Response-adapted lenalidomide-dexamethasone (LenDex) intensification after CyBorD induction for transplant-eligible multiple myeloma: the PIANO study.

Introduction

High-dose chemotherapy with autologous stem cell transplantation (ASCT) after induction therapy is the standard treatment for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM), as evidenced by improved progression-free survival (PFS) in clinical studies [ 1 , 2 ]. Although an optimal induction therapy has not yet been established, triple-drug or four-drug regimens combining multiple novel agents with dexamethasone (DEX) have been widely used [ 3 – 11 ]. However, increasing the number of induction agents may increase toxicity and result in overtreatment in some patients. In Japan, three or four courses of bortezomib (BOR) + lenalidomide (LEN) + DEX, the standard induction regimen in Europe and the United States, are recommended for induction therapy. Other recommended regimens include BOR plus DEX (BD) [ 12 ], cyclophosphamide, BOR, and DEX (CyBorD) [ 13 ], and doxorubicin plus BD [ 14 ].

The role of additional induction therapy in patients with an insufficient response to induction therapy has not been established. The Myeloma XI trial, a multicenter, open-label, randomized, phase 3 trial, evaluated response-adapted intensification with CyBorD compared with no intensification in patients with NDMM who had a suboptimal response to initial immunomodulatory triple therapy. CyBorD intensification substantially improved PFS but not overall survival (OS) compared with no intensification [ 15 ].

In this multicenter prospective intervention study (Proteasome inhibitor and IMiDs before and after autologous stem cell transplantation for untreated multiple myeloma aiming normalization of para-protein; PIANO study), we aimed to evaluate the effectiveness of a response-adapted induction strategy that added a second induction therapy based on the response to initial treatment. The results were compared with those of a historical control from a previous multicenter collaborative study, the TUBA study [ 16 ] (Targeting complete response with upfront bortezomib consolidation versus observation after the achievement of complete response following autologous transplantation for multiple myeloma).

Patients and methods

Patients and definitions

This multicenter, single-arm, open-label, nonrandomized study was conducted at 10 centers in Japan. Previously untreated patients with symptomatic MM who were eligible for ASCT were prospectively enrolled between March 2014 and December 2017. The median follow-up was 1,602 days (4.4 years), and the data cutoff date was December 31, 2022. MM was diagnosed according to International Myeloma Working Group criteria [ 17 ]. High-risk cytogenetic abnormalities (CA) were defined as the detection of deletion (17p13), IgH-FGFR3 [t(4;14)(p16;q32)], or IgH-MAF [t(14;16)(q32;q23)] by fluorescent in situ hybridization (FISH) analyses. As the study protocol was designed in 2014, gain/amplification of 1q21 was not included among the predefined high-risk CA according to the contemporary consensus at that time. Inclusion criteria were age 20–70 years with preserved major organ function, Eastern Cooperative Oncology Group performance status (PS) of 0–2 (PS 3 for bone symptoms was acceptable), and written informed consent. This study was performed in accordance with the principles of the Declaration of Helsinki and was registered in Japan as a clinical trial (UMIN000012465) ( https://rctportal.niph.go.jp/detail/um?trial_id=UMIN000012465 ).

Treatment

Figure 1 illustrates the study protocol. The protocol consisted of four courses of induction therapy with CyBorD. Patients who achieved very good partial response (VGPR) or better proceeded to ASCT, whereas those who did not achieve VGPR received up to four courses of LEN and DEX (LenDex). Peripheral blood stem cells were collected after mobilization with filgrastim alone or high-dose cyclophosphamide therapy followed by filgrastim. ASCT was performed after administration of high-dose melphalan. Maintenance therapy with LEN was administered from 90‒180 days after ASCT and continued for 2 years or until progressive disease (PD).

Response assessment

Patients with measurable disease, defined as the presence of at least one of the following criteria at diagnosis, were evaluable for response assessment: (1) serum monoclonal protein (M-protein) ≥ 1.0 g/dL; (2) urinary M-protein excretion ≥ 200 mg/day; or (3) involved free light chain (iFLC) ≥ 100 mg/L in patients with an abnormal serum FLC-κ/λ ratio (normal range, 0.26–1.65), measured using the serum Freelite™ FLC assay (Freelite, The Binding Site Ltd., Birmingham, UK). Serum M-protein levels were measured by densitometry using serum protein electrophoresis. Response to therapy was assessed according to the 2016 International Myeloma Working Group (IMWG) response criteria [ 18 ].

Statistical analysis

The primary endpoint was the percentage of patients achieving complete response (CR) or better (stringent complete response [sCR] and CR) 100 days after ASCT. Secondary endpoints included the overall response rate after treatment, treatment completion rate, 3-year PFS, 3-year OS, and safety. Comparisons of patient characteristics were performed using Fisher’s exact test for categorical variables and the Mann–Whitney U test for continuous variables. PFS was defined as the time from registration to PD or death. OS was defined as the time from registration to death. The probabilities of OS and PFS were estimated using the Kaplan–Meier method and compared using the log-rank test. Multivariate analysis of factors associated with response at 100 days after ASCT was performed using logistic regression, and factors associated with PFS were evaluated using Cox proportional hazards regression. Because cytogenetic data were unavailable for 10 patients, analyses involving cytogenetic risk were performed using a complete-case analysis without imputation. Variables with P < 0.25 in the univariate analysis were used as independent variables in the multivariate analysis according to a previously described purposeful selection approach [ 19 ]. The study was designed using a historical benchmark derived from the previous TUBA study, which evaluated BOR plus DEX induction followed by ASCT. Assuming an improvement in the CR-or-better rate with the response-adapted CyBorD/LenDex strategy from 40% to 55%, the required sample size was estimated to be approximately 72 patients using a one-sided alpha level of 0.05 and 80% power. A one-sided test was selected because this study was designed to evaluate superiority over the historical control. Although 64 patients were enrolled during the planned enrollment period, one patient was subsequently deemed ineligible, leaving 63 evaluable patients, corresponding to 87.5% of the planned sample size and an estimated 75% statistical power. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a modified version of R Commander that includes statistical functions frequently used in biostatistics [ 20 ].

