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Just In... Meeting News
Key news updates and reports from the latest meetings in oncology and hematology.

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Wednesday, January 27, 2016

ASCO 16 GI Sym logo WEB.jpg
 

BY ROBERT H. CARLSON

Results from a Phase III Polish study point to a potential new standard of treatment for patients with advanced rectal cancer, short-course chemoradiation. Patients in the Polish II trial who received five days of neoadjuvant radiation followed by consolidation chemotherapy saw a statistically significant improvement in three-year overall survival compared with patients treated with standard five-week chemoradiation. Results of the multicenter, Phase III study were presented at the Gastrointestinal Cancer Symposium 2016 (Abstract 489).

The study compared neoadjuvant 5x5 Gy and consolidation chemotherapy versus standard preoperative chemoradiation in “unresectable” fixed cT3 cancer with limited movability, or cT4 rectal cancer with threatened resection margin. None had distant metastases.

The experimental treatment resulted in a higher radical resection (R0) rate, the primary study endpoint, and also higher pathological complete response, although the differences were not statistically significant.

And while three-year overall survival was greater for the experimental group, disease-free survival and the cumulative incidence of local failure were not statistically different between the two groups.

But there was a trend toward lower toxicity and lower cost, as well as greater convenience in the experimental arm of the study, the researchers reported.

“The new regimen has similar efficacy but causes fewer side effects and is more convenient for patients. It is also less costly compared to standard chemoradiation, so it may be especially valuable in limited-resource settings,” said first author Lucjan Wyrwicz, MD, PhD, Professor and Chief, Medical Oncology Unit, Department of Gastrointestinal Cancer, Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, Poland, who spoke on behalf of the Polish Colorectal Study Group. Principal investigator is Krzysztof Bujko, MD, PhD.

In a presscast held ahead of the symposium, Wyrwicz said two earlier studies had shown that chemoradiation is of equal efficacy to short course radiotherapy in patients with resectable rectal cancer T3N0-2M0 tumors – Polish I (Br J Surg2006;93:1216-23) and the Trans Tasman trial (J Clin Oncol2012;30:3827-33). This new report includes patients with more advanced disease, he pointed out.

The trial included 515 patients recruited in Poland and randomly assigned to the experimental group for a short course of five days of radiotherapy at 5 Gy per day followed by three courses of FOLFOX4 delivered over two days per week in weeks 3, 5, and 7 (261 patients); or to a control group receiving 50.4 Gy delivered in 28 fractions given simultaneously with a regimen of 5-Fu bolus, leucovorin and oxaliplatin (254 patients).

Oxaliplatin use was at the discretion of the patient's physician. By study end, 70 percent of patients had received oxaliplatin. Both groups underwent surgery approximately 12 weeks after starting radiation and six weeks after neoadjuvant chemotherapy.

Wyrwicz said acute toxicity rates were lower in the experimental group compared with controls (74% versus 83%). The major toxicities associated with radiotherapy include inflammation of the rectum, diarrhea, inflammation of the bladder, and local skin radiation response. The rate of patients with grade 3/4 toxicity was identical in the two groups, at 24 percent.

Improved Radical Resection Rate
The primary endpoint, rate of resections with negative margins (R0), was 77 percent in the experimental group versus 71 percent in the control group. Pathological complete response rates were 16 percent versus 11.5 percent, respectively.

With a median follow-up of 35 months, three-year overall survival for the experimental group was 73 percent versus 65 percent for controls; disease-free survival rates were almost identical at 53 percent and 52 percent, respectively; and the cumulative incidence of local failure was 22 percent in the experimental group and 21 percent in the controls.

Wyrwicz said short-course radiotherapy may be a particularly helpful option for patients with advanced rectal cancer with metastases in liver or lungs who are potential candidates to have all sites of disease resected.

“A shorter duration of radiotherapy allows such patients to start chemotherapy to control metastases much earlier,” Wyrwicz said. "This seems to be feasible and also effective in this rare subgroup of patients.”

The study was funded by the Polish Ministry of Science and Higher Education.

