The data being amassed about novel multiple myeloma therapies have the potential to change the way patients with relapsed or refractory disease are currently being treated, according to experts who participated in a recent 

The investigational monoclonal antibodies elotuzumab and daratumumab are generating hopes that combining these agents with existing drugs would improve outcomes. Evidence is growing that carfilzomib represents an advanced proteasome inhibitor that may provide further benefit if employed with a higher dosage. And, the histone deacetylase (HDAC) inhibitor panobinostat appears effective even in high-risk populations as part of an all-oral regimen.

These were among the topics discussed by a panel of multiple myeloma experts during the Peer Exchange roundtable, entitled “Emerging Concepts in the Treatment of Multiple Myeloma.” The discussions focused on data presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting convened in June.

Sagar Lonial, MD, a leading investigator into the emerging monoclonal antibodies, served as moderator of the discussion, which covered a wide range of topics. The panelists agreed that much work remains to be done in the field to determine how best to combine emerging agents with immunomodulatory (IMiD) drugs and other currently available therapies.

Some of the most exciting data in future myeloma treatment that were presented at ASCO involved elotuzumab and daratumumab, which both have applications pending under the FDA’s priority review program.

Elotuzumab is being evaluated in combination with lenalidomide and dexamethasone for patients who have relapsed after one or more prior therapies; daratumumab is under review as monotherapy for patients who have failed at least three lines of prior therapy or who are double refractory to a proteasome inhibitor and an IMiD.

The phase III ELOQUENT-2 trial showed that more patients with relapsed/refractory multiple myeloma responded to lenalidomide and dexamethasone combined with the monoclonal antibody elotuzumab (79%) compared with lenalidomide and dexamethasone alone (66%). In addition, the triplet combination resulted in a progression-free survival (PFS) benefit of almost 5 months, as well as an approximately 30% reduction in the risk of progression.

“I think this is a new milestone in myeloma, and if you think about monoclonal antibodies, I think we can learn something from our lymphoma colleagues,” said Noopur Suresh Raje, MD, director, Multiple Myeloma Program, Massachusetts General Hospital. “Rituximab is generally slapped on to whatever backbone treatment they have, and the good news with monoclonal antibodies [is that] once we’re able to manage those infusion-related reactions, we can piggyback these monoclonal antibodies on any kind of combination approach that we’re using in myeloma.”

Jatin J. Shah, MD, associate professor, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, noted that rituximab was a “major step forward” in lymphoma that specialists were able to deploy widely. In contrast, Shah said, myeloma specialists likely will have more than one novel antibody to launch into clinical practice in the same time frame and it will be challenging to figure out how best to use each drug.

While elotuzumab targets signaling lymphocytic activation molecule F7 (SLAMF7), daratumumab targets CD38. In a phase II trial of patients who were heavily pretreated, daratumumab monotherapy resulted in a PFS of 3.7 months, with nearly 30% of patients responding and a duration of response of 7.4 months.

Lonial, chief medical officer, Winship Cancer Institute, Emory University School of Medicine, said some of the responses seen in this trial were stringent complete responses (CRs), which he found “quite striking” considering that the participants had received a median of five prior lines of therapy, including carfilzomib and pomalidomide as well as other drugs.

“I think that’s really compelling data in this setting where we are now able to show single-agent activity in a very heavily pretreated population. I think it’s going to change the field,” said Shah. He also added that, “As you move these active drugs in earlier lines of therapy, you’re going to see even more activity. So I think this is really a very strong statement about the activity of daratumumab.”

	Resetting the Conversation About Carfilzomib

Rafael Fonseca, MD, Chair, Department of Medicine, Mayo Clinic, agreed that the monoclonal antibodies will make a significant impact beyond the refractory setting. “I do envision monoclonals will quickly move to the front line because of their ability to combine well with treatments,” he said.

Data about carfilzomib presented at ASCO “suggest that actually carfilzomib is a superior proteasome inhibitor, at least when it comes down to antitumor activity,” said Fonseca. Carfilzomib, initially approved in 2012 as a third-line therapy after disease progression, gained an expanded approval in July 2015 in combination with lenalidomide and dexamethasone for patients who relapse after one to three prior lines of therapy.

In the ENDEAVOR trial, which he said was “one of the most important abstracts” presented at the meeting, patients with one to three prior lines of therapy had higher PFS rates with carfilzomib and dexamethasone treatment (18.7 months) than with bortezomib and dexamethasone treatment (9.4 months). Importantly, all patient subgroups benefited from carfilzomib, including those with prior bortezomib exposure.

