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Why high-dose therapy plus auto-SCT still plays a role in newly diagnosed multiple myeloma?

Oct 15, 2020

High-dose therapy (HDT), often coupled with autologous stem cell transplantation (auto-SCT), has been a mainstay of treatment for newly diagnosed patients with multiple myeloma (MM). With the advent of highly effective new induction therapies, it is necessary to reexamine the role of HDT. Should HDT still be part of the treatment regimen for MM, or do these new therapies supersede it?

During the eighth annual meeting of the Society of Hematologic Oncology (SOHO), Ajay Nookapresented a talk that discussed the part that HDT plus auto-SCT still plays in the management of MM. 1

Key points

Importance of upfront transplantation

The IFM2009 ( NCT01191060 )and SWOG S0777 ( NCT00644228 )trials both used the same induction regimen of lenalidomide (R), bortezomib (V), and dexamethasone (d) for newly diagnosed patients with MM, but some of those enrolled in the IFM2009 trial received HDT plus auto-SCT after VRd induction. Despite the similarities, different progression-free survival (PFS) and overall survival (OS) were achieved with VRd, and transplant improved both the PFS and measurable residual disease (MRD) negativity rates.

Similar data have been reported in the real-world setting by Nisha S. Joseph, et al., 2after analyzing the outcomes of 1,000 newly diagnosed patients treated with VRd induction. After a median of four cycles of VRd (range, 2–15), almost every patient had an evaluable response (overall response rate, 97.1%), and in line with previously reported prospective clinical trials, the responses deepened after transplantation (CR rates, 35.9% post-induction and 71% after HDT + auto-SCT). You can find more details about this study here.

A greater response rate is seen when transplantation is used in these previous studies, but how deep a response should one aim for when treating newly diagnosed patients? As MRD has become a surrogate endpoint in multiple trials, its use may help demarcate the treatment threshold necessary to achieve durable survival outcomes. It is not yet a question of using a triplet/quadruplet induction regimen or an upfront transplant, because the induction therapy followed by HDT and auto-SCT is needed to achieve the most profound response.

MRD negativity and improved induction regimens

The benefit of assessing and gaining MRD-negative status was demonstrated in a meta-analysis (14 trials for PFS and 12 for OS) by Nikhil Munshi, et al. 3This study showed that achieving MRD negativity affected both the PFS and OS. PFS survival was significantly decreased by 59% in the MRD positive group with a HR = 0.41 (95% CI, 0.36−0.48; p < 0.001). The impact on OS was slightly less marked, with a 43% reduced risk, but still a significant HR = 0.57 (95% CI, 0.46−0.71; p < 0.001). These results show that modern induction regimens should aim to reach MRD negativity and that transplantation can be used to attain the required depth of response.

Ajay Nooka confirmed and expanded these results by analyzing 240 patients treated in his institution [unpublished results]. Using a VRd induction regimen and R maintenance, his group found that patients with disease progression were all in the cohort that did not achieve MRD-negativity status at < 10 −5level.

The value of MRD-negative status remains evident even when using different induction regimens. The CASSIOPEIA trial ( NCT02541383) explored the use of daratumumab (dara) in combination or compared with thalidomide (T) plus Rd in transplant-eligible patients with MM. MRD status was measured using flow cytometry at a threshold of < 10 −5for MRD-negativity status. In this trial, dara-VTd was superior across all subgroups, including patients with high-risk diseasecompared with VTd alone. At 18 months, PFS was 93% in the dara-VTd arm compared with 85% in the VTd arm (p < 0.0001). Similar results were achieved in the GRIFFIN trial ( NCT02874742), in which dara-VRd was compared with VRd alone. In this study, MRD negativity rates were found to increase over time: with dara-VRd, the percentage of patients reaching MRD negativity increased from 19.2% to 44.2% between the end of induction and the end of consolidation. This change was seen with VRd too, although in significantly reduced rates (end of induction, 5.8% versusend of consolidation, 14.6%). Further information on the GRIFFIN trial can be found on the Multiple Myeloma Hub here.

Binod Dhakal, et al., 4performed a meta-analysis of four randomized, controlled clinical trials to assess the value of HDT compared with standard-dose therapy. There was a 27% increase in the percentage of patients achieving a complete response in the HDT group compared with the non-HDT group. PFS was analyzed across the groups, and the results were unanimous in supporting the use of HDT with an odds ratio of 0.55 (95% CI, 0.41−0.74; p < 0.001). However, for OS, the overall estimate did not find a statistically significant reduction in hazard of death with upfront HDT plus auto-SCT (odds ratio 0.76; 95% CI, 0.42−1.37; p = 0.36).

Lastly, the FORTE trial ( NCT02203643 ) compared KCd versusKRd followed by HDT plus auto-SCT versusKRd alone in the frontline setting. Both arms containing KRd showed superior outcomes, inducing high-quality responses. However, when analyzing high-risk patient subset, they benefited the most from HDT plus auto-SCT, experiencing significantly lower early relapses (≤ 18 months) than those who did not undergo transplantation.

Conclusion

While the field of multiple myeloma has seen the introduction of several new treatments with high therapeutic efficacy, using HDT and auto-SCT can still help achieve deep responses. Obtaining MRD-negative status should be the goal of treating newly diagnosed patients with MM.

  1. Nooka A. Role of HDT in current treatment for multiple myeloma. Eighth annual meeting of SOHO; Sept 10, 2020; Virtual.
  2. Joseph NS, Kaufman JL, Dhodapkar MV, et al. Long-term follow-up results of lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance approach in newly diagnosed multiple myeloma. J Clin Oncol. 2020. DOI: 1200/JCO.19.02515
  3. Munshi NC, Avet-Loiseau H, Rawstron AC, et al. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: A meta-analysis. JAMA Oncol. 2017;3(1):28-35. DOI: 1001/jamaoncol.2016.3160
  4. Dhakal B, Szabo A, Chhabra S, et al. Autologous transplantation for newly diagnosed multiple myeloma in the era of novel agent induction: A systematic review and meta-analysis. JAMA Oncol.2018;4(3):343-350. DOI: 1001/jamaoncol.2017.4600