Oxaliplatin Not Standard
Smitha Krishnamurthi, MD, an ASCO spokesperson and moderator of the presscast, said the short course of radiation is more popular in the Europe than in the U.S., “but these results may lead to increased usage of this method of radiation.

“However, we must keep in mind that chemoradiation in this trial included oxaliplatin, which is not a standard treatment and has been shown to increase toxicity of the regimen,” said Krishnamurthi, Associate Professor in the Department of Medicine-Hematology and Oncology at Case Western Reserve University School of Medicine and leader of the Gastrointestinal Oncology Disease team.

“There were several randomized trials that started before this Polish study started that asked the question, ‘what is the value of adding oxaliplatin to 5-Fu and radiation therapy as adjuvant therapy for rectal cancer?’ and they found it did not increase the efficacy of the radiation but did increase toxicity,” she said. “That's why, when those results came out, the [Polish II] study we discussed today gave participants the option of eliminating the oxaliplatin.”

Wyrwicz explained that the patients in his study were advanced cases with what would have been considered unresectable if surgery were done first.

“At the time the trial started, adding extra chemotherapy sounded reasonable since the aim was to maximize the efficacy of the experimental arm,” he said. “But looking back to the start of this trial, I would not have included oxaliplatin because of the toxicity.”

‘A Lot of Interest’
The study is nonetheless relevant, Krishnamurthi said, since it may be the first study to show the short-course radiation achieving a reduction in tumor. That may have been due to the use of chemotherapy afterward radiotherapy, she said, but could also be due to the delay in surgery, allowing time for the tumor to shrink.

“There is a lot of interest in incorporating short-course radiation because of its convenience and less expense in treatment of rectal cancer, and some randomized trials of short-course radiotherapy are ongoing that will provide us with more data.”

The Gastrointestinal Cancers Symposium 2016 is sponsored by the American Gastroenterological Association Institute, American Society for Radiation Oncology, American Society of Clinical Oncology, and Society of Surgical Oncology.
 


Wednesday, January 27, 2016

 

BY ROBERT H. CARLSON

The radioisotope 177Lu-DOTATATE (Lutathera) has a favorable safety profile with no clinically relevant adverse effects in treatment of patients with midgut neuroendocrine tumors (NETs) who have progressed on somatostatin analogue treatment, according to new data from the phase III NETTER-1 trial.

The data were discussed at a presscast in advance of the Gastrointestinal Cancer Symposium 2016 (Abstract 194).

NETTER-1 Trial
NETTER-1 is a multicenter, randomized, placebo-controlled trial that compared Lutathera with Ocreotide LAR in patients with inoperable, progressive, somatostatin-receptor positive midgut NETs.


In the first report from NETTER-1, presented at the 2015 European Cancer Congress (ECC) meeting in Vienna, Austria, patients treated with the experimental drug had a 79 percent lower risk of disease progression or death compared with those treated with Octreotide LAR.

“Currently, there are limited therapeutic options for patients with advanced midgut neuroendocrine tumors progressing on first-line somatostatin analog therapy,” said study author Jonathan R. Strosberg, MD, Associate Professor at the H. Lee Moffitt Cancer Center, in the presscast previewing the symposium. “Midgut NET is highly resistant to systemic therapy and Lutathera has a major therapeutic benefit for this patient population.”

Lutathera is a peptide receptor radionuclide that targets somatostatin receptors, which are overexpressed in approximately 80 percent of NETs, to deliver cytotoxic radiation directly to the tumor, Strosberg said.

At this meeting, Strosberg reported in greater detail on adverse events in NETTER-1. Overall, he said, the numbers of adverse events, including serious side effects, were similar between the two treatment groups (see "Adverse Events" below).

The NETTER-1 data are on 230 patients with Grade 1-2 metastatic midgut NETs who were randomly assigned to receive treatment with Lutathera every eight weeks for four cycles (115 patients), or the somatostatin analogue Octreotide LAR 60 mg every four weeks (115 patients). Octreotide LAR is the current standard of care for GI NETs.

Patients in the control arm had progressed on Ocreotide LAR 30 mg, the label use.

Each Lutathera treatment dose was 7.4 GBq (gigabecquerels), equal to 200 millicurie.

