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Myeloma: Recommendation to Switch to Second-Generation Novel Agents After Failure of Frontline Resistance

Fuerst, Mark

doi: 10.1097/01.COT.0000431567.68594.a8
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NEW YORK—Transplant-eligible multiple myeloma patients who do not respond to initial treatment should be switched to second-generation novel agents that have been proven effective in clinical trials. That was the consensus of the attendees who voted for the best options at the Great Debates & Updates in Hematologic Malignancies meeting here after a point-counterpoint presentation.

In his opening remarks, Kenneth C. Anderson, MD, Director of the Jerome Lipper Multiple Myeloma Center and the LeBow Institute for Myeloma Therapeutics and Kraft Family Professor of Medicine at Dana-Farber Cancer Institute, noted that all of the novel agents used to treat multiple myeloma, including bortezomib, lenalidomide, and more recently carfilmozib, and pomalidomide, were approved for use in patients who did not respond to initial therapy: “The claim to fame [for these drugs] is that they are effective in patients who were not responsive. In fact, bortezomib plus dexamethasone is better than VAD [vincristine, doxorubicin, dexamethasone], leading to significant responses as an induction regimen before transplant. Clearly, we can increase responses by switching.”

Before the debate, the vast majority of the attendees agreed with Anderson that the best option is to switch to a novel regimen when a transplant-eligible patient is resistant to frontline therapy. His argument was then persuasive enough to get those who were not sure which therapy to use to ultimately agree with him.

Switch to Novel Agent Regimen

While the first-generation of novel agents consisted of proteasome inhibitors and immunomodulatory drugs (IMiDs), “we are now blessed to have second-generation agents. Why wouldn't we switch if a patient does not respond?” he asked.

“In the old days, we would use a combination of agents, including bortezomib. Now we have a number of effective agents. These multiple options have been studied in Phase II and III trials. We have the ability to switch to other agents if patients don't respond.”

Novel therapies have been integrated into the management of multiple myeloma. These agents target myeloma in the bone marrow microenvironment to overcome conventional drug resistance in vitro and in vivo. They are effective in relapsed/refractory, relapsed, induction, consolidation, and maintenance settings.

Median survival for patients with multiple myeloma has increased in recent years from a range of three to four years to now six to seven years, with additional prolongation from maintenance. “Even newer approaches are needed, though, to treat and ultimately prevent relapse,” Anderson said, noting that he was particularly excited about adding bortezomib to IMiDs.

The addition of bortezomib to dexamethasone leads to a 58 percent response in patients who are refractory to lenalidomide plus dexamethasone, he said. “Why not switch? By switching to bortezomib plus dexamethasone we can get patients to respond.”

A combination of bortezomib, thalidomide, and dexamethasone in consolidation post-transplant can yield a molecular response. “This is exciting. Like chronic myeloid leukemia treatments in the early 1990s, we can get molecular complete responses, which is important.”

Three-drug maintenance regimens have the potential application to treat primary refractory myeloma patients. Patients show a major response to a combination of lenalidomide, bortezomib, and dexamethasone (RVD) in ongoing studies, with or without transplant.

“We are beginning to see responses. There is no need for a patient not to respond to induction therapy in 2013,” Anderson said.

Carfilmozib and Pomalidomide

However, some responses do not last, and these patients require salvage therapy. “We can use some new combinations in salvage therapy,” he said. There are also other options for relapsed myeloma, with two treatments approved in the last seven months—carfilmozib and pomalidomide plus low-dose dexamethasone.

Carfilmozib was approved for use in patients with myeloma refractory to bortezomib, and in most cases IMiDs as well. Carfilmozib is in a novel chemical class with highly selective and irreversible proteasome binding. It shows improved antitumor activity with consecutive day dosing, and durable responses in relapsed and relapsed/refractory multiple myeloma patients, without neuropathy.

Carfilmozib is “a huge advance,” said Anderson. About 25 percent of multiple myeloma patients respond, and their responses last about eight months. Combining carfilmozib with lenalidomide and dexamethasone in relapsed myeloma leads to an overall response rate (ORR) of about 80 percent.

KENNETH C. ANDERSON, MD: “Early data suggest a high rate of response when the newer agents are used as induction and consolidation therapy. Two new kids on the block—carfilmozib and pomalidomide—each have significant response rates that are durable. People live years longer.”

Trials in relapsed myeloma also show that taking new agents earlier leads to impressive results. “Virtually all patients respond to a combination of carfilmozib, lenalidomide, and low-dose dexamethasone. The complete response is overwhelming with, in general, more long-term complete molecular responses,” he said.

The other newly approved drug, pomalidomide, is “a blessing for us,” Anderson continued. It works in relapsed/refractory myeloma, with about one-third of patients responding to a combination of pomalidomide plus low-dose dexamethasone. Pomalidomide has been effective in heavily pretreated patients who had already received lenalidomide and bortezomib and who had disease progression on their last line of therapy.

