How do you treat newly diagnosed multiple myeloma with 1q gain?

Given the recent reclassification of gain(1q21) as a high risk cytogenetic abnormality, has this changed your practice in managing newly diagnosed patients? Specific issues to address: 1. Is intensified induction therapy (eg. KRd) preferred over more conventional triplet therapy (eg. VRd) as some would suggest for fit, high-risk patients? 2. Should upfront autologous transplant be considered in all eligible patients? 3. Following autologous SCT what type of post-transplant maintenance therapy would you choose, if any? PI monotherapy, IMiD monotherapy, or a combination?

1 Answer

Mednet MemberInvited Expert

Medical Oncology · University of Nebraska Medical Center

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There is still a lack of randomized phase 3 data demonstrating that KRD is superior to VRD for patients with high-risk cytogenetics. However, the recently presented ENDURANCE study only excluded t(14;20), t(14;16) and del(17p) and did include +1q (ASCO 2020 LBA3). The investigators did not report on +1q as a subset, but there were no statistically significant differences for t(4;14), 13q, or normal/abnormal between the two treatment groups. And overall, there were no differences in CR rates or PFS between the two arms. Thus, I would not pre-emptively choose KRD over VRD for a newly diagnosed transplant eligible patient with 1q+.

I believe that upfront ASCT should be considered for all newly diagnosed transplant-eligible patients. The most modern phase III data that we have to support this recommendation comes from the IFM 2009 study (NEJM 376:1311-1320, 2017) which is most relevant because of the use of RVD induction, as well as the EMN02/HO95 study (Lancet Haematol 7:e456-e468, 2020) (less relevant because of the use of VCD induction). Both of these studies demonstrated a PFS benefit for upfront ASCT. In addition, emerging data from the FORTE trial is showing evidence that persistent MRD negativity rates at one year are higher with KRD-ASCT, compared to KRD without ASCT. In addition, there is an emerging signal that there is a reduced risk of early relapse in patients with high-risk disease in the KRD-ASCT arm compared to the KRD (no ASCT) arm (ASCO 2019, abstr 8002). Thus, I currently recommend upfront ASCT for all transplant-eligible myeloma patients, including those with high-risk disease.

The first three lenalidomide maintenance studies established lenalidomide as the standard of care, but did not have much cytogenetic information (meta-analysis JCO 29:3279-3289, 2017). Myeloma XI, however, did have more cytogenetic risk information and showed that patients with high-risk or ultra-high disease do have PFS benefit with single agent lenalidomide (Lancet Oncol 20:57, 2019). I do tend to use lenalidomide/PI-based maintenance therapy for patients with traditional high-risk cytogenetic features based on the Emory experience (Leukemia, 28: 690–693, 2014) with RVD maintenance for high-risk disease. In this report, 1q+ was not considered to be part of the definition of high risk disease.

In general, if +1q is the only high-risk abnormality, I tend to use single agent lenalidomide maintenance, but certainly other factors might influence that decision, such as other non-cytogenetic markers of high risk (R-ISS III, extramedullary disease). I do not believe that single agent PI therapy should be used as maintenance therapy unless there is a strong contra-indication to lenalidomide. The magnitude of PFS benefit for ixazomib maintenance seen on the TOURMALINE MM-3 study was quite small compared to lenalidomide (Lancet 393:253, 2019). In addition, while the HOVON 65 study (Leukemia 32:383, 2018) is often cited as evidence that bortezomib improves outcomes for high-risk cytogenetics, there are multiple caveats. First, this study really addressed the effect of adding bortezomib both before and after transplant, not just maintenance. Second, the only subgroup that had improved outcome was del(17p). Third, the control arm used thalidomide maintenance, and there are data which suggest that patients with high-risk disease do worse with thalidomide compared to observation (Blood 119:7, 2012). Thus, the HOVON study could not demonstrate that bortezomib maintenance is better than observation.