	Professor Dean for Research Mayo Clinic Scottsdale, AZ

	Medical & Scientific Director Institute for Myeloma and Bone Cancer Research Los Angeles, CA

	Director, Multiple Myeloma Research Program Professor, Medicine The Tisch Cancer Institute Mount Sinai Medical Center New York, NY

	Professor, Medicine Mayo Clinic Rochester, MN

	Professor Vice Chair, Clinical Affairs Department of Hematology & Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

	Associate Professor, Medicine Barbara Ann Karmanos Cancer Institute Wayne State University Detroit, MI

With the advent of safer and more effective treatments, early diagnosis of multiple myeloma (MM) has become an important goal. Recent data show that early intervention in high-risk smoldering MM can prolong survival, according to experts who participated in a recent OncLive Peer Exchange program. Led by the moderator, 

, MB ChB, a panel of clinical and research experts discussed the evolving treatment of MM, including upfront approaches, managing patients with relapsed and refractory myeloma, and emerging regimens during a Peer Exchange session entitled “Treatment of Multiple Myeloma.”

, described the new diagnostic criteria developed by the International Myeloma Working Group to help define symptomatic myeloma (Table 1).

 These changes include: 1) the presence of >1 focal bone lesion by MRI or PET scan; 2) free light chain ratio ≥100; and 3) ≥60% plasma cells in the bone marrow. These additions are based on the identification of biomarkers associated with near-inevitable development of CRAB features (hypercalcemia, renal failure, anemia, and bone lesions) in patients who would otherwise be regarded as having smoldering multiple myeloma. Delaying diagnosis and treatment in these active MM patients could be harmful and result in poor outcomes.

Pretransplant Regimens: Two or Three Agents

 and Lonial agreed that optimal treatment of MM incorporates the administration of three medications, rather than two, in most transplant-eligible patients. Sundar Jagannath, MD, stated that clinical trials, including large international studies (FIRST, UPFRONT

), have demonstrated efficacy with two-medication regimens, such as lenalidomide and dexamethasone, and bortezomib- based regimens.

	On this basis, Jagannath stated that it is difficult to only recommend the use of three medications. In his practice, he explained, they administer bortezomib, lenalidomide, and dexamethasone, noting that giving a proteasome inhibitor, an immunomodulatory agent, and a steroid is important, as MM has numerous clones and physicians should cover most of the clones in newly diagnosed individuals.

Examining Transplant and Maintenance Therapy

 explained that stem cell transplant in patients with MM deepens response in the subset of patients who have not achieved complete response on therapy prior to transplant. Studies have demonstrated that pretransplant individuals in apparent complete remission, but not minimum residual disease (MRD)—negative, become MRD–negative after transplant, noted Zonder. Lonial added that achieving complete remission is “only the middle of the iceberg.”

Maintenance therapy is often given after the achievement of complete remission. Berenson described that his practice administers bortezomib- based therapy as frontline therapy, typically giving bortezomib every other week and maintaining steroids. Lonial noted that choice of maintenance therapy regimens is guided by the patient’s risk level; for instance, he said that patients facing the highest risk—those with a 17p deletion or abnormal cytogenetics&mdash;would receive RVD (lenalidomide, bortezomib, and dexamethasone) maintenance therapy after receiving upfront RVD and a single transplant.

Zonder highlighted the importance of selecting regimens that patients can tolerate, since individuals who cannot continue on maintenance therapy will lack sustained benefit.

Efficacy Results From ASPIRE Trial (Table 2) 

					Carfilzomib/lenalidomide/dexamethasone

					Lenalidomide/dexamethasone (control)

Treatment for patients who have early relapsed MM, failing one to three previous lines of therapy, is evolving with new data and emerging therapies. To determine the next treatment for a patient who experiences his first relapse,

suggested that clinicians take a similar approach as they did with a newly diagnosed patient 10 years ago. “…Pretty much the same principles hold true. You need to take into account what toxicity is left behind from the previous treatments they have had. We certainly want to see how long a response they have had with their previous treatment, and [whether] some of the risk factors that we identified at baseline, especially some of the FISH characteristics, still hold true and should be taken into account when you design the next regimen for that patient.”

The standard treatment for relapsed MM has traditionally been lenalidomide plus dexamethasone. The ASPIRE trial, which Stewart presented at the 2014 American Society of Hematology (ASH) Annual Meeting in December, demonstrated that the addition of carfilzomib to this combination results in significant improvements in median progression- free survival (PFS) and overall response rates (Table 2).

Results from the trial have been submitted to the FDA to support full regulatory approval for carfilzomib as a treatment for patients with relapsed MM who have received at least one prior therapy; the agent gained an accelerated approval in a more restrictive MM setting in 2012.

 In terms of side effects in the trial, Kumar stated that, “I think the worry always is when you use a triplet you’re going to have more side effects than if you’re going to use a doublet. And I think from that perspective, the ASPIRE trial was really very interesting because when you look at the side effect profile between the two arms, they were very comparable, and I think from that perspective, the ASPIRE trial was really very interesting because when you look at the side effect profile between the two arms, they were very comparable, and I think that is one of the key findings of the study.”

Additionally, Berenson briefly highlighted a phase I trial he and colleagues conducted examining adjusting the dose of carfilzomib from twice weekly to once weekly. Preliminary results demonstrated that the maximum tolerated dose of weekly carfilzomib with dexamethasone had an acceptable safety and tolerability profile with promising efficacy after a short follow-up period in patients with relapsed or refractory MM.

The Role of Pomalidomide and Panobinostat

Other immunomodulatory agents are also being tested in patients with relapsed multiple myeloma. Zonder described pomalidomide as third in the family of immunomodulatory drugs, and very similar in some respects to lenalidomide; for example, both have the risk of thrombotic adverse events. Pomalidomide is currently used in patients who relapsed on previous therapy that included an immunomodulatory drug and a proteasome inhibitor.

Kumar suggested that pomalidomide may have two roles. One is in the frail, older patients who have already been treated with some of the novel agents, such as the participants in the FIRST trial.

 Thus, for patients relapsing on a lenalidomide/dexamethasone regimen, pomalidomide/dexamethasone would be a safe and well-tolerated option. The second role for pomalidomide is going to be in combinations.

Panobinostat is a histone deacetylase (HDAC) inhibitor. Lonial stated that the HDAC class is very active,not as a single-agent therapy but as a partner with proteasome inhibitors and potentially with immunomodulatory drugs as well. Zonder described the PANORAMA- 1 trial comparing bortezomib/dexamethasone with or without panobinostat.

He stated that the study showed a modest improvement in PFS with approximately a 4-month difference favoring the combination arm. Patients in the combination arm, however, experienced significantly higher levels of toxicity, particularly diarrhea.

He explained that, “It’s hard to know how to use a new medication which offers a modest improvement in outcomes but at the cost of significant toxicity.”

 Lonial added that the challenge with the study combining panobinostat with bortezomib was that it was using IV bortezomib; in fact, in the subcutaneous series, the gastrointestinal toxicities appear to be lower. “Jonathan Kaufman from our group presented at ASH 2014 data on carfilzomib plus panobinostat, and the GI [toxicity] was markedly less with PFS of almost 11 months in a refractory patient population. So I think it’s a good drug. We just have to figure out how to use it.”

The FDA currently is reviewing a new drug application for the use of panobinostat in combination with bortezomib and dexamethasone for patients with previously treated multiple myeloma.

			Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma [published online October 26, 2014]. Lancet Oncol. 2014;15(12):e538-e548.

			Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10):906-917.

			Niesvizky R, Flinn IW, Rifkin R, et al. Efficacy and safety of three bortezomib-based combinations in elderly, newly diagnosed multiple myeloma patients: results from all randomized patients in the community-based, phase 3b UPFRONT study. Blood (ASH Annual Meeting Abstracts). 2011;118: Abstract 478.

			Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma [published online December 6, 2014]. N Engl J Med. 2015;372(2):142-152.

			Amgen submits applications in the US And Europe for Kyprolis (carfilzomib) for the treatment of relapsed multiple myeloma [press release]. Thousand Oaks, CA: Amgen; January 27, 2015.

			Berenson JR, Klein LM, Rifki RM, et al. Results of the dose-escalation portion of a phase 1/2 study (CHAMPION-1) investigating weekly carfilzomib in combination with dexamethasone for patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2014;32:5s(suppl; abstr 8594).

			Richardson PG, Hungria VTM, Yoon SS, et al. Panorama 1: A randomized, double-blind, phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol. 2014;32:5s(suppl; abstr 8510).

			Kaufman JL, Zimmerman T, Rosenbaum CA, et al. Phase I Study of the combination of carfilzomib and panobinostat for patients with relapsed and refractory myeloma: a Multiple Myeloma Research Consortium (MMRC) clinical trial. Blood. 2014;124(21): Abstract 32.

			Novartis announces extension to FDA review period for multiple myeloma investigational compound LBH589 [press release]. Basel, Switzerland: Novartis; November 25, 2014.

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