At the time of statistical analysis, the number of confirmed disease progressions or deaths was 23 in the Lutathera group and 67 in the Octreotide LAR 60 mg group, Strosberg said. The study also suggested that Lutathera may extend patient survival: there were 13 deaths in the Lutathera group versus 22 with standard care.

“This is the first interim look at overall survival and not statistically significant at this point, but it does suggest an overall survival advantage for Lutathera,” Strosberg said.

At the time of the report, median PFS had not been reached for Lutathera, and was 8.4 months with Octreotide LAR.

Responses
Among 201 patients currently evaluable for tumor response, there were 19 (18.8%) complete and partial responses in the Lutathera group—1 CR and 17 PRs—versus three (3.0%, 3 PRs) in the Octreotide LAR 60 mg group.

This study received funding from Advanced Accelerator Applications (AAA), the maker of Lutetium.

‘Impressive Ability’
In April 2015, the FDA granted Fast Track designation to Lutathera for the treatment of patients with inoperable, progressive, well-differentiated, somatostatin-positive carcinoid tumors of the midgut.
Smitha Krishnamurthi, MD, an ASCO spokesperson and moderator of the presscast, said Lutathera showed impressive ability to slow the growth of midgut NETs that have progressed on somatostatin analogue therapy.

“Also notable was the Lutathera response rate of 18 percent in tumors which are typically unresponsive to systemic therapy,” said Krishnamurthi, Associate Professor in the Department of Medicine-Hematology and Oncology at Case Western Reserve University School of Medicine and leader of the Gastrointestinal Oncology Disease team.


Adverse Events
Adverse events with Lutathera versus Ocreotide LAR, respectively:
· nausea all grades: 59 percent versus 12 percent;
· nausea grade-3/4: 4 percent versus 2 percent;
· vomiting all grades: 47 percent versus 10 percent;
· vomiting grade-3/4: 7 percent versus 0 percent;
· diarrhea all grades: 29 percent versus 19 percent;
· diarrhea grade-3/4: 3 percent versus 2 percent;
· thrombocytopenia all grades: 25 percent versus 1 percent;
· thrombocytopenia grade-3/4: 2 percent versus 0 percent;
· anemia all grades: 14 percent versus 5 percent;
· anemia grade-3/4: 0 percent versus 0 percent;
· lymphopenia all grades: 18 percent versus 2 percent; and
· lymphopenia grade-3/4: 9 percent versus 0 percent.

 


Saturday, January 16, 2016

 

BY ROBERT H. CARLSON

 

Cancer care does not end when treatment stops. Three pertinent examples of the importance of continuing care were discussed in an online presscast preview of the 2016 Cancer Survivorship Symposium:

  • Older female cancer survivors with chemotherapy-induced peripheral neuropathy have a 50 percent greater risk of serious falls;
  • In a study of adolescent and young-adult (AYA) Hodgkin lymphoma survivors, only half of the patients received all recommended care within the first post-treatment year; and
  • A randomized controlled trial of survivorship care plans for low-income breast cancer survivors showed that women who receive tailored plans and counseling have an 8 percent higher adherence to recommended long-term care.

 

The inaugural symposium, Jan. 15-16, is sponsored by the American Academy of Family Physicians (AAFP), American College of Physicians (ACP), and the American Society of Clinical Oncology (ASCO), and is focused on efforts to better understand the needs of millions of cancer survivors worldwide. Merry-Jennifer Markham, MD, ASCO Spokesperson and Associate Professor of Hematology/Oncology at the University of Florida, who moderated the presscast, noted that there are more than 14 million cancer survivors in the U.S. today.

 

Persistent Peripheral Neuropathy, Linked to Falls

In a study of 462 female cancer survivors enrolled in exercise trials, mean age 62 years, 45 percent reported having symptoms of chemotherapy-induced peripheral neuropathy (CIPN) at a median of six years after treatment (Abstract 130). And compared with controls, women with CIPN had significantly worse physical function, with altered gait patterns and other indicators of poor mobility associated with more falls than asymptomatic women (31 percent versus 19 percent, respectively).

