Sagar Lonial, MD, professor and chair, Department of Hematology & Medical Oncology, Emory University School of Medicine, chief medical officer, Winship Cancer Institute of Emory University, discusses ongoing phase III studies in patients with multiple myeloma.

Carfilzomib (Kyprolis) with lenalidomide (Revlimid) and dexamethasone versus bortezomib (Velcade) with lenalidomide and dexamethasone is currently being studied in an ECOG trial called E1A11. This trial has enrolled almost 800 patients, and is investigating which proteasome inhibitor is more beneficial upfront, and as maintenance therapy. This trial is still enrolling, so doctors have the opportunity to refer their patients to it, explains Lonial.

In the phase III ASPIRE trial, the median overall survival (OS) with the carfilzomib combination was 48.3 months versus 40.4 months with lenalidomide/dexamethasone alone (HR, 0.79, 95% CI, 0.67-0.95). The OS benefit seen at the final analysis was consistent, even in those who received prior treatment with bortezomib. There was a 25% reduction in the risk of death with carfilzomib in those not treated with bortezomib versus a 16% reduction for those treated with the proteasome inhibitor.

Ixazomib (Ninlaro) with lenalidomide and dexamethasone versus lenalidomide and dexamethasone is being tested for both transplant-eligible and ineligible-patients with myeloma. According to Lonial, physicians are eagerly awaiting follow-up results from this study.

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Dr. Lonial Discusses Ongoing Phase III Trials in Multiple Myeloma

Sagar Lonial, MD, professor and chair, Department of Hematology & Medical Oncology, Emory University School of Medicine, chief medical officer, Winship Cancer Institute of Emory University, discusses differentiating patients with smoldering myeloma and multiple myeloma.

There are new definitions of multiple myeloma and ways to differentiate patients with smoldering myeloma, explains Lonial. It is known that smoldering myeloma can be risk stratified with simple tests, such as a bone marrow biopsy, magnitude of the M protein, and free light chain ratio.

It is also known that the Myeloma Working Group redefined myeloma a few years ago, says Lonial. Patients with high free light chain ratios of greater than 100 or bone lesions detected by MRI or PET scan that were greater than 60% are now considered as multiple myeloma and not smoldering myeloma.

Additionally, a skeletal survey in a patient with smoldering or monoclonal gammopathy of undetermined significance (MGUS) myeloma is no longer the standard of care. More advanced imaging is needed to ensure that patients do not have occult bone disease that might have been missed with a skeletal survey.

Dr. Lonial on Differentiating Patients With Smoldering and Multiple Myeloma

Sagar Lonial, MD, professor and chair, Department of Hematology & Medical Oncology, Emory University School of Medicine, chief medical officer, Winship Cancer Institute of Emory University, discusses updates in multiple myeloma.

Recently, highly active induction regimens that combine proteasome inhibitors and IMiDS with transplant and risk adapted maintenance have been shown to put most patients into remission for 3 to 5 years. This contrasts with the past 15 years of treatment that, according to Lonial, lacked effective drugs in the induction therapy setting.

Immune-based agents such elotuzumab (Empliciti) and daratumumab (Darzalex) are also in the mix, as well as other small molecules in development, says Lonial.

Dr. Lonial Discusses Recent Updates in Multiple Myeloma

Sagar Lonial, MD, professor and chair, Department of Hematology & Medical Oncology, Emory University School of Medicine, chief medical officer, Winship Cancer Institute of Emory University, discusses the potential of the combination regimen of pomalidomide (Pomalyst) and daratumumab (Darzalex) for the treatment of patients with multiple myeloma.

Clinical trial data of the combination demonstrates that two non-cross reactive agents can perform synergistically, Lonial explains. Studies have shown that in the relapsed/refractory setting, pomalidomide and dexamethasone demonstrated an overall response rate (ORR) of 30%, while single-agent daratumumab elicited an ORR of 30% in a similar setting.

Together, pomalidomide and daratumumab demonstrated an ORR of approximately 70%, and a significant number of patients achieved a very good partial response or better, Lonial adds. The combination enhances the immune system's ability to make daratumumab more effective, he says.

Dr. Lonial on Daratumumab Plus Pomalidomide in Multiple Myeloma

Sagar Lonial, MD, professor and chair, department of Hematology & Medical Oncology, Emory University School of Medicine, Chief Medical Officer, Winship Cancer Institute of Emory University, discusses treatment for smoldering multiple myeloma.

One of the biggest questions regarding smoldering multiple myeloma is whether or not patients with it require early treatment or simply observation. Lonial believes patients who are classified as having high-risk smoldering who need earlier treatment, should be reclassified as having standard multiple myeloma.

There may be non-high-risk patients that require treatment as well, says Lonial. There are small studies that are investigating this, but currently there is no evidence that patients with true smoldering should be treated earlier.

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 Sagar Lonial, MD, professor and chair, department of Hematology & Medical Oncology, Emory University School of Medicine, Chief Medical Officer, Winship Cancer Institute of Emory University, discusses treatment for smoldering multiple myeloma.


Dr. Sagar Lonial on Early Treatment Versus Observation for Smoldering Multiple Myeloma

Sagar Lonial, MD, chief medical officer at Winship Cancer Institute of Emory University, discusses novel mechanisms of agents used for the treatment of patients with multiple myeloma.

The monoclonal antibody elotuzumab (Empliciti) works through activation of natural killer cells, Lonial explains. Daratumumab (Darzalex), another monoclonal antibody, induces antibody-dependent cell-mediated cytotoxicity and also works through direct signaling inhibition. Antibodies that are in development include CD138-targeted agents and PD-1/PD-L1 agents.