Carfilzomib was approved at a dose of 27 mg/m

 given over a period of 10 minutes, but the dose used in ENDEAVOR was 56 mg/m

 given over 30 minutes, which aided the tolerability of the higher dose.

According to Shah, the results of ENDEAVOR show that, “We should reset the conversation. Carfilzomib 56 mg/m

 is not a high dose or doubling the dose. It’s really in fact full-dose carfilzomib. And then when you combine it, you have to use lower doses.”

The phase I/II CHAMPION-1 trial went even further, testing carfilzomib plus dexamethasone up to a maximum tolerated dose of 70 mg/m

 in patients with relapsed/refractory multiple myeloma with one to three prior lines of therapy. Even though half of the patients were bortezomib-refractory, the response rate was 72%, with a PFS of 10 months.

	Finding the Right Partner for Panobinostat

Shah said the key to the dosing questions would be answered in two upcoming phase III studies that would compare the approved dose against investigational doses of 56 mg/m

In February 2015, the orally available panobinostat became the first HDAC inhibitor approved for the treatment of multiple myeloma; it is indicated in combination with bortezomib and dexamethasone for patients who have received at least two standard lines of therapy.

In a subset of the PANORAMA-1 trial, bortezomib and dexamethasone treatment led to a higher overall response rate when given with panobinostat (58.5%) compared with placebo (41.4%) in patients who had received both prior bortezomib and either lenalidomide or thalidomide. The PFS time was also 4.8 months longer with panobinostat than with placebo.

Another analysis of the quality and duration of responses in PANORAMA-1 showed that the near CR and CR rate was higher with panobinostat than with placebo (27.6% vs 15.7%). In addition, the patients who achieved near CR or CR had an impressive PFS of 16.5 months.

	Unfortunately, combining panobinostat with bortezomib can cause a significant amount of diarrhea and fatigue. Combining panobinostat with either lenalidomide or carfilzomib, on the other hand, may offer all-oral combination regimens without the high rates of gastrointestinal toxicity or fatigue.

	In a small study in relapsed/refractory multiple myeloma, combination panobinostat, lenalidomide, and dexamethasone treatment produced durable responses, even in high-risk, lenalidomide-refractory patients, without the same side effects.

	In response to these data, Heather J. Landau, MD, attending physician, Memorial Sloan Kettering Cancer Center, said, “I think that having an option for lenalidomide- refractory patients— an all-oral combination without the associated GI toxicity or fatigue or the schedule problems that carfilzomib poses&mdash;I think that this is a great option for our patients.”

	Raje added, “I think it’s still finding what the best partners are and, in my mind, I think the IMiDs may be the better partner for the HDAC inhibitors going forward.”

Beyond the consideration of new drugs in the pipeline, Morie A. Gertz, MD, is looking for agents that improve patients’ quality of life.

“Although proteasome inhibitors have been a real breakthrough for myeloma patients, the scheduling is still a challenge,” said Gertz, Chair, Internal Medicine, Mayo Clinic, noting that some patients must come to the clinic every week for 9 months to receive infusions.

For this reason, he added, “I’m very excited about oral proteasome inhibitors. Being able to take one pill, fixed dose, once a week I think has a real impact on the quality of life that patients have.”

Oral dosing such as with the novel second-generation proteasome inhibitor ixazomib would offer patients more flexibility, allowing them to travel instead of being “tethered” to the clinic, as they often have are with current therapies.

Despite the excitement generated by the discussion of the data presented at ASCO, Gertz reminded the panel and the audience that, “I think it’s a little early to declare victory. Ninety percent of myeloma patients still die of myeloma, so there’s still an unmet need.

“And, advancing our understanding of appropriate combinations and the development of new drug classes is still an imperative for the myeloma community.”

However, Lonial used his moderator’s prerogative to make the last note a positive one:

“I think seeing randomized phase III data in the context of relapsed myeloma with elotuzumab showing improvements sort of across the board in PFS, overcoming potential high-risk disease in certain subsets as well, and then the availability of something like daratumumab in the refractory myeloma setting—these are, to me, game changers.

“And I think we all have patients that walk in, or drive in, or fly in from wherever who are looking for hope. And I think these approaches provide hope and that’s really important.”

			Lonial S, Dimopoulos MA, Palumbo A, et al. ELOQUENT-2 Investigators. ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). 

			Lonial S, Weiss BM, Usmani SZ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). 

			Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): results from the phase III study ENDEAVOR. 