 

“While there are no effective treatments for this side effect, rehabilitative exercise programs may preserve physical functioning and mobility in the presence of neuropathy to help prevent falls and resulting injuries,” said lead author Kerri M. Winters-Stone, PhD, Research Professor at Oregon Health and Science University, Portland.

 

Winters-Stone said women with CIPN have specific underlying impairments that put them at risk for falls, which may be different from the impairments that occur with other conditions, or old age.

 

For example, CIPN does not cause muscle weakness; rather, it has a distinct effect on movement and gait patterns. Therefore, commonly recommended exercise such as walking may be safer for women with CIPN when done on a treadmill with handrails instead of outdoors because their altered gait puts them at increased risk of falling.

 

As well, neuropathy does not decrease leg strength so machine-based resistance training may not be beneficial. Rehabilitation efforts should instead focus on improving balance and gait training.

 

Winters-Stone noted that men with cancer are as likely to experience CIPN as women, but there are fewer data on CIPN and physical functioning specifically in men.

 

The study was supported through grants from the National Cancer Institute, American Cancer Society, and Susan G. Komen for a Cure Foundation.

 

Markham commented: “We owe it to our cancer survivors to take chemotherapy-induced peripheral neuropathy very seriously. Strategies to reduce the likelihood of developing the symptoms and improve rehabilitation for those who have symptoms are sorely needed.”

 

Some Young HL Survivors Not Receiving Full Care

Adolescent and young adult Hodgkin lymphoma survivors are known to be at high risk for long-term and late effects, and the National Comprehensive Cancer Network (NCCN) and others have issued guidelines for post-treatment care.

 

But a study of 354 Hodgkin lymphoma survivors treated and followed by the Kaiser Permanente of Southern California system showed that more than half did not receive recommended care within the first year post-treatment (Abstract 107). The adolescent and young adult population was defined as between the ages of 15-39 years.

 

Researchers compared NCCN recommended services, including oncology visits, labs, and CT during the first year post-treatment versus non-recommended services such as PET scan and CT after the first year. The average follow-up was six years.

 

Overall, 52 percent of survivors did not receive all recommended care within the first year post-treatment, said first author Erin E. Hahn, PhD, a research scientist at Kaiser's Department of Research and Evaluation. Only 20 percent overall received flu vaccine, she said. And in long-term care, only 30 percent of patients at high risk for cardiac damage received echo/electrocardiograms at 10 years.

 

Ninety-six percent had the recommended oncology visits, and 70 percent received the recommended lab tests within the first five years, she said.

 

“The results show there is a need to improve care delivery for these patients,” she said.

 

Markham commented at the presscast that adolescents and young adults still have long lives ahead of them after completing treatment.

 

“While it’s great news that so many young adult survivors are receiving critical aspects of their post-treatment care, this study helps us understand where there is more work to be done,” she said. “Despite the existence of post-treatment guidelines for this population of survivors, there are opportunities for improvement to increase adherence and improve survivorship outcomes.”

 

Personalized Survivorship Plans Benefit Low-Income Breast Cancer Survivors

Survivorship care plans can significantly improve patient outcomes for low-income women, said researchers at the University of California in Los Angeles (Abstract 1). They randomly assigned 212 low-income women with stage 0-III breast cancer to survivorship care intervention (107 patients) or to usual care (105 patients). Women in the intervention group completed a questionnaire assessing their needs and concerns, such as hot flashes, memory problems, weight gain, and sexual dysfunction. Based on their responses, the researchers provided individualized recommendations for further care.

 

Survivorship care nurses then developed survivorship care plans for the intervention patients, which were given to the patients and their physicians of record (oncologist, surgeon, primary care physician). Besides recommendations for further care, the plans included personalized breast cancer treatment summaries and a list of resources, such as patient support groups.

 

Low-income women may be a population in particular need of treatment summaries and survivorship care plans during the transition from breast cancer patient to breast cancer survivor, said lead author Rose C. Maly, MD, Associate Professor of Family Medicine.

 

The researchers identified three factors that affect survivor health outcomes: the survivors’ breast cancer knowledge, their confidence in interacting with physicians, and having a usual source of health care such as a primary care provider.

