Experts Share Hopes for the Future of Myeloma Treatment

Sagar Lonial, MD

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 OncLive Peer Exchange® program.

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.

Monoclonal Antibodies Stir Excitement

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.¹

Noopur Suresh Raje, MD

“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.

Jatin J. Shah, MD

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.²

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.”

Rafael Fonseca, MD

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.³

Carfilzomib was approved at a dose of 27 mg/m² given over a period of 10 minutes, but the dose used in ENDEAVOR was 56 mg/m² given over 30 minutes, which aided the tolerability of the higher dose.³

According to Shah, the results of ENDEAVOR show that, “We should reset the conversation. Carfilzomib 56 mg/m² 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/m² 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.⁴

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/m² in one trial and 70 mg/m² in the other study.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.⁵

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.⁶

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.⁷

Heather J. Landau, MD

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—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.”

Improving Patients’ Quality of Life

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.”

Morie A. Gertz, MD

Hope Precedes the Victory

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.”

References

1. 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). J Clin Oncol. 2015;33(suppl; abstr 8508).
2. 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). J Clin Oncol. 2015;33(suppl; abstr LBA8512).
3. 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. J Clin Oncol. 2015;33(suppl; abstr 8509).
4. 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). J Clin Oncol. 2015;33(suppl; abstr 8527).
5. 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. J Clin Oncol. 2015;33(suppl; abstr 8526).
6. 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. J Clin Oncol. 2015;33(suppl; abstr 8575).
7. Chari A, Cho HJ, Parekh SS, et al. A phase II study of panobinostat with lenalidomide and weekly dexamethasone in myeloma. J Clin Oncol. 2015;33(suppl; abstr 8528).