Treatment for Relapsed/Refractory Multiple Myeloma Based on Biology, Time to Relapse

Natalie S. Callander, MD

The treatment approach for patients with relapsed/refractory (R/R) multiple myeloma (MM) should be tailored based on biology of the disease, frailty of the patient, and comorbidities, said Natalie S. Callander, MD, in a presentation at the NCCN 12th Annual Congress: Hematologic Malignancies in San Francisco, California.¹

Immediate considerations in the treatment of the relapsed patient are whether the relapse is biochemical or symptomatic, whether relapse is occurring on maintenance or other treatments, whether the relapse is early (<12 months), and how extensive the relapse is, said Callander, a professor of medicine at the Division of Hematology/Oncology, University of Wisconsin Cancer Center, Madison.

“If you had a patient who had a symptomatic relapse, you would treat them much more vigorously than if it was biochemical, and it’s important to know [when looking at study results] what we mean by refractory; this is a patient who relapses on therapy, within 60 days of stopping therapy, or has never really reached more than stable disease,” she said. The better outcome with biochemical relapse versus symptomatic is likely a reflection of biology, she explained. One caveat for clinicians to look out for is the patient who develops light chain escape and appears to do worse as a result of clonal evolution.

For patients with early relapse, monoclonal antibodies and triplet combinations with carfilzomib (Kyprolis) and pomalidomide (Pomalyst) are attractive, Callander said.

Preferred regimens for patients with previously treated MM, per the NCCN guideline v2.2018, are:

• Repeat primary induction therapy (if relapse occurs at >6 months)
• Bortezomib (Velcade)/lenalidomide (Revilmid)/dexamethasone
• Carfilzomib/dexamethasone (category 1)
• Carfilzomib/lenalidomide/dexamethasone (category 1)
• Daratumumab/bortezomib/dexamethasone (category 1)
• Daratumumab/lenalidomide/dexamethasone (category 1)
• Elotuzumab (Empliciti)/lenalidomide/dexamethasone (category 1)
• Ixazomib (Ninlaro)/lenalidomide/dexamethasone (category 1)

Several other regimens are recommended (with phase II data to support them) and others can be useful in certain circumstances.

Lenalidomide-based regimens for early (first) relapse have produced excellent response rates and progression-free survival (PFS) superior to dexamethasone in phase III clinical studies, similar to rates observed in newly diagnosed patients, said Callander. Bortezomib-based regimens for early (first) response are also associated with high response rates and superior PFS rates versus dexamethasone. These regimens “looked to be equally efficacious in patients with high-risk relapsed multiple myeloma, which is also something to keep in mind,” she said.

A second autologous transplant for R/R MM “is often a very good choice, particularly for patients who are looking to do something and try to get back on as little therapy as possible,” Callander said.

Patients who meet a definition of “frail” have worse outcomes than fit patients, or those with intermediate fitness, and also have double the rate of therapy discontinuation compared with fit patients.² “I tend to try to focus on oral agents,” she said, “and limit steroids when feasible. With the monoclonal antibodies in this population, consider moving to biweekly or monthly dosing after response is confirmed.”

“You can use [carfilzomib (Kyprolis)] in older individuals…but you have to be careful with the dosing, and I don’t give it to patients who have either significant pulmonary disease or heart failure,” she said.

Pomalidomide-dexamethasone is an easy regimen for older patients to tolerate.

An all-oral regimen of ixazomib/cyclophosphamide/dexamethasone was associated with a higher overall response rate and a higher rate of complete remission plus very good/partial response in patients age 65 years or older versus those younger than 65 years.³ “This is a very reasonable regimen to consider for older patients,” she said.

Patients with high-risk R/R MM are often difficult to treat, Callander stated. These patients are typically symptomatic with falling counts, new bone lesions, and extramedullary presentations. In a fit patient with high-risk MM at baseline who relapse, disease control should be established quickly. “That’s where those regimens useful in special circumstances can come in, such as VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) or high-dose cyclophosphamide,” she said. Outcomes are particularly poor in elderly or unfit patients with high-risk R/R MM, for whom “I try to use a monoclonal antibody early,” she said. “Hopefully, this is a group that will benefit in the future from some targeted agents.”

Most patients with R/R MM respond initially but eventually will develop refractory relapse. The chance of obtaining at least a partial response in such patients is low. Median overall survival (OS) for this group, if untreated, is about 2 months.⁴ For those patients receiving 1 or more regimens, the OS is 15.2 months.⁴ “Obviously, these patients need more treatment options,” said Callander. Patients who are salvaged with carfilzomib/pomalidomide/dexamethasone seem to have better outcomes compared with other treatment options. Bendamustine/pomalidomide/dexamethasone has “a lot of hematology toxicity” but in patients with multiple relapses, the overall response rate is 68%.⁵

Checkpoint inhibition using pembrolizumab (Keytruda) in combination with pomalidomide and dexamethasone was not effective in the KEYNOTE-183 trial, leading the US Food and Drug Administration to close the trial.

References

1. Callander N. Treatment of relapsed/refractory multiple myeloma. Presented at: NCCN 12th Annual Congress: Hematologic Malignancies; October 6-7, 2017; San Francisco, CA.
2. Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125:2068-2074. doi: 10.1182/blood-2014-12-615187.
3. Kumar S, Grzasko N, Delimpasi S, et al. Phase 2 study of the all-oral combination of ixazomib plus cyclophosphamide and low-dose dexamethasone (ICd) in patients (Pts) with relapsed/refractory multiple myeloma (RRMM). Presented at: 58th American Society of Hematology Annual Meeting & Exposition; December 3-6, 2016; San Diego, CA. Abstract 3327. http://www.bloodjournal.org/content/128/22/3327.
4. Kumar SK, Dimopoulos MA, Kastrititis E, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017. doi: 10.1038/leu.2017.138.
5. Sivaraj D, Green MM, Kang Y, et al. Phase I/II dose expansion of a trial investigating bendamustine and pomalidomide with dexamethasone (BPd) in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2017;35(suppl; abstr 8008). http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.8008.