 

Women in the intervention group also received an hour-long counseling session with a survivorship care nurse. Through role-play, the women were coached on how to communicate with their physicians about survivorship care recommendations.

 

At 12 months, patients in the intervention group reported approximately 9.5 percent greater adherence to survivorship care recommendations than those in the usual care group, 60.6 percent versus 51.1 percent, respectively.

 

And physicians were more likely to implement the care plan for women in the intervention group compared with controls, in 64.6 percent of cases versus 52.6 percent.

 

“Breast cancer knowledge about survivorship issues, as measured by the Preparing for Life as a New Survivor Scale, and confidence in the ability to interact with the physician, as measured by the Perceived Efficacy in Patient-Physician Interactions Scale, were associated with greater adherence to recommended care,” Maly said.

 

The Institute of Medicine recommends the implementation of treatment summaries and survivorship care plans to improve ongoing clinical care and coordination of care, and to address the immediate post-treatment and long-term effects of cancer treatment, Maly added.

 

“That includes the ongoing psychosocial burden of a cancer diagnosis,” she said.

 

This study received funding from the National Cancer Institute.

 

Presscast moderator Markham said there is no standard best way to implement care plans, but this study “nicely demonstrates that when a personalized care plan is provided, in conjunction with one-on-one counseling about that care plan, adherence to the plan's recommendations is higher.

 

“The combination of the survivorship care plan and the counseling, which engages and empowers the survivor, may be the key to improved survivor outcomes.”

Friday, January 15, 2016

BY MEERI N. KIM, PHD

While improvements in the treatment of Hodgkin lymphoma (HL) have led to higher survival rates, recent research has revealed that patients face a long-term elevated risk of cardiovascular disease for decades after their radiotherapy or chemotherapy regimens. The results of a new, retrospective, case-control study has assessed the dose-response relationship for cardiac radiation and risk of coronary heart disease (CHD) after radiotherapy in HL survivors. The data were published online ahead of print in the Journal of Clinical Oncology (doi: 10.1200/JCO.2015.63.4444).

 

Study Details

The total cohort included 2,617 subjects who had survived for at least five years after HL diagnosis and were treated in the Netherlands between 1965 and 1995. Out of these patients, 325 cases were identified as those who developed CHD in the form of either symptomatic myocardial infarction or angina pectoris requiring intervention as their first clinically significant heart disease. Each CHD case had four individually matched, CHD-free survivors for comparison, leading to a total of 1,204 controls.

 

In terms of estimated dose-response relationship, the risk of CHD appeared to increase linearly with higher mean heart dose—specifically, the analysis found an excess relative risk of 7.4 percent per Gray. Chemotherapy was not associated with CHD risk. The study is the first to report a linear dose-response relationship for mean heart dose and development of CHD in survivors of HL. The results can be used by clinicians to predict CHD risk for future patients and help plan follow-up care for survivors.

 

Comparative Analysis

“For patients treated in the past, these results can be helpful in estimating the risk of coronary heart disease for survivorship care,” said first author Frederika van Nimwegen, MSc, a PhD student in the Department of Epidemiology at The Netherlands Cancer Institute. “For patients treated nowadays, it's a bit harder to estimate this risk as the late effects of currently given treatment are not known yet, but since the results show a linear dose-response relationship, you can also use it to estimate the risk for patients treated today who have been given lower doses of radiation—about 8 to 15 Gray.”

 

This study is a follow-up to an earlier investigation by van Nimwegen and her colleagues published in JAMA Internal Medicine earlier this year, where they found a persistently higher risk of cardiovascular disease in HL survivors with longer follow-up, even up to 40 years after initial treatment (OT 7/10/15 issue).The effect was particularly prominent for patients treated at a younger age, although those treated as adults were still at greater risk than healthy control subjects. In particular, mediastinal radiotherapy was linked to CHD, heart failure, and valvular heart disease.

 

Radiotherapy to the heart area—particularly for children who may be more radiosensitive—can cause significant tissue damage. Radiation can damage the coronary arteries and the microvasculature of the heart, causing them to stiffen and calcify, potentially leading to increased atherosclerosis and coronary heart disease, according to van Nimwegen.

