Frontline therapy in multiple myeloma therapy: current evidence and future research

Professor Graham Jackson (Newcastle, UK) held a ‘meet the expert’ session at BSH 2019 covering the rapidly changing world of frontline therapy in myeloma.

Interviewer: Hannah Chatfield. Article: Maria Dalby.

MM patients with risk factors such as frailty, high ISS stage or poor response to standard therapy face a dismal prognosis even in the era of novel treatments. In a well-attended Meet-the-Expert session at the BSH annual meeting 2019, Professor Graham Jackson (Newcastle upon Tyne Hospitals NHS Trust) used recently published Myeloma XI study data to argue that there is an urgent unmet need for better and more powerful combination therapies in the upfront setting.

Early relapse following autologous stem cell transplantation is a major risk factor for poor survival in MM. While novel therapies have improved long-term outcomes overall, there has been very little impact among patients who relapse early – the outlook for these patients remains consistently bleak.  In the Myeloma XI study, a total of 1,274 patients underwent ASCT. Of these, 14% relapsed within 12 months. Patient and disease characteristics that were found to be significantly associated with early relapse were lambda disease, decreased haemoglobin levels, increased plasma cell count, and having ISS stage III disease. Age, gender, paraprotein type or concentration, and induction therapy were not significantly associated with early relapse. Patients with lambda disease were found to have around three to four months shorter PFS compared with patients with kappa disease; this difference translated into an OS difference of approximately six months in favour of kappa disease. High-risk cytogenetics were common among patients who relapsed early – 33% of patients who relapsed within one year had at least one high-risk lesion, and 31% had two or more lesions (ultra-high risk MM, so-called double-hit or triple-hit myeloma). Lesions such as t(4;14), del(17p) and gain(1q) were all significantly more common among patients who relapsed early compared with those who did not. That said, it follows that a substantial proportion of patients who relapsed early had standard-risk cytogenetics – of patients who relapsed within 100 days of transplantation, 64% had standard-risk cytogenetics – suggesting that cytogenetic profile alone cannot account for all patients with poor prognosis. Poor PFS post ASCT predicted poor PFS down the line; median PFS2 among patients who relapsed within one year of transplantation was 28 months, compared with 67 months among patients who did not relapse early. OS at three years was 28% for patients who relapsed early compared with 53% for those who did not. Given these outcomes, Professor Jackson suggested that this patient group could potentially benefit from early use of immunotherapies such as BiTEs, CAR T-cell therapy or antibody-drug conjugates.

Frontline treatment in transplant-eligible MM patients has been transformed by the introduction of bortezomib. A meta-analysis of three large phase 3 randomised clinical trials of bortezomib-based regimens showed that bortezomib in the frontline setting has had a major impact on OS.¹ In the UK bortezomib induction is widely used, preferably in combination with thalidomide and dexamethasone for a better response, but switching to cyclophosphamide and dexamethasone may be necessary to avoid persistent peripheral neuropathy. Looking into the future, Professor Jackson predicted that quadruple combination therapy with carfilzomib, cyclophosphamide, lenalidomide and dexamethasone (KCRD) could become a frontline treatment option that may even spell the end of ASCT. The Myeloma XI study included a treatment arm in which patients received KCRD upfront until maximum response, followed by ASCT (intensive therapy). This therapy was generally well tolerated; fewer than 5% of patients had to discontinue treatment permanently due to adverse effects. Patients treated with KCRD achieved deeper responses than patients treated with triplet therapy; 79.5% of patients in the KCRD arm achieved at least VGPR, compared with 53% and 61% in the CTD and CRD arms, respectively. A greater proportion of patients in the KCRD arm proceeded to ASCT than in any of the triplet arms, and the deeper response persisted after ASCT – an unprecedented 92% of patients in the KCRD arm achieved VGPR post-ASCT, compared with 77% and 82% in the CTD and CRD arms, respectively. However, whereas a large proportion of patients in the triplet arms upgraded their response to MRD negativity post-ASCT, the number who upgraded was much smaller in the KCRD arm, suggesting that ASCT may have less of a role to play in an era of more powerful induction regimens. Patients in the KCRD arm also had significantly better PFS than either of the triplet regimens, regardless of cytogenetic risk.

In MM patients who are not considered for immediate transplantation, bortezomib in combination with lenalidomide and dexamethasone is the standard frontline treatment option in the US and in most European countries based on the results of the SWOG S0777 study, and Professor Jackson expressed hopes that this option will soon become available in the UK. In patients who are deemed ineligible for transplantation, adding bortezomib to melphalan and prednisone (VMP) has been shown to prolong the time to progression and OS with manageable toxicity. Combining carfilzomib with MP failed to improve PFS in the CLARION study;²instead Professor Jackson predicted that the next major development in this setting will be daratumumab, as induction therapy in combination with VMP and followed by continuous daratumumab until progression or toxicity as in the ALCYONE study,³ or in combination with Rd as in the MAIA study.⁴ In the MAIA study, patients who received daratumumab in combination with Rd had a 44% lower risk of progression or death compared with patients receiving Rd alone. After 30 months of treatment the PFS rate was 71% in the dara-Rd arm compared with 56% in the Rd arm. Patients on dara-Rd also had significantly higher overall response rates compared with Rd, and 24% of patients on dara-Rd achieved MRD negativity compared with 7% in the Rd arm. The MAIA investigators concluded that these results support the use of dara-Rd as a new standard of care for transplant-ineligible MM patients, but Professor Jackson added the caveat that affordability will be a key issue in implementing this regimen in the MM treatment algorithm in the UK.

References

1. Sonneveld P, Goldschmidt H, Rosinol L, et al. Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials. J Clin Oncol 2013;31:3279-87.
2. Facon T, Lee JH, Moreau P, et al. Randomized phase 3 study of carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible, NDMM patients. Blood 2019:blood-2018-09-874396.
3. Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med 2018;378:518-528.
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-LBA-2.