The combination of pomalidomide and low-dose dexamethasone improves the ORR due to synergy between immunomodulatory agents and glucocorticoids. In trials, the combination yields a 34 percent ORR compared with 15 percent with pomalidomide alone.

Responses of about eight months have been durable with pomalidomide regardless of the addition of low-dose dexamethasone. Also, pomalidomide is generally well-tolerated, with low rates of discontinuations due to adverse events.

A combination of carfilzomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma shows limited grade 3 or 4 non-hematologic toxicities. The regimen is well-tolerated with no unexpected toxicity and is highly active in a heavily pretreated, refractory patient population, he said.

Anderson also noted another new agent, MLN9708, for relapsed myeloma patients: Given upfront in Phase I/II trials, it shows slower overall response than other agents, but the response continues to improve.

In conclusion, Anderson said, “second-generation proteasome inhibitors when used alone and in combination can help achieve responses in patients who are refractory to first-generation novel therapies. Early data suggest a high rate of response when these newer agents are used as induction and consolidation therapy. Two new kids on the block—carfilmozib and pomalidomide—each have significant response rates that are durable. People live years longer.”

To answer the specific question of the debate about whether patients should switch, Anderson said, “It's a moot point. The question is what to use to increase response when you do switch. There isn't any reason a patient shouldn't respond initially. It's exciting that if we use new, more potent, second-generation agents early on that we might have even better results.”

Use a Traditional Cytotoxic Chemotherapy Regimen

P. Leif Bergsagel, MD, Professor of Medicine at the Mayo Clinic in Scottsdale, Arizona, took the more difficult debate position, advocating for a traditional cytotoxic chemotherapy regimen: “I still think that melphalan is a good drug,” he said. “Those patients with stable disease who do not achieve a good response to induction should go ahead to transplant. We should use novel agents in a more measured fashion.”

He pointed out that patients with progressive disease before induction, or whose disease is not controlled, cannot go to transplant—“Only patients with stable disease, or a minor response, should proceed to transplant.”

Is response before transplant important? “We know that response is a great prognostic marker,” Bergsagel said. “Those who respond do better. But that doesn't mean we should necessarily switch therapies to achieve a response.”

The results of randomized controlled trials offer little guidance, because they have used different post-induction therapies. “We can't compare progression-free survivals, and there is no overall survival difference. A higher response rate before induction doesn't really make a difference.”

For patients with poor prognostic features, induction does make a difference. For example, patients with high creatinine levels need to receive optimal induction therapy. A combination of bor-tezomib doxorubicin, and dexamethazone helps patients with high creatinine levels, he said.

LEIF BERGSAGEL, MD: “With less than optimal induction, use a novel regimen, then go to transplant. Or go straight to transplant and then use a novel regimen. I would use a combination of cyclophosphamide, bortezomib, and dexamethasone; go to transplant; and then use a different drug, such as lenalidomide, if need be.”

Trials show that bortezomib plus dexamethasone can double the complete response rate compared with that for VAD, but progression-free survival (PFS) and overall-survival (OS) are no different. Similarly, a combination of thalidomide plus dexamethasone leads to good early results, but there is no difference in OS—“A higher response to induction doesn't mean better survival,” he said.

Other trials have investigated pre-transplant salvage therapy prior to autologous hematopoietic cell transplant (AHCT) in patients not responding to initial induction for multiple myeloma. “Planned upfront AHCT after initial induction increases both OS and PFS.

It is unknown, however, if patients with less than partial responses after a finite period of initial induction should receive AHCT immediately or undergo salvage therapy to improve the level of response pre-AHCT,” said Bergsagel.

He noted that about half of salvage patients respond by switching to other regimens before transplantation. But, again, there is no difference in PFS or OS. “Switching regimens adds cost and toxicity, and doesn't seem to benefit patients. And it seems to create higher non-relapse mortality,” he said. “The first time we use a drug in maintenance should be when the tumor burden is low so that we don't select resistant clones.”

In conclusion, Bergsagel said, “With less than optimal induction, use a novel regimen, then go to transplant. Or go straight to transplant and then use a novel regimen. I would use a combination of cyclophosphamide, bortezomib, and dexamethasone, go to transplant, and then use a different drug, such as lenalidomide, if need be.”

Post-Debate Survey

The post-debate audience survey found Anderson to be the winner: 95 percent said they would switch to a different novel agent, and only five percent would use a traditional cytotoxic chemotherapy.

In the question-and-answer period, session moderator Robert Orlowski, MD, PhD, Professor in the Department of Lymphoma/Myeloma, Division of Cancer Medicine, at the University of Texas MD Anderson Cancer Center, asked about the use of the RVD combination: “If a patient progresses on RVD, I would switch to another novel agent. If a patient is proliferating, I might use DCEP. We can't forget conventional therapies in an aggressive relapse.”

Bergsagel said, “If the patient had a minor response to RVD, I would proceed to transplant.”

Getting in the last word, Anderson said: “To be able to incorporate new drugs before consolidation is huge. Every study shows this improves the extent of response.”

© 2013 Lippincott Williams & Wilkins, Inc.
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