Results

Patient characteristics

A total of 64 patients were enrolled from 10 participating centers in Japan. One patient was subsequently found to be ineligible, leaving 63 patients for analysis. The median age of the patients was 60 years (range: 30–70 years). Chromosomal data obtained by FISH analysis at diagnosis were available for 53 of the 63 patients. Among these, nine patients (17.0%) had high-risk CA, including t(4;14), t(14;16), or del(17p). According to the International Staging System (ISS), 19 patients (30.2%) had stage I disease, 25 (39.7%) had stage II disease, and 19 (30.2%) had stage III disease. The Revised-ISS was assessable in 53 patients; 16 (30.2%) had stage I disease, 31 (58.5%) had stage II disease, and 6 (11.3%) had stage III disease. Table 1 summarizes the patient characteristics at enrollment.

Treatment

Of the 63 patients, four discontinued treatment during CyBorD therapy (two discontinued owing to adverse events, and two discontinued at the investigator’s discretion) (Fig. 1 ). Thirty-eight patients did not achieve VGPR after CyBorD therapy. Among them, five discontinued treatment (two at the patients’ request and three at the investigator’s discretion), two proceeded to ASCT at the investigator’s discretion, and 31 received LenDex therapy. An additional patient who achieved VGPR after CyBorD therapy received LenDex because the response had initially been assessed as a partial response (PR). Thus, 32 patients received LenDex. One patient discontinued LenDex owing to adverse events.

A total of 53 patients (84.1%) completed induction therapy. Five patients discontinued treatment (three at the patients' request, one owing to adverse events, and one owing to PD), and the remaining 48 (76.2%) underwent peripheral blood stem cell collection. Of the 48 patients, four discontinued treatment (one owing to PD, one owing to poor stem cell collection, one at the investigator’s discretion, and one owing to protocol deviation), and the remaining 44 (69.8%) underwent ASCT. After ASCT, treatment was discontinued in five patients before initiation of maintenance therapy (one at the patients' request, three at the investigator’s discretion, and one owing to failure to meet the criteria for treatment initiation), and the remaining 39 patients (61.9%) started maintenance therapy. Among them, 24 patients discontinued treatment during maintenance therapy: eight within 3 months, six between 3 and 6 months, three between 6 and 12 months, five between 12 and 18 months, and two between 18 and 24 months. The reasons for discontinuation were hematologic toxicities ( n = 4), the investigator’s discretion ( n = 4), PD ( n = 10), the patients’ request ( n = 3), and adverse events ( n = 3). Maintenance therapy was continued for 24 months ( n = 15; 23.8%) or until PD ( n = 10; 15.9%).

Response

The primary endpoint was the CR-or-better rate at 100 days after ASCT in all enrolled patients. Six of the 63 enrolled patients achieved CR or better (9.5%; 95% confidence interval [CI], 3.6%–19.6%). Among the 44 patients who underwent ASCT, six achieved CR or better at 100 days after ASCT (13.6%; 95% CI, 5.2%–27.4%). After four cycles of CyBorD induction, 46 patients achieved PR or better (sCR, n = 3; CR, n = 3; VGPR, n = 14; and PR, n = 26), but five discontinued treatment. Among the 32 patients who received LenDex therapy, responses before LenDex were VGPR in one patient, PR in 23, and stable disease (SD) in eight, whereas responses after LenDex were VGPR in 12 patients, PR in 17, SD in one, and PD in one. The patient with PD discontinued protocol treatment and did not proceed to ASCT, and one additional patient discontinued LenDex therapy. Seventeen patients showed an improved response, whereas one patient experienced PD (Fig. 2 a).

Of the 44 patients who underwent ASCT, 42 achieved PR or better 100 days after ASCT (sCR, n = 3; CR, n = 3; VGPR, n = 22; PR, n = 15). Overall, six patients (9.5%) achieved CR or better. Of the 32 patients who received LenDex induction, only one (3.1%) achieved CR or better. The best responses after ASCT and LEN maintenance therapy were sCR in 10 patients, CR in one, VGPR in 23, PR in eight, SD in one, and PD in one. Overall, 11 patients (17.4%) achieved a CR or better (Fig. 2 b).

Figure 2 b shows a Sankey diagram of the changes in response after CyBorD, LenDex, and ASCT, as well as the best response after ASCT.

Factors associated with response at 100 days after ASCT

At 100 days after ASCT, patients who achieved VGPR or better ( n = 29) were compared with those who did not achieve VGPR or discontinued treatment without achieving VGPR ( n = 34) (Table 2 ). Those who achieved VGPR or better were significantly younger ( P = 0.02) and more frequently had > 60% bone marