Carfilzomib Continues to Show Frontline Potential in Myeloma

Carfilzomib (Kyprolis) is an agent that should be considered for use in the frontline setting for high-risk patients with multiple myeloma as induction therapy prior to early autologous stem cell transplant, said Juan P. Alderuccio, MD.

“Bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone remain the standard of care in the frontline setting for elderly patients older than 75 years old or unfit patients. We usually use induction chemotherapy with lenalidomide plus dexamethasone and we keep patients on that combination until progression of disease,” said Alderuccio. “For patients with high-risk features, however, I believe that new proteasome inhibitors, such as carfilzomib, should be strongly considered in the frontline setting associated with an early autologous stem cell transplant in those patients.”

The proteasome inhibitor carfilzomib was initially approved by the FDA in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed/refractory disease who have received 1 to 3 lines of therapy. Carfilzomib is also approved as a single agent for patients with relapsed/refractory myeloma who have received 1 or more lines of therapy.

In October 2018, the agency approved a once-weekly dosing option of carfilzomib to use in combination with dexamethasone for patients with relapsed/refractory disease. This approval was based on positive data from the phase III ARROW study, in which carfilzomib administered once weekly at 70 mg/m² with dexamethasone (11.2 months; 95% CI, 8.6-13.0), led to a prolonged progression-free survival (PFS) compared with the standard twice-weekly schedule (7.6 months; 95% CI, 5.8-9.2) in those with relapsed/refractory disease.¹

Although bortezomib, lenalidomide, and dexamethasone (VRd) is a commonly used regimen in the United States for patients with newly diagnosed disease, carfilzomib has shown potential to replace bortezomib as the proteasome inhibitor of choice in this combination based on promising phase II data from the ASPIRE trial.²

In terms of maintenance therapy following autologous stem cell transplantation, headway has also been made with ixazomib (Ninlaro), as was evidenced by positive findings from the phase III TOURMALINE-MM3 trial, which showed that this approach resulted in prolonged PFS compared with placebo.³

“I believe that ixazomib offers an opportunity for patients who are not able to tolerate lenalidomide maintenance or who don't want to take the risk of secondary malignancies,” said Alderuccio, an assistant professor of clinical medicine at Sylvester Comprehensive Cancer Center, University of Miami Health System.

Although lenalidomide-based therapies have been the standard for patients with newly diagnosed disease who are ineligible to undergo stem cell transplantation, daratumumab (Darzalex) has also emerged as a potential option. Results from an international study presented at the 2018 ASH Annual Meeting showed that the addition of daratumumab to lenalidomide plus dexamethasone resulted in a 44% reduction in the risk of progression or death.⁴

OncLive: What is the current approach for stratifying patients with multiple myeloma for frontline therapy?

What advances have been made with proteasome inhibitors?

What is the current role of stem cell transplant in this space?

Could you speak to the recent data with ixazomib as maintenance therapy following stem cell transplant?

Have any other advances been made in the frontline setting?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Alderuccio discussed the current state of the treatment paradigm in multiple myeloma and ongoing challenges that remain. Alderuccio: We stratify patients based on cytogenetics. In terms of patients with high-risk cytogenetics, usually if a patient is a young patient, we prefer to use 1 of the new proteasome inhibitors such as carfilzomib. [However, there are] potential adverse reactions with this medication. Although it usually doesn't produce much peripheral neuropathy as is produced with bortezomib, in around 8% to 10% of patients, carfilzomib may produce [transient] heart failure. However, most of the time, after the continuation of this drug, the function of the left ventricle returns to baseline.Proteasome inhibitors are used in the frontline setting; usually it’s bortezomib with cyclophosphamide or lenalidomide plus dexamethasone. For some patients, bortezomib is a subcutaneous injection. In patients who are not able or already present with neuropathy, ixazomib is an FDA-approved drug that can be used in this setting. In patients with high-risk features, such as 17p deletions, we know that with carfilzomib we are able to achieve a deeper response and better survival. Therefore, I believe that carfilzomib is a drug that needs to be considered in the frontline setting for high-risk patients.I believe that autologous stem cell transplant still has a role in the treatment of multiple myeloma, especially in patients who are not able to achieve a complete response after induction chemotherapy with a regimen such as VRd or cyclophosphamide, bortezomib, and dexamethasone (CyBorD), which are the most common induction therapies that we use nowadays. With autologous stem cell transplant, we are able to achieve a deeper response. Some patients convert from having a positive minimal residual disease (MRD) to MRD-negative disease. Further, usually, we are able to achieve a deeper response with a maintenance therapy with lenalidomide. Therefore, there is still a role for stem cell transplant in multiple myeloma.[At the State of the Science Summit™,] we discussed the new clinical trials recently published in the Lancet regarding the use of ixazomib maintenance after a stem cell transplant. Usually the standard of care is lenalidomide for 2 years, usually at a dose of 10 mg daily, and if the patient is able to tolerate a higher dose, we will increase to 15 mg after 3 months of therapy. There is a concern about secondary malignancies in these patients. Thus far, there is no evidence of secondary malignancies with this medication as there is with lenalidomide. However, [regardless], the standard of care remains lenalidomide after autologous stem cell transplant for most patients with multiple myeloma.Several trials have been recently published or presented at the 2018 ASH Annual Meeting regarding the incorporation of daratumumab in the frontline setting in patients who are not candidates for stem cell transplant. One of the studies that were published in the New England Journal of Medicine was an international study that used daratumumab, melphalan, bortezomib, and dexamethasone, which has shown better survival in the daratumumab arm.

What unanswered questions still need to be addressed?

There is also an ongoing trial with daratumumab plus lenalidomide and dexamethasone. Further, results from an interim analysis showed better survival in those patients [who received daratumumab] as well. Therefore, it seems that daratumumab will play a role in the frontline setting for patients who are not candidates for autologous stem cell transplant.[We still do not know what the] role of MRD is in multiple myeloma. MRD has been shown to correlate with PFS and overall survival and there is a clear benefit of patients achieving negative MRD in myeloma.

What is your take-home message to colleagues working in the myeloma space?

However, there are several features that are not clear. When a patient has a negative MRD, with the technology that we have nowadays, it's not clear if this is because the plasma cells are gone or if it's because we are not able to reach the plasma cells. In future clinical trials, we will need to incorporate what therapeutic intervention are we going to take in patients with MRD positivity.In terms of the role of MRD, it has been correlated with survival. However, I don't think that at this point in time, that I'm not sure that we should be making a therapeutic decision based on MRD because there are no strong data to support a change in therapy. Ixazomib has become an option for patients who are unable to tolerate lenalidomide after autologous stem cell transplant. However, I believe that lenalidomide remains the standard of care for most of the patients. In high-risk patients, we can consider bortezomib maintenance, as well.

References

1. Mateos M-V, Moreau P, Berenson JR, et al. Once-weekly vs twice-weekly carfilzomib (K) dosing plus dexamethasone (d) in patients with relapsed and refractory multiple myeloma (RRMM): results of the randomized phase 3 study A.R.R.O.W. J Clin Oncol. 2018;36(suppl 15; abstr 8000). doi: 10.1200/JCO.2018.36.15_suppl.8000.
2. Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36(8):728-734. doi: 10.1200/JCO.2017.76.5032.
3. Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36(8):728-734. doi: 10.1200/JCO.2017.76.5032.
4. Facon T, Kumar SK, Plesner T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D—Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Blood. 2018;132(LBA-2). doi: 10.1182/blood-2018-120737.