ASH 2018: Advances in RRMM

Relapsed and refractory MM continues to challenge clinicians and several oral abstracts at ASH 2018 presented new and updated data on delaying disease progression and prolonging survival after first line treatment.

Article written by Maria Dalby. Interviews by Hannah Chatfield.

The Myeloma UK (MUK) five study is a phase 2 randomised, controlled, parallel-group, multi-centre study which compares carfilzomib, cyclophosphamide and dexamethasone (KCd) with cyclophosphamide, bortezomib and dexamethasone (VCd) for the treatment of first relapse and primary refractory MM. Professor Kwee Yong from University College London presented two abstracts from the MUK five study: the first (abstract 306) showed that KCd was non-inferior to VCd with respect to the proportion of patients achieving at least VGPR, which meant that the primary endpoint of the study was met. ORR was significantly higher among patients receiving KCd versus those receiving VCd (84% versus 68%; p=0.004) in the overall patient population. KCd was significantly superior to VCd for achieving at least VGPR in patients with high-risk cytogenetics, especially del(17p) and adverse IgH, and the ORR benefit was particularly pronounced in patients who relapsed within the first year and patients who had not undergone transplantation.

The second abstract from MUK five presented by Professor Yong (abstract 802) showed data from the second randomisation where patients who had completed VCd or KCd were randomised to either carfilzomib maintenance therapy at a dose of 36mg/m² for up to 18 cycles or observation. A total of 61 patients received a median of eight cycles of carfilzomib maintenance therapy and 18% of patients received the full 18 cycles. The primary endpoint was PFS from second randomisation; this was significantly superior in the carfilzomib maintenance arm compared with the observation arm at 11.9 versus 5.6 months (HR=0.59; 95% CI 0.46, 0.77; p=0.0086). The combined PFS with KCd followed by carfilzomib maintenance was 18.1 months. After six months of maintenance therapy, 24.4% of patients in the carfilzomib maintenance arm had achieved MRD negativity at 10^-4 sensitivity level compared with only 3.3% in the observation arm (p=0.007). Carfilzomib maintenance was well tolerated with no new safety signals, and the investigators concluded that carfilzomib should be investigated further in combination protocols.

EMN011/HOVON 114 MM is an ongoing, prospective, randomised multicentre study in which patients with RRMM who have progressed on bortezomib and lenalidomide receive salvage therapy with carfilzomib, pomalidomide and dexamethasone (KPd) or followed by pomalidomide as monotherapy or in combination with dexamethasone until disease progression. A planned interim analysis presented by Professor Pieter Sonneveld (Rotterdam, The Netherlands) (abstract 801) included 60 patients, one third of whom had high-risk cytogenetics and 95% of whom had progressed on lenalidomide maintenance therapy. The primary results showed that ORR after eight cycles of KPd was 87%, and 65% of patients had achieved at least VGPR and 31% had achieved at least CR. No difference in response was seen with high-risk and standard-risk cytogenetics. Median PFS was 18 months which Professor Sonneveld stressed compares favourably with other trials in lenalidomide-refractory patients, and the KPd triplet was well tolerated.

A triplet regimen of venetoclax plus carfilzomib and dexamethasone was evaluated for the treatment of RRMM in a phase 2 study presented by Dr Luciano Costa (University of Alabama, Birmingham) (abstract 303). A total of 42 patients were enrolled in the first dose escalation part of this study, and the expansion part with the selected dose of 800mg venetoclax and 70mg/m² carfilzomib included 22 patients. ORR was 79%, and more than a third of patients (38%) achieved at least CR. Nearly half of patients (43%) who were refractory to proteasome inhibitors achieved at least CR, as did 23% of patients who were IMiD-refractory and 29% of those who were double refractory. Patients with high-risk cytogenetics had an ORR of 83% and a CR rate of 33%. The safety profile was acceptable and the study is continuing with further expansion of the patient population.

Another novel agent that could provide an option in patients who are refractory to both proteasome inhibitors and IMiDs is the XPO1 inhibitor selinexor. Dr Cristina Gasparetto (Duke University Medical Center, Durham, North Carolina) presented the results of a phase 1b/2 study in RRMM patients with at least three prior lines of therapy who received combination therapy with selinexor, daratumumab and dexamethasone (SDd) (abstract 598). A total of 28 patients were enrolled and achieved an ORR of 73%; among patients who were naïve to daratumumab ORR was 79%. At a median follow-up period of 7.7 months more than one quarter of all patients (27%) had achieved at least VGPR. The response was especially pronounced in patients previously exposed to bortezomib, lenalidomide and carfilzomib (ORR 85%; 31% at least VGPR). Median PFS had not been reached at the time of presentation. The safety profile was acceptable with the most common Grade 3 and 4 adverse events being thrombocytopenia (44%), anaemia (28%), leukopenia (28%) and neutropenia (24%). The investigators concluded that the SDd combination appears highly effective and should be investigated further in RRMM.

New data from the TOURMALINE trial programme for ixazomib included an abstract presented by Dr Ajeeta Dash from Millennium Pharmaceuticals (abstract 473) which utilised data from the pivotal TOURMALINE-MM1 study to demonstrate that combination therapy with ixazomib, lenalidomide and dexamethasone (IRd) is effective in patients with non-canonical pathway mutations and biomarkers of non-canonical pathway activation including low TRAF3 expression and high NIK expression. As tumours with t/4;14) and amp 1q21 cytogenetics have been shown to have reduced TRAF3 expression, Dr Dash hypothesised that non-canonical NF-κB pathway inhibition may contribute to the efficacy of IRd in high-risk patients.

A poster presented by Professor Roman Hájek (Czech Republic) showed a pooled analysis from the INSIGHT MM observational study and the Czech Registry of Monoclonal Gammopathies which show that IRd is as effective for treating RRMM in routine clinical practice as in the clinical study setting. The pooled analysis included 163 RRMM patients treated with IRd in nine countries in Europe, the United States and Taiwan, and showed an ORR of 74% and a median PFS of 20.9 months which the investigators concluded was comparable with the ORR of 78% and median PFS of 20.6 months reported in the TOURMALINE-MM1 study.¹ IRd was well tolerated in routine clinical practice with low rates of permanent discontinuations.

In the IMF satellite symposium, advances in the treatment of RRMM were discussed by Professor Jesús San Miguel (University of Navarra, Spain). Professor San Miguel emphasised that the duration of the previous response is a key factor in the choice of treatment –patients who relapse in the first 1–3 years post transplantation should receive combination therapy with non-cross resistant agents to overcome drug resistance, and sequential novel agent combinations to prolong survival until curative treatments have been developed. In contrast, patients who relapse beyond 3-4 years should be re-induced and undergo a second transplantation. Combination regimens containing novel agents including carfilzomib, ²daratumumab,^{3, 4} elotuzumab,⁵ pomalidomide⁶ and panbinostat⁷ have been documented in RRMM at third and subsequent relapses, and emerging options include selinexor, venetoclax and melflufen. Combination therapy with different classes of drugs with complementary immunological strategies administered earlier in the natural history of MM could offer the prospect of long term disease control and even disease eradication in a subset of patients.

References

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