidomide at 25 mg on days 1 and 21-28, plus low-dose dexamethasone at 40 mg on days 1, 8, 15, and 22-28, continuously until disease progression;
* Arm B “Ld18,” 541 patients: Same regimen as Ld, but given for 18 cycles (72 weeks);
* Arm C “MPT,” 547 patients: Melphalan at 0.25 mg/kg on days 1-4/42, prednisone at 2 mg/kg on days 1-4/42, and thalidomide at 200 mg on days 1-4/42, for 72 weeks.
In patients over age 75 years, the daily doses were reduced: lenalidomide to 20 mg; thalidomide to 100 mg; and melphalan to 0.20 mg/kg.
Patients with renal impairment were enrolled but those on dialysis were excluded.
The starting doses of lenalidomide and dexamethasone were adjusted based on renal function and age; melphalan starting doses were adjusted based on age, absolute neutrophil count, platelet count, and renal function; and thalidomide was adjusted for age.
Dose adjustments were also permitted for adverse events, and all patients were required to receive anti-thrombotic prophylaxis.
The response rate for Rd was 75 percent versus 62 percent with MPT, with a median duration of 35 months—“which is quite long,” Falcon said.
The final median progression-free survival times were 25.5 months for the patients in Arm A, 20.7 months for Arm B; and 21.2 months for Arm C. At the interim analysis, the estimated four-year overall survival rates were: Arm A 59.4 percent, Arm B 55.7 percent, and Arm C 51.4 percent.
“After a median follow-up of 37 months, there was a 28 percent reduction in risk of progression or death, and a 22 percent reduction in risk of death in favor of Arm A vs. Arm C,” Facon reported, adding that both hematological and nonhematological adverse events were as expected for these regimens.
Second primary malignancies were a concern with these drugs but there was no increase above what would be expected from historical data, he said, reporting 12 patients with hematologic second malignancies in the MPT arm (2.2%), and two (0.2%) for each of the Ld and Ld18 arms.
Novel Drugs Combined
Studies of the proteasome inhibitor bortezomib were also in evidence at the meeting, combined with a histone deacetylase (HDAC) inhibitor in the Phase II PANORAMA 2 study (Abstract 1970).
In that study, as reported by Paul G. Richardson, MD, Clinical Director of the Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, the combination of panobinostat with bortezomib and dexamethasone in heavily pretreated relapsed and bortezomib-refractory patients demonstrated a median progression-free survival time of 5.4 months and a median overall survival of 17.5 months.
The 55-patient Phase II study had a partial response rate of 35 percent. “That relates favorably to historical controls and other active combinations in this setting, such as pomalidomide-dexamethasone and carfilzomib-dexamethasone,” he said.
As expected, patients who achieved a partial or major response or better appeared to have a longer median progression-free and overall survival than patients who did not, he said. “This is supportive of a clinical benefit for this combination in this vulnerable population with otherwise limited treatment options.”
The large, randomized, Phase III PANORAMA 1 study will further define the role of panobinostat in relapsed and relapsed/refractory myeloma. “The HDAC story hit a bit of a bump in the road with vorinostat, which showed very modest improvement in PFS, and had been challenged by toxicities,” Richardson said in his presentation. “But now with the positive results around the PANORAMA study, this is encouraging.”
He said HDACs have been considered something of a disappointment, “and what's being realized is that that's not the case.”
Sequencing Novel Agents
In an interview, Richardson predicted that how to sequence novel agents in triplet—and quadruplet—regimens will be driven by further tailoring of biology.
Most upfront regimens, even for older patients, are typically three drugs, he said. “The question is, will Rd be enough? For older patients we've got other strategies. You could have proteasome inhibitors, you could have monoclonal antibodies—all of those things are being tested. And then the question will become: Should we be adding antibodies to that platform, to make a fourth?”
Discussant: FIRST Study Not Designed to Answer Question about Aklylators
The expert asked to speak just before the plenary presentation of results of the FIRST Trial to put the findings into context, Jesus F. San Miguel, MD, PhD, Head of the Hematology Department and Professor of Medicine at Centro de Investigación del Cáncer at Hospital Universitario de Salamanca in Spain, said, “We should congratulate [the researchers] for having a new standard of care that is active, convenient, and has excellent tolerability.”
And, based on the FIRST results, many doctors will probably consider that the alkylators are dead. “But I don't think this is the case, because the study was not designed to answer this question. To answer this question it would have been necessary to have a randomized trial comparing lenalidomide-dexamethasone with and without an alkylator, either melphalan or cyclophosphamide, with identical treatment duration—and in the end it could be that the lenalidomide is not the best partner for the alkylators.”
The most challenging question now is the duration of lenalidomide treatment, he said. The data indicate that the best option is to treat until progression, but it would prove interesting to know the outcome according to response: “It could be that in patients taking lenalidomide-dexamethasone for one or one-and-a-half years, and who achieve a complete response with prolonged stability, additional treatment may not add too much.”
Not adding other agents would also reduce the cost and toxicities of unnecessary, prolonged treatment, and perhaps even more important, reduce the possibility of retreatment after a period of time without treatment, San Miguel said.
“I would also like to know how this regimen benefits specific populations: patients with high-risk genetics, with renal insufficiency, and the very elderly population, for which this combination is probably extremely appropriate.”
There is an issue with lenalidomide about second primary malignancies, he acknowledged, but he said the good news in this study is that there is no apparent increased risk.
“But is this due to the absence of melphalan, or is this due to a potential protective effect of the dexamethasone in that combination?” he asked. And it would be important to identify the 25 percent of patients who did not achieve a partial response, in order to offer them alternative rescue therapies early on.