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G.H. Jackson et al.
observed in patients who received CRD induction and lenalidomide maintenance. The median PFS in this group was not reached, while it was 49 months in those who received CTD and lenalidomide maintenance, 32 months in those who received CTD and observation, and 24 months in those who received CRD and observation (Figure 3A). Similarly, the longest OS was observed in patients who received CRD induction and lenalidomide maintenance. The median OS was not reached in any group, but 3-year OS rates were 92.3% for those who received CRD induction with lenalidomide maintenance, 89.0% in those who received CTD and lenalidomide maintenance, 86.0% in those who received CTD and observation, and 90.3% in those who received CRD and observation (Figure 3B).
Discussion
This is the largest study to evaluate the CRD regimen as induction therapy before ASCT in patients with multiple myeloma. We show that it is associated with excellent efficacy and safety data and the results are consistent with prior studies evaluating either CTD,17,18,24 CRD as induc- tion therapy,25 or CRD as treatment in the relapsed/refrac- tory disease setting.26
A direct comparison of thalidomide and lenalidomide as the immunomodulatory component of induction ther- apy has not been previously undertaken in the context of a randomized trial for transplant-eligible newly diag- nosed myeloma patients. Our results demonstrate the superiority of lenalidomide over thalidomide both in terms of efficacy and tolerability in the context of com- bination with an alkylating agent (cyclophosphamide), supporting the findings of previous non-randomized analyses.27,28 Previous randomized studies in patients not eligible for stem-cell transplant have compared thalido- mide to lenalidomide in combination with the alkylating agent melphalan.29,30 In these studies no difference between lenalidomide and thalidomide in terms of response, progression-free or overall survival was identi- fied. The differences between these prior studies and the finding from Myeloma XI might be explained by the dif- ferent patient population or the different alkylating agent, cyclophosphamide, which may be better tolerated than melphalan.
Response rates obtained with CRD in the current study were good: 60% of patients achieved at least a very good partial response after induction and 82% did so after ASCT. This compares favorably with other novel-agent-based triplet induction therapies, including bortezomib, doxorubicin, and dexamethasone (VAD),31,32 CVD,32 bortezomib, thalidomide, and dexamethasone (VTD),5,10,33,34 and even the immunomodulatory drug/pro- teasome inhibitor regimen bortezomib, lenalidomide, and dexamethasone (VRD)9,35 (Online Supplementary Table S3). However there are many caveats when trying to compare results across trials. Particularly in comparing response rates it should be noted that patients in Myeloma XI received induction until maximum response rather than for a fixed duration and this may have led to deeper responses prior to transplantation than in other studies. Although immunomodulatory drug and protea- some inhibitor combinations (e.g. VTD/VRD) have recently become widely used in the European Union and
USA this was not the situation when the study was ini- tially implemented. At that time either an immunomod- ulatory-based regimen or a proteasome inhibitor-based regimen (e.g., MPV or VD) was used. The standard of care in the UK, as in a number of other countries, was CTD. The addition of a proteasome inhibitor to induc- tion regimens offers the potential to target immunomod- ulatory agent-resistant subclones of disease with a sec- ond novel agent. This concept was explored in the inten- sification randomization aspect of the study which has been previously reported22 and demonstrated that inten- sification treatment with CVD significantly improved PFS in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induc- tion therapy compared with no intensification treatment.
The combination of a fourth agent with a different mechanism of action to induction, such as daratumumab plus VTD (Dara-VTD) investigated in the recently pub- lished Cassiopeia trial, is able to induce even deeper responses, with 83% of patients achieving at least very good partial response.36 PFS was longer in patients treated with Dara-VTD than in those treated with VTD alone, suggesting the addition of further agents to active triplets can improve outcomes yet further. In contrast, however, CRD offers an all oral regimen requiring only one hospital visit per month and including only one more expensive agent, lenalidomide. As such it is comparatively easier to deliver and likely to be cheaper in terms of both drug and administration costs. The lower incidence of peripheral neuropathy seen with CRD than that seen with combina- tions including bortezomib and/or thalidomide may also be beneficial for some patients.
The Myeloma XI data support the continued use of ASCT, since in a previous study of CRD without ASCT,7 the median PFS was 28.6 months, which is shorter than that achieved with CRD and ASCT in the Myeloma XI trial (36 months). Similarly, in the IFM 2009 study compar- ing VRD with or without ASCT, the combination of VRD and ASCT led to significantly better PFS than VRD alone (median: 50 vs. 36 months; P<0.001).9 The median OS in that study was similar in both groups, likely due to the fact that 79% of patients assigned to VRD alone received salvage ASCT at relapse and the short current follow-up. These findings and data from several other studies suggest a complementary role for novel agents and ASCT.
We have shown that treatment with lenalidomide maintenance therapy after ASCT is associated with improved PFS and OS, a finding consistent with other reports.6,19,20,37 We show that in Myeloma XI, the efficacy of lenalidomide maintenance was not diminished by prior exposure to lenalidomide; in fact, the best outcomes were achieved when lenalidomide was given as both induction and maintenance. This is similar to results seen in previ- ous lenalidomide maintenance studies, which showed sig- nificant heterogeneity of effect of lenalidomide mainte- nance with outcomes favoring those who had received lenalidomide induction.20,38 This suggests that patients with disease sensitive to immunomodulation with lenalidomide will continue to benefit from its continued use, perhaps as the maintenance therapy targets quiescent cells as they come out of cycle.
We noted that patients receiving CRD and observation appeared to have slightly inferior PFS than patients receiv- ing CTD and observation. This was not due to any appar- ent difference in early discontinuation of therapy or dose
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haematologica | 2021; 106(7)