1. Fuerst, Mark

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NEW YORK-Although the optimal therapeutic approach for myeloma patients with bortezomib-lenalidomide relapsed/refractory disease is combination therapy, second-generation novel agents, such as carfilzomib and pomalidomide, show promise as single agents, with or without corticosteroids and appear to be effective for patients with unfavorable cytogenetics. That was the consensus of speakers here at the Great Debates and Updates in Hematologic Malignancies meeting.

Figure. No caption a... - Click to enlarge in new windowFigure. No caption available.

"As disease progresses after multiple lines of therapy, a myeloma patient becomes refractory to therapy, and eventually develops resistant clones," said Rafael Fonseca, MD, Chair of the Department of Medicine at Mayo Clinic in Arizona. "We may be able to beat the clones with new combination approaches."


He discussed the role of novel doublets, with or without corticosteroids, in the debate, describing a relatively new concept of identification of subclones using next-generation sequencing: "When we can look at cells at the genetic level, they all show common ancestry. We can find variants in small subsets among those who are refractory to treatment. This may be one way to use combination strategies."


Doublet Combinations

A combination of pomalidomide, bortezomib, and low-dose dexamethasone shows an overall response rate (ORR) of 75 percent, with about one-third of patients showing a very good partial response (VGPR) or better, even in patients who have been previously exposed to bortezomib plus lenalidomide. The time to relapse is short, about one month, he said, noting that larger randomized trials are needed.


At his institution, he and colleagues have started a trial combining pomalidomide, bortezomib, and dexamethasone in 25 relapsed/refractory myeloma patients. Preliminary results, he said, show a 94 percent response rate, with five complete responses and four VGPRs-this appears to be an attractive approach," he said.

RAFAEL FONSECA, MD. ... - Click to enlarge in new windowRAFAEL FONSECA, MD. RAFAEL FONSECA, MD: "As disease progresses after multiple lines of therapy, a myeloma patient becomes refractory to therapy, and eventually develops resistant clones. We may be able to beat the clones with new combination approaches."

Similarly, the combination of carfilzomib, pomalidomide, and dexamethasone shows promise in patients with relapsed/refractory multiple myeloma, he noted. A multicenter, Phase I/II trial found a 70 percent ORR and 13 percent minor response rate for a clinical benefit rate of 83 percent. Median duration of response was 17.7 months, and median overall survival has not yet been reached at 18 months.

RUBEN NIESVIZKY, MD.... - Click to enlarge in new windowRUBEN NIESVIZKY, MD. RUBEN NIESVIZKY, MD: "Combinations may appear more active and result in high response rates, but four agents is not better than three. Use of more than four lines of therapy leads to a partial response of less than 20 percent, and is even lower for patients who take immunomodulatory agents and then go on to transplant. The only other option is serial single agents."

All of these patients were refractory to lenalidomide, and 89 percent had received bortezomib; more than half had had a prior stem cell transplant. "These patients have a dearth of options. Now we have a combination with an excellent response," Fonseca said.


In summary, he said, "combinatorial strategies are probably best. They have an unprecedented ability to induce responses. We are also seeing a good duration of response. But the majority of these patients go on to progress. Many more strategies are needed."


Sequential Single Agents

Ruben Niesvizky, MD, Director of the Multiple Myeloma Service at the Center for Lymphoma and Myeloma at Weill Medical College at Cornell University, made the case for an approach using sequential single agents, with or without corticosteroids, although he admitted: "In my practice, I follow guidelines similar to those just outlined by Dr. Fonseca."


He mentioned that overall survival for myeloma patients with refractory disease is nine months using doublet therapy. "The duration of response is short. We need new drugs and new approaches. Perhaps a randomized trial of multiple agents versus sequential agents is needed.


"The truth is," he continued, "as the disease progresses, the burden gets higher. Myeloma is a heterogeneous disease, and resistance prevails. We need newer therapies."


Some of the questions clinicians face when deciding on treatment of relapsed/refractory multiple myeloma patients include the following, he said: Should you use single agents versus combinations? Should you use fixed cycles, or treat until maximum response or until progression? Should you stop treatment and transplant a second time?


Multiple treatment choices are available in the management of multiple myeloma, he noted, including cytotoxic agents, transplant options, thalidomide, bortezomib, lenalidomide, carfilzomib, and pomalidomide/dexamethasone.


"Combinations may appear more active and result in high overall response rates and high complete response rates, but four agents is not better than three," Niesvizky pointed out. "Use of more than four lines of therapy leads to a partial response of less than 20 percent, and is even lower-eight percent-for patients who take immunomodulatory agents and then go on to transplant. The only other option is to use serial single agents."