 

“In the previous study, we found there was an increased risk of radiation therapy for cardiovascular disease in Hodgkin lymphoma, but we wanted to look more in depth at the association,” said van Nimwegen. “It has been found in childhood cancer and breast cancer survivors that there is a dose-response relationship, and we wanted to see what the relationship was for Hodgkin lymphoma survivors and what the shape of the relationship is.”

For the current study, van Nimwegen and her colleagues used the same cohort of Dutch HL survivors derived from hospital-based cancer registries of four large university hospitals and one cancer center. Cases with CHD were matched with four controls from the cohort based on sex, age at HL diagnosis, and date of HL diagnosis. Data on treatment and medical history, medication use, smoking, cardiovascular risk factors, and lifestyle information were gathered from medical records, radiation charts, and questionnaires.

 

The median age of HL diagnosis was 32.2 years, while the average time interval between HL and development of CHD was 19.0 years. The vast majority of CHD cases (91%) had received mediastinal radiotherapy during HL treatment compared to 79% of the controls, and it was associated with a 2.63-fold increased likelihood of CHD. The data was best described by a linear radiation dose-response relationship; for instance, there was a 1.74-fold increased risk at a mean heart dose of 10 Gray and a 2.48-fold increased risk at 20 Gray.

Mean Heart Dose

To estimate mean heart dose, the researchers employed a previously published method that uses the percentage of cardiac volume within the radiation field. They used any available HL simulation radiographs, which provide the treatment fields, as well as the location, size, and shape of each patient's heart. For each patient, the contours of the heart were outlined to obtain the percentage of cardiac volume within the radiation field. Then, a correction factor was applied to transform a 2D surface to a 3D volume.

 

In terms of cardiovascular risk factors, patients with hypertension, obesity, recent smoking activity, and a first-degree family history of CHD had a higher likelihood of developing CHD. In an adjusted analysis, a high level of physical activity (more than three hours per week of walking, cycling, or sports) compared to inactivity (less than one hour per week) at the time of follow-up was associated with a lowered risk of CHD.

 

Study Comments

“Studies like this are painting a clear picture for us clinicians to be able to identify the risk factors that we need to pay attention to, and when someone walks in our door with a history of cancer and has had these exposures, we can gauge how concerned we should be,” said Linda Overholser, MD, MPH, Assistant Professor of Medicine at the University of Colorado Hospital. “There seems to be a tremendous amount of momentum for looking at cardiovascular risk in cancer survivors now, and I think it's exciting.”

 

When asked for her opinion on the study, Overholser remarked that this follow-up investigation is well-done and impressive. As a primary care physician, she is seeing more in her field's literature about how to best treat cancer survivors while taking past radiotherapy and chemotherapy into account as risk factors. In her opinion, primary care practices need to be aware and proactive about treating this subset of patients—and studies like this one help to guide proper care.

 

“Even 20 years ago, we weren't seeing so many survivors, but as much as the childhood and adult cancer survivor population is growing now, they still make up a pretty small percentage of overall patients,” she said. “I may have one or two patients on my entire panel who have had this type of history, but the picture of increased morbidity and mortality is so striking that this is really a component we need to recognize.”

 

In the Works

Van Nimwegen and her colleagues are working on a similar case-control study involving the radiation dose-response relationship with respect to heart failure in the same population. Later on, they hope to investigate the role of single nucleotide polymorphisms that might be related to cardiotoxicity to help future patients decide whether chemotherapy would be a better option than radiotherapy, while taking into account the increased future risk of cardiovascular disease.

Friday, January 15, 2016

BY MARK L. FUERST

 

NEW YORK—Oral proteasome inhibitors and immunotherapy may be the future of maintenance for multiple myeloma, but what is the best form of maintenance now—proteasome  inhibitors or immunomodulatory drugs (IMiDs)? Or do some patients not need maintenance? Three myeloma experts debated this topic at the 2015 Lymphoma & Myeloma meeting.