			Berenson JR, Cartmell A, Bessudo A, et al. Updated results from CHAMPION-1, a phase I/II study investigating weekly carfilzomib with dexamethasone for patients (Pts) with relapsed or refractory multiple myeloma (RRMM).

			San Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma who received prior bortezomib and IMiDs: a predefined subgroup analysis of PANORAMA 1. 

			Hungria VT, San Miguel JF, Yoon SS, et al. Analysis of outcomes based on response for patients with relapsed or relapsed and refractory multiple myeloma in the phase 3 PANORAMA 1 study. 

			Chari A, Cho HJ, Parekh SS, et al. A phase II study of panobinostat with lenalidomide and weekly dexamethasone in myeloma. 

Articles

The data being amassed about novel multiple myeloma therapies have the potential to change the way patients with relapsed or refractory disease are currently being treated.

Experts Share Hopes for the Future of Myeloma Treatment

When Bernard Fisher, MD, first became involved in breast cancer research, the only treatment option available to patients was the radical mastectomy, a horribly disfiguring surgery that had been the undisputed standard of care since the late 1800s. In 1894, William Halsted developed the procedure for the radical mastectomy, which involved removing the entire breast, the underlying chest wall muscles, and all of the underarm lymph nodes. At that time, cancer was widely thought to be a local disease that spread in a predictable way, and so it was believed that extensive surgery could theoretically remove all of the cancer cells and cure the patient. Despite a lack of reproducible data to prove this theory or the success of the radical mastectomy, Halsted’s procedure remained the unequivocal treatment for breast cancer for nearly 100 years. The only thing physicians disagreed about was whether or not the surgery was sufficiently radical.

In the 1960s, Fisher and his brother, Edwin Fisher, MD, a worldrenowned breast cancer pathologist, conducted laboratory experiments that questioned the Halstedian view of metastasis. Through these experiments, which were conducted on animals, they discovered that tumor cells spread via the lymph nodes and the bloodstream, indicating that breast cancer is a systemic disease, not a local one as had always been theorized.

Over the next several decades, Fisher conducted laboratory investigations and prospective clinical trials that systematically advanced the understanding of tumor biology, resulting in an improvement in the standard of care for women with breast cancer. Fisher’s research proved that radical mastectomy is no more effective than the less extensive total (simple) mastectomy, which limits the surgical procedure to removal of the breast only.

Fisher’s subsequent investigations showed that lumpectomy followed by breast irradiation is as effective as modified radical mastectomy (total mastectomy plus the removal of the underarm lymph nodes). Then, in the early 1970s, his research revealed that adjuvant chemotherapy administered after surgery can improve the survival of women with early-stage breast cancer. In another study, he demonstrated that the oral hormonal therapy tamoxifen could reduce the risk of breast cancer recurrence and improve survival, and also that tamoxifen could reduce the incidence of breast cancer by nearly 50% when given to healthy women at high risk for developing the disease.

Step by step, Fisher’s research launched the breast cancer community into the modern era of new, promising treatment strategies that improved patient outcomes. The most important aspect to remember, though, is that each of these advancements was supported by laboratory research and clinical evidence.

Something that may not be readily understandable to the modern reader is that clinical trials as we know them today have not always been the answer to clinical questions. The first randomized clinical trial, conducted by Austin Bradford Hill on the use of streptomycin for tuberculosis, took place more recently than one might think, in 1948. Before then, anecdotes were the main source of information informing treatment strategies. According to Norman Wolmark, MD, current chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP), who was a protégé of Fisher’s for decades, “Clinical trials were not yet in the mainstream, so Bernie was certainly a pioneer.”

Early on in his medical career, Fisher’s interest in research was initiated by his work in the late 1940s with Julius M. Rogoff, MD, who was professor of Endocrine Research at the University of Pittsburgh, Pennsylvania, and then from 1950 to 1952, when he was under the tutelage of Isidor S. Ravdin, MD, chairman of the Department of Surgery and director of the Harrison Department of Surgical Research at the University of Pennsylvania. When the first clinical trial was being conducted, Fisher was studying liver regeneration, hypothermia, transplantation biology, and biology of metastasis in the laboratory setting. He was invited in 1957 to discuss the creation of the organization that would become the NSABP. As a result of his laboratory experience, Fisher was familiar with the scientific method, and he consequently viewed clinical trials with proper controls, statistics, and other elements as the appropriate venue for evaluating alternative hypotheses such as the worth of radical mastectomy, and then the worth of lumpectomy.