Next steps with these agents include investigating them in earlier lines of therapy, Lonial adds. Incorporating these antibodies as an upfront treatment approach and in combination with other therapies will likely be part of future treatment paradigms. Secondly, novel ways of administering agents such as panobinostat and filanesib should also be researched, Lonial says.

Sagar Lonial, MD, chief medical officer at Winship Cancer Institute of Emory University, discusses novel mechanisms of agents used for the treatment of patients with multiple myeloma.


Dr. Lonial on Novel Mechanisms in Multiple Myeloma

	Winship Cancer Institute of Emory University

The landscape of therapeutic options for patients with myeloma at all phases of treatment has rapidly changed with the development of new drugs and targets. While these have been focused predominantly on the proteasome inhibitors and immunomodulatory agents (IMiDS), the recent approval of the first histone deacetylase inhibitor (HDACi) panobinostat represents the first new target approved in more than a decade.

With recent data presented at 2015 ASCO and European Hematology Association meetings, this scenario is likely about to change dramatically for the better as we develop new treatment paradigms based upon the use of immune-based targeting through monoclonal antibodies. Most other areas of oncology and hematology already are reaping the benefit of targeted immune-based treatments first demonstrated through agents such as rituximab and trastuzumab, but up until recently the benefit for antibody-based treatments in myeloma had been disappointing. Now we have two agents that are likely to be ready for clinical use in the near future, and several others in development that also look very promising.

Elotuzumab is a humanized monoclonal antibody that targets a protein called SLAMF7 (signaling lymphocyte activating molecule F7), formerly known as CS1, which is present on plasma cells as well as natural killer (NK) cells. Though the protein is present on both NK cells and plasma cells, the effect of binding with elotuzumab is different. SLAMF7 on NK cells results in signaling through EAT2, which then activates NK cells, while plasma cells do not have EAT2, and thus no signaling is initiated when elotuzumab binds the receptor.

The net result is that elotuzumab tags tumor cells for destruction via mechanisms based on antibody-dependent cell mediated toxicity while at the same activating the NK effector cells. While having no single-agent activity, the combination of elotuzumab plus lenalidomide/dexamethasone demonstrated a higher overall response rate (ORR) and progression-free survival (PFS) when compared with lenalidomide/dexamethasone alone in early-phase development. This led to the ELOQUENT-2 randomized trial of lenalidomide/ dexamethasone with and without elotuzumab.

What was noted in the initial report at ASCO

 published at the same time was a higher ORR and improved PFS for the elotuzumab arm compared with the standard therapy. Additionally, there appeared to be significant activity among patients with deletion of 17p (del17p), and a PFS that matched the PFS of patients who did not have del17p, suggesting that the addition of the antibody was able to overcome the negative prognostic findings associated with this very poor risk feature. Moreover, when depth of response, measured as greater than a partial response (PR) or a very good partial response (VGPR), was compared between the two arms, the duration of remission was longer when the patients received elotuzumab, suggesting that the immune component was improving not only depth of response but also durability over the long term. Additional toxicities were related only to infusion reactions, which occurred in 10% of patients, and were seen predominantly with the first dose. Thus, from this trial, the benefit of elotuzumab was seen in combination with lenalidomide/dexathemasone as it improved ORR, PFS, and was effective among high-risk subsets of myeloma as well as prolonging duration of response for all patients who achieved a PR or greater on the elotuzumab treatment arm.

The other target of significant interest and activity is CD38, known to be present on nearly all plasma cells as well as some cells within the lymphoid and myeloid lineage. There are two antibodies targeting CD38, daratumumab and SAR690584, in mid- to advanced development.

Both have demonstrated single- agent activity of approximately 30% in early phase I studies, with good combination activity when used with bortezomib and lenalidomide.

The largest of the CD38 trials, reported at ASCO this year, showed significant activity as a single agent.

 In the Sirius trial, 106 patients with double refractory myeloma and a median of five prior lines of therapy were treated with a daratumumab dose of 16 mg/kg. Overall, 66% of the patients were refractory to three of four approved novel agents, and a significant number of patients were refractory to alkylator agents as well. The ORR was 29% with several patients achieving a stringent complete response or VGPR. Median duration of response was 7.4 months, median PFS was 3.4 months, and median projected overall survival at 1 year was 65%. Of note, 29 of the 31 responders remained alive at the time of data cutoff.

Response rates appear to be consistent across different levels of refractoriness, and responses were seen among patients with extramedullary disease as well as high-risk disease. The main added toxicity associated with daratumumab was infusion reactions, which occurred in 43% of patients, more than 90% of which occurred with the first dose of treatment. Based upon this data in a highly refractory patient population, the use of single-agent daratumumab in a refractory myeloma patient population suggests that this is a new treatment option in a setting where other treatments do not have consistent activity.

Additional potential targets in development include antibodies targeting CD138, CD56, PD-1, and PDL-1. These all have shown some activity among patients with relapsed or refractory myeloma and, when coupled with IMIDs as we have seen with elotuzumab, the synergy for these monoclonal antibodies can be quite impressive, providing additional new options in the near future.

Based upon these data, it appears that the era of antibodies is here now for myeloma therapy and, while the studies currently have focused on a relapsed or refractory setting, it is clear that these agents will have a major impact in large part due to their novel targets and mechanisms of action, in all phases of treatment. These are very exciting data, and represent new hope and treatments for patients.

			Lonial S, Dimopoulos MA, Palumbo A, et al. 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, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma [published online June 2, 2105]. 

			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).

Articles

The landscape of therapeutic options for patients with myeloma at all phases of treatment has rapidly changed with the development of new drugs and targets. 

Sagar Lonial, MD