Using the New Therapeutic Options in Multiple Myeloma

Sundar Jagannath, MD

Since the 1980s, there have been waves of advancements in the treatment of multiple myeloma (Figure). Similarly, further exploration of existing regimens and research into novel therapeutics hold the promise of advances in other types of blood cancers. The 17th Annual International Congress on Hematologic Malignancies:® Focus on Leukemias, Lymphomas, and Myeloma featured presentations from leading oncology researchers on current and potential new therapies. The congress, which Physicians’ Education Resource (PER) hosted, was held on February 15−17 in New York City.

With the approval of carfilzomib in July 2012 and pomalidomide in February 2013, new therapeutic options are available for the treatment of multiple myeloma (MM). At the 17th Annual International Congress on Hematologic Malignancies, Sundar Jagannath, MD, professor of Medicine and Director, Multiple Myeloma Program, The Tisch Cancer Institute at Mount Sinai Medical Center, New York City, spoke about evidence for use of these treatment options in clinical practice.

Thalidomide, lenalidomide, and pomalidomide are structurally similar, but functionally they are different, both qualitatively and quantitatively, said Jagannath. “That’s very important when we talk about having a new drug for the treatment of relapsed and refractory multiple myeloma.” Mechanisms that lead to resistance with lenalidomide and thalidomide do not necessarily impact the use of pomalidomide, he said.

Figure. Developments in Multiple Myeloma Research

Adapted from Anderson KC. Bench to bedside translation of targeted therapies in multiple myeloma.

Presented at 2011 American Society of Clinical Oncology Annual Meeting; June 4, 2011; Chicago, Il.

MM-002 was the pivotal trial that led to the approval of pomalidomide.¹ The study examined the use of pomalidomide in combination with low-dose dexamethasone in patients with relapsed and refractory MM who had received two or more prior therapies, including lenalidomide and bortezomib. At the 2012 American Society of Hematology (ASH) meeting in December, Jagannath presented updated results of the phase II study, including an age subgroup analysis.A total of 221 patients were randomized 1:1 to receive either pomalidomide (4 mg/d for days 1 to 21 in a 28-day cycle) plus low-dose dexamethasone (40 mg/ wk; n = 113) or pomalidomide alone (n = 108). Patients randomized to the pomalidomide-alone group were allowed to add low-dose dexamethasone upon disease progression; approximately 60% of patients in that arm eventually took dexamethasone.

The overall response rate (ORR) was 34% in the combination therapy group versus 15% in the pomalidomide- alone group. The median progression-free survival (PFS) in the pomalidomide/dexamethasone group was 4.6 months versus 2.6 months for the pomalidomide- alone group (hazard ratio [HR] = 0.67; P = .002).

However, the median duration of response was the same in both groups: 8.3 months for pomalidomide plus dexamethasone versus 8.8 months for pomalidomide alone (HR = 0.89; P = .734). “At this stage [of the disease], it’s not that dexamethasone is the key. It does synergize, but pomalidomide is the key, and there is a durability of the response if [patients] do respond,” Jagannath said.

Overall survival (OS) was the same in the two treatment arms (16.5 months for pomalidomide/dexamethasone vs 13.6 months for pomalidomide alone; HR = 0.92; P = .609).

Pomalidomide was generally well tolerated and did not cause as significant neutropenia as generally occurs with lenalidomide, or as significant neuropathy as occurs with thalidomide, Jagannath said. The most common grade 3 or 4 adverse events (AEs) occurring in more than 5% of study participants were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), fatigue (14%), dyspnea (13%), leukopenia (10%), back pain (10%), and urinary tract infection (9%).¹

Neutropenia occurred in nearly 60% of patients older than 65 years in the pomalidomide-only group, Jagannath said, “so there are significant adverse events in these patients.” Furthermore, he said, “when you combine [pomalidomide] with dexamethasone, especially in the elderly patient, you have to be careful…because the incidence of pneumonia is a little higher.” Jagannath also noted that rates of deep vein thrombosis were very low (2%, all grades) because patients received anticoagulation.

Dose reductions occurred in approximately 30% of patients, but 90% of patients maintained dose intensity. “So this was really well tolerated even in the very advanced patient,” Jagannath said. “Why? Because the study did allow liberal use of Neupogen [filgrastim; granulocyte colony-stimulating factor].”

Pomalidomide can be combined with bortezomib, Jagannath said, as demonstrated by study results presented at the ASH 2012 meeting, which found favorable efficacy and tolerability for the combination of pomalidomide, bortezomib, and dexamethasone in relapsed/refractory disease.² The study is ongoing.

In July 2012, carfilzomib, a next-generation proteasome inhibitor, was approved for treatment of patients with MM who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression or are within 60 days of completion of their last therapy. Other next-generation proteasome inhibitors are in development, and include ixazomib (MLN9708) and oprozomib (ONX 0912), Jagannath said.

The phase II PX-171-003-A1 study of carfilzomib enrolled patients with relapsed or refractory MM who had received at least two prior lines of therapy; participants had a median of five prior lines of therapy.³ Patients received single-agent carfilzomib 20 mg/m² intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m² for up to 12 cycles. A total of 266 patients were evaluable for safety and 257 for efficacy.

In this heavily pretreated population, the ORR was 24%, and the mediation duration of response was 8.3 months (95% CI, 6.5-9.7). Median PFS was 3.7 months (95% CI, 2.8-4.6) and median OS was 15.6 months (95% CI, 13.0-19.2).

“So clearly, these two drugs [pomalidomide and carfilzomib] are going to improve the survival of myeloma patients under your care,” Jagannath said.

Common AEs in the trial were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Peripheral neuropathy, primarily grades 1 or 2, occurred in 33 patients (12.4%).

Jagannath noted that one-third of patients in the trial developed dyspnea, 17% of which was due to carfilzomib. Rates of grade 3-4 dyspnea were low, however, and occurred in only 3.4% of patients. Congestive heart failure occurred in 3.8% of patients in the trial, and myocardial infarction or cardiac arrest occurred in 2.3%. Jagannath noted that physicians should be aware of and monitor for cardiac safety in patients.

Carfilzomib can be readily combined with other agents for the treatment of MM, including pomalidomide and low-dose dexamethasone, Jagannath said.⁴ Clinical trials are currently exploring various combination therapies, as well as different dosages of carfilzomib, he said.

References

1. Jagannath S, Hofmeister CC, Siegel DS, et al. Pomalidomide (POM) with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior therapy with lenalidomide (LEN) and bortezomib (BORT): updated phase 2 results and age subgroup analysis. Presented at: 54th ASH Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 450.
2. Richardson PG, Hofmeister CC, Siegel D, et al. MM-005: a phase 1, multicenter, open-label, dose-escalation study to determine the maximum tolerated dose for the combination of pomalidomide, bortezomib, and low-dose dexamethasone in subjects with relapsed or refractory multiple myeloma. Presented at: 54th ASH Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 727.
3. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):2817-2825.
4. Shah JJ, Stadtmauer EA, Abonour R, et al. A multi-center phase I/II trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma. Presented at: 54th ASH Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 74.