According to Daniel A. Osman, MD, who just recently retired from his 30-year tenure as the director of the Miami Breast Cancer Conference—a conference organized in large part due to Fisher’s groundbreaking data&mdash; Fisher had a credo, “In God we trust; all others require data,” which was a radically new viewpoint then.

Not only was Fisher challenging the status quo, but he was also admitting that surgeons did not have all the answers for treating breast cancer. Another of his colleagues, Jay R. Harris, MD, chair of the Department of Radiation Oncology at the Dana- Farber Cancer Institute, said that “One of his [Fisher’s] fundamental contributions globally was [that] he was an American surgeon who got up at meetings and said, ‘We don’t know the answer to this question. We need to do a clinical trial to answer it.’ Even to this day, surgeons are not prone to saying, ‘We don’t know the answer.’ And in the 1960s, it was unheard of.”

As one can imagine, this practice did not make him particularly popular among his colleagues. Harris said, “He was practically vilified by his specialty initially.” Osman also recalled, “When he started with lumpectomies, the surgeons of the United States hated him for it.” Luckily for the breast cancer community, Fisher was not to be dissuaded by the negative feedback. According to Wolmark, Fisher “was driven by applying the scientific method to clinical problem solving. He was driven by the truth. He was driven by the value of the data rather than by the value of opinion.”

It was his devotion to discovering the scientific truth that made it possible to persevere with cuttingedge research, which takes a special kind of personality. “There’s no doubt he has a big personality, and that’s what was required. He made such fundamental changes in the thinking of American physicians in getting them to do clinical trials. The ego strength that he had to have to face all that pushback and rejection, to keep on going…I could see somebody calling him brash, but that’s not the part of it that I think is key to the man. He had a vision for advancing care for breast cancer patients, and he was relentless in pursuing it,” recalled Wolmark.

In addition to a drive for truth, a facet of Fisher’s personality that has enabled him to succeed as a clinical scientist is the ability to reformulate his own hypotheses when needed. Wolmark reflected that “No matter how enamored he was of a hypothesis, the minute the data indicated that the hypothesis was not supported, it was abandoned, which is absolutely remarkable. No matter how much time and effort and intellectual commitment there was, if the data showed that the hypothesis was not supported, Fisher abandoned the research.” Anyone who has devoted hours and energy to a difficult cause knows how hard it is to let go of a theory when it is proved to be incorrect, and it is rare indeed to find someone who has the strength to relinquish that intellectual attachment and move on.

Fisher also challenged his colleagues to be objective. According to Wolmark, “His standard admonition to the membership of the NSABP was, ‘When you cross the threshold into this room, you cease to be a medical oncologist or a surgeon or a radiotherapist. You become a clinical investigator, and you leave your biases outside.” It may have been a difficult expectation to live up to, but Fisher gave this NSABP membership all of the tools they needed for success. “Bernie provided a unique environment. Aside from the clinical trials, we had a very active bench research lab, and there was a seamless interface between the lab and the clinical trial process, where hypotheses developed in the lab could be tested globally in a clinical trial. We weren’t certain where this was leading, but we knew that, wherever it was going, that the treatment of breast cancer would be inexorably and irreversibly changed,” continued Wolmark.

Fisher’s tenure at the NSABP spanned 47 years, as a founding member in 1958 and as chairman from 1967 to 1994.

He is currently a Distinguished Service Professor of Surgery at the University of Pittsburgh. He lectures occasionally and is writing a historical account of his 50-plus years of laboratory and clinical research related to cancer. Throughout his medical career to date, his contributions have been recognized by countless awards, chairs, and appointments, including appointments by Presidents Carter and Reagan, and he has participated in both national and international committees and panels devoted to furthering the science and treatment of breast cancer.

The breast cancer community is very fortunate to have such a living legend as a champion of its cause, and perhaps owes a thank you to his wife, three children, and five grandchildren for their willingness to share him with this cause. His clinical trials have provided the evidence to transform the way breast cancer is viewed, treated, and how it can be prevented, and Fisher has provided a legacy whereby alternative hypotheses can be formed and rigorously tested. As Wolmark asked, “How many of us can say that we left the state of the art in far better shape than we found it?” Fisher may be one of the few.

When Bernard Fisher, MD, first became involved in breast cancer research, the only treatment option available to patients was the radical mastectomy, a horribly disfiguring surgery that had been the undisputed standard of care since the late 1800s

Cheryl Zigrand

Articles

Experts Share Hopes for the Future of Myeloma Treatment

Fisher's Respect for Scientific Methods Propelled Landmark Advances