 

All three experts agreed that the goals of maintenance therapy in myeloma are to reduce the risk of relapse and extend progression-free survival (PFS) and overall survival (OS). Maintenance of response is achieved following a new treatment with the administration of drugs for a prolonged time period. Therapy must be convenient, safe, and well-tolerated over the long-term, and not prevent the use or reduce the efficacy of other future treatments.

 

Proteasome Inhibitor Maintenance

James Berenson, MD, President and CEO, Institute for Myeloma and Bone Cancer Research in West Hollywood, CA, took up the cause for proteasome inhibitor maintenance. He began by noting that “only one study of lenalidomide maintenance, with or without steroids, has shown an OS benefit. Three studies show improvements in PFS, but no difference in OS.”

 

A new meta-analysis of 7,730 multiple myeloma patients from 18 phase 3 trials shows a PFS improvement in both transplant and non-transplant patients, as well as when patients are stratified for both lenalidomide and thalidomide treatment. “However, there is no OS benefit, and no benefit in either transplant or non-transplant patients or for either lenalidomide or thalidomide,” Berenson said. Grade 3/4 adverse events show increased thromboembolic events, peripheral neuropathy, neutropenia, and infection.

 

Berenson said, “There are fairly consistent results showing improvement in PFS with lenalidomide maintenance; however, inconsistent results showing improvement in OS. There are no studies that show using lenalidomide for patients responding to non-IMiD-containing regimens is effective in terms of PFS or OS.”

 

There are a few randomized trials of bortezomib as a maintenance drug, but inadequate trial design makes it hard to determine the impact of bortezomib itself in the maintenance setting, he said. One trial of bortezomib as maintenance therapy in multiple myeloma compared bortezomib-melphalan-prednisone-thalidomide plus bortezomib-thalidomide maintenance with bortezomib-melphalan-prednisone alone in newly diagnosed elderly myeloma patients. After a median follow-up of 54 months, the 3-year PFS was superior with the bortezomib-based maintenance therapy (51%) compared to without it (32%), and OS was also superior, he said.

Berenson noted that treatment discontinuation due to adverse events was higher with the bortezomib-based maintenance therapy regimen, in particular in those patients over age 75.

 

“The landmark analysis after nine cycles found a 52 percent reduced risk of progression with bortezomib maintenance, irrespective of response and in patients under age 75, but not in patients age 75 and older,” Berenson said. “This was not a randomized look at the data and we have no clear-cut answer from this trial.” Prognostic factors included response, age, staging, and cytogenetic abnormalities.

 

In the phase 3 PETHEMA/GEM trial, bortezomib as maintenance therapy in previously untreated multiple myeloma patients found those who responded before maintenance did better. After median follow-up of 34.9 months from onset of maintenance therapy, the addition of bortezomib to thalidomide maintenance resulted in significantly longer PFS as compared to thalidomide or interferon. There was no difference in OS. Bortezomib maintenance conferred a significant PFS advantage in patients with low-risk, but not high-risk, cytogenetics, he said.

 

In summary, Berenson said: “Lenalidomide maintenance therapy with or without steroids is well-tolerated and improves PFS, but not OS among multiple myeloma patients (also with thalidomide) and in both the transplant and non-transplant settings. There are no data showing activity after induction with other drugs. Bortezomib-responding patients tolerate its long-term use as maintenance therapy, and responses deepen during maintenance therapy. However, its efficacy in term of PFS or OS has not been clearly demonstrated due to trial design limitations. Oral proteasome inhibitors, such as ixazxomib, now in clinical development, offer convenience, which makes them more ideal as maintenance drugs.”

 

Immunomodulatory Maintenance

Antonio Palumbo, MD, Chief, Myeloma Unit, at the University of Torino in Torino, Italy, stated that maintenance with IMiDs was best. Pointing to his own studies, Palumbo said, “If we give continuous treatment of IMiDs instead of fixed-duration therapy, we can delay tumors, and there is a PFS and OS advantage.”

 

There is not much difference between IMiDs and proteasome inhibitors, he said. “Lenalidomide maintenance leads to PFS improvement. A meta-analysis of a combination of thalidomide-lenalidomide-bortezomib shows an OS benefit. One regimen is not superior to another. For efficacy data, bortezomib is not clearly superior to IMiDs, but it does require injections every 15 days and there is some peripheral neuropathy.”

