Carfilzomib-based triplet regimen a potential upfront treatment for high-risk MM

The combination therapy comprising carfilzomib, cyclophosphamide and dexamethasone (KCd) is effective, with a tolerable safety profile, in an Asian cohort with high-risk multiple myeloma (MM) — thus providing a more economical alternative as a potential upfront regimen in resource-limited settings, according to leading experts during a myeloma education webinar.

“Management for high-risk MM remains an unmet need in Singapore because currently, we don’t have a good treatment for this subgroup, particularly in Singapore whereby most patients are under subsidized care,” said Dr Chen Yun Xin from Singapore General Hospital (SGH), Singapore.

Patients with high-risk disease often die within 3–4 years of diagnosis due to disease progression and rapid development of drug resistance upfront, she explained.

What defines high-risk MM?

There are many ways high-risk MM is defined, one of which is based on cytogenetics. In general, chromosomal abnormalities is detected by iFISH*, which reveals the location of specific DNA sequence on a chromosome.

Under the modified risk stratification mSMART** 3.0 classification, the high-risk group is characterized by the presence of chromosomal abnormalities such as del17p, t(14;16), t(14;20), p53 mutation, or amplification of chromosome 1q.

Beyond genetic classification, there are also clinical features indicative of high-risk disease, including extra-osseous extramedullary disease, plasma cell leukaemia, central nervous system involvement, circulating tumour cells, or high LDH*** levels.

The R-ISS^# is one prognostic staging system which combines both genetics and clinical features/biochemical findings, in addition to the original ISS. Stage III, the highest risk category in R-ISS, is defined as serum beta-2 microglobulin of ≥5.5 mg/L and either the presence of high-risk chromosomal abnormalities or high LDH.

According to Chen, risk stratification using these tools can help understand disease prognosis and may have a role in guiding risk-adapted therapy.

Scenario in Singapore

“Over the last 20 years, we have seen an improvement in survival of MM patients,” said Chen, who noted that the median overall survival (OS) curve has trended upward from 3 years in the earlier years up to 5 years more recently due to advances in treatment.  

However, improvement in survival is mostly seen in low-risk patients but not in those with high-risk disease, based on registry data from SGH.

For non-high-risk patients, Chen reported that there were patients who survived for up to 8 years in this cohort. By contrast, high-risk patients did not improve much despite the evolution of better therapies.  

“How then can we do better for high-risk patients?” raised Chen.

“One of the ways we can help our high-risk patients is to optimize upfront treatment,” she stated. For example, this may be achieved by adding a monoclonal antibody to a proteasome inhibitor-based backbone or to an immunomodulatory drug.

For transplant-eligible patients, outcomes may be improved via tandem autologous haematopoietic stem-cell transplantation, or even allogeneic transplantation (ASCT) for patients with very high risk, she explained.

“[Nonetheless,] the upfront use of monoclonal antibody or more than one novel agent followed by maintenance is actually unaffordable for most patients in Singapore,” Chen pointed out. This is because 70–80 percent of patients in Singapore are treated in the public sector — meaning they derive funding from a combination of state subsidy, compulsory savings, healthcare insurance, and co-payment out of their own pockets.

“While we want the treatment to be efficacious and tolerable for the patients, it also has to be affordable,” highlighted Chen.

KCd a potential option

To find out if survival outcomes for high-risk patients can be improved by attainment of deep response using a potent proteasome inhibitor upfront, Chen and colleagues conducted a phase II study of KCd as a frontline treatment for transplant-eligible patients with newly diagnosed MM (NDMM).

Carfilzomib is a potent and selective second-generation proteasome inhibitor and has demonstrated ability to induce deep and sustained responses in MM.

In the SGHMM1 trial, 30 eligible patients received induction therapy with KCd for six 28-day cycles. Participants were patients aged <70 years (median age 63 years, 51.7 percent male) with high-risk NDMM (either ISS-3, del17p, t(4:14), t(14:16) or 1q21amp), who were eligible for ASCT. 

After induction, patients underwent transplant with high-dose melphalan (200 mg/m²) followed by consolidation therapy with two cycles of KCd, as the trial was conducted at a time when there was no definitive evidence yet for maintenance therapy in this setting.

“Even in this very high-risk population, a median progression-free survival [PFS] of 40.3 months was attained,” Chen reported.

The median OS was not yet reached, after a median follow-up of 43.4 months. Best response was seen in 60 percent of patients overall.

For patients who successfully completed consolidation treatment, they were assessed for minimal residual disease (MRD) status. Being MRD negative has been associated with better survival in previous studies, and was attained in 42.9 percent of patients.

Those who did not achieve MRD negativity were put on carfilzomib maintenance for further 2 years or until disease progression.

When stratified by MRD status, those who were MRD negative had better outcomes than those who were not (median PFS, 41.3 vs 29.5 months; hazard ratio [HR], 0.39; p=0.09). 

Nonetheless, patients who did not achieve MRD negativity and received maintenance therapy were able to achieve a median PFS of 40.3 months, matching that of the MRD-negative subgroup.

In terms of safety profile, Asian patients were known to have slightly more toxicity compared with other counterparts elsewhere in the world, said Chen.

The regimen was tolerable, with the most common adverse events (AEs) being haematological toxicities, such as anaemia, neutropenia, and cytopenia. Serious AEs were rare, which included acute coronary syndrome and acute pulmonary event occurring in one patient each.

“Our study shows that KCd is efficacious, well tolerated, and did not adversely affect mobilization of patients,” Chen summed up.

Deep responses, including MRD negativity, are achievable with this regimen even in high-risk MM patients, she added. The study also suggests that KCd can be a potential upfront regimen in a resource-limited setting like Singapore.

“A proteasome inhibitor + an immunomodulator regimen such as bortezomib + lenalidomide in the upfront setting is unattainable in most patients in the local setting … the addition of lenalidomide adds to the cost that patients have to bear,” Chen explained.

“Hence, a potent proteasome inhibitor such as carfilzomib, in combination with a cheaper alkylator such as cyclophosphamide, can help patients achieve deep response in MM.”  

 

*iFISH: Interphase fluorescence in situ hybridization

**mSMART: Mayo Stratification for Myeloma and Risk-Adapted Therapy

***LDH: Lactate dehydrogenase

^#R-ISS: Revised Multiple Myeloma International Staging System