He noted that about half of well-selected myeloma patients respond to bortezomib alone or in combination.


Niesvizky suggested that clinicians consider a clinical trial with a novel agent for a relapsed myeloma patient. For early in relapse, he said, use initial therapy that is lenalidomide-based or bortezomib-based, or transplant. For patients with aggressive, rapid, relapse or multiple relapses, clinicians should consider a chemotherapy-based approach using dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) or oral dexamethasone, thalidomide, and continuous-infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide (DT-PACE); stem cell transplant-based (which is likely to be short-lived but provides quick disease control and reconstitutes marrow); or chemotherapy plus a novel agent, such as combinations of lenalidomide with bortezomib or other agents.


Second-Generation Novel Agents

Two second-generation novel agents-carfilzomib and pomalidomide (with or without dexamethasone)-show activity as monotherapy. New classes of agents, such as vorinostat, panobinostat, elotuzumab, perifosine, and bendamustine, plus bortezomib or lenalidomide (with or without dexamethasone) can be used as enhancers.


Carfilzomib is designed to promote selective and sustained proteasome inhibition, he said. Carfilzomib has been tested in Phase I and II trials of heavily pretreated multiple myeloma patients, including those who have had more than four lines of therapy. The ORR rate is 24 percent and the clinical benefit rate is 37 percent with a median duration of eight months.


"Unfavorable cytogenetics do not significantly impact response rates or duration of response," he said.


In multiple myeloma patients treated with bortezomib who have received up to three prior therapies, carfilmozib has led to a 21 percent ORR with a median duration of response of 11.5 months. "This shows that the drug can be used as monotherapy in patients who have received prior bortezomib therapy," Niesvizky said.


Toxicity with carfilmozib is mostly hematologic, with a lack of peripheral neuropathy, which is common with some multiple myeloma therapies, he noted.


Researchers are now investigating whether an enhanced dose of carfilmozib increases response rates. Giving the drug twice a week over three weeks and then escalating the dose appears to lead to a better response, with an ORR of 67 percent. The depth of response is enhanced as well, he said. "We can infuse the drug longer with less toxicity and improved efficacy.


"Our work is cut out for us to determine the best dose of the drug. We await Phase III trial results."


For pomalidomide, response rates range from 20 to 30 percent-in particular for double-refractory patients he said, noting that pomalidomide plus low-dose dexamethasone appears to lead to superior progression-free survival (PFS) and overall survival with enhanced myelosuppression over pomalidomide plus high-dose dexamethasone.


To take this approach further, researchers are studying the addition of clarithromycin to pomalidomide plus low-dose dexamethasone (ClaPD) in patients with relapsed/refractory multiple myeloma. For those with five prior therapies and high-risk cytogenetics, this oral regimen leads to an overall response rate of 57 percent, Niesvizky said.


"PFS results are similar in double-refractory or single-refractory patients. The use of pomalidomide with clarithromycin and dexamethasone overcomes double-refractory disease and poor cytogenetics, and offers similar effectiveness as compared with more toxic combinations."


The incidence of venous thrombosis for those on low-dose aspirin prophylaxis is five percent, and the discontinuation rate due to adverse events is also low, at three percent.


In conclusion, Niesvizky said, "ClaPD has proven to be a highly effective regimen for a large cohort of heavily treated relapsed or refractory multiple myeloma patients. The addition of clarithromycin to pomalidomide and low-dose dexamethasone appears to enhance expected efficacy. ClaPD demonstrates clinical activity in patients with advanced multiple myeloma who have received multiple prior therapies, including many who are refractory to both lenalidomide and bortezomib. PFS in patients treated with ClaPD is sustained for more than eight months in the majority of patients."


In addition, he pointed out, high-risk cytogenetics did not adversely affect either progression-free or overall survival in patients treated with ClaPD. Although having a history of being refractory to prior lenalidomide, bortezomib, or double-refractory to both agents did not adversely influence PFS in patients receiving treatment with ClaPD, there is a trend towards shorter survival in double-refractory patients, he said.


In response, Fonseca said, "The effect of clarithromycin is not novel. It has been around for quite a while."



The audience of about 200 was asked to vote on the question, "For your multiple myeloma patients with bortezomib-lenalidomide relapsed/refractory disease, what is your choice for optimal therapy?"


Both before and after the debate, about three-quarters of them voted for novel doublets. However, Niesvisky convinced 14 percent of the "Undecided" pre-debate voters to use sequential single agents, leading the debate's moderator, Robert Orlowski, MD, PhD, of the University of Texas MD Anderson Cancer Center, to declare, "I give Dr. Niesvizky the win."