 

He also noted two recent studies of carfilzomib combinations, ASPIRE (carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone) and ENDEAVOR (carfilzomib-dexamethasone versus bortezomib-dexamethasone), also found a PFS advantage to continuous therapy.

 

“Carfilzomib-lenalidomide is an option in maintenance,” Palumbo said. “There is no issue with peripheral neuropathy, which may represent an alternative.” He noted that infusion of carfilzomib is only for the short-term.

The next advance may be an oral proteasome inhibitor, ixazomib, shown to be compatible with lenalidomide in combination. “Evidence suggests this is an interesting drug, but there is not enough data yet. We must wait for two major randomized trial comparisons of ixazomib versus placebo in transplant and non-transplant eligible patients.” He noted that one of the common adverse events with ixazomib is diarrhea, but there is less peripheral neuropathy and hematologic toxicity.

 

The most friendly treatment approach, Palumbo said, is lenalidomide maintenance. This may need dose reduction, but there is no major peripheral neuropathy or non-hematologic toxicity. “I believe it is the best available agent,” he said. “Several studies show a clear benefit of 12 to 18 months improvement in remission prolongation.”

 

In conclusion, Palumbo said: “Lenalidomide has extensive efficacy, it’s an oral drug, has no peripheral neuropathy side effects, and there is extensive data. Ixazomib in the future may be major competition, but the phase 2 data is too early and gastrointestinal toxicity may represent an issue. There is limited value for intravenous drugs.”

 

He added that monthly exposure to monoclonal antibody in the future might represent an alternative to IMiDs as a maintenance approach.

 

No Maintenance

Sundar Jagannath, MD, Director, Multiple Myeloma Program, and Professor of Medicine at Tisch Cancer Institute at Mount Sinai Medical Center in New York, debated that no maintenance is necessary.

 

“The purpose of maintenance therapy is to prolong remission duration and life expectancy without compromising quality of life,” Jagannarth said.

 

Strategies for maintenance include low-intensity chemotherapy to eliminate or suppress the minimal residual disease; immunotherapy with antibodies or checkpoint inhibitors; and vaccines.

 

Clinical controversies include when to provide maintenance—after maximum tumor cytoreduction has been achieved post-transplant with fixed-durations or in non-transplant patients with variable doses? Is PFS a surrogate endpoint for OS? What is best for high-risk patients?

 

“PFS is not a primary endpoint for OS,” Jagannarth stated flatly. “There is minimal change, about 25 percent, in paraprotein, which has little impact on OS. A median absolute increase in PFS by six to nine months has no impact on OS. Post-progression therapy influences OS.”

 

He offered evidence on why maintenance improves PFS but not OS. “Altering the tumor population induces drug resistance, and altering the microenvironment leads to evolution of aggressive clones and myelodysplastic syndrome.”

 

He agreed with Palumbo that continuous therapy is better than fixed-dose therapy. “Continuous therapy gives better outcomes. Induction of more than 12 months leads to no further improvement in the complete response (CR) rate. Adding a proteasome inhibitor does increase CR,” Jagannarth said.

 

Jagannarth concluded: “We should provide chemotherapy maintenance to treat until there is maximum tumor cytoreduction after a minimum of 12 months. Good risk patients need no maintenance. High-risk patients need continuous therapy. Post-transplant, consider second transplant or consolidation if the patient achieves less than very good partial response (VGPR). Also consider maintenance for a patient not in VGPR or better.”

 

The future of maintenance is immunotherapy, Jagannarth said. He believes a new paradigm may develop from the use of elotuzumab, check point inhibitors, and vaccines.

 

Audience Response

Before the debate, two-thirds of the audience believed that IMiDs were the best maintenance therapy and one-quarter voted for proteasome inhibitors. No one voted for no maintenance. However, after hearing the three speakers, the votes changed dramatically: Only 10 percent said proteasome inhibitors, 42 percent IMiDs and now 30 percent chose no maintenance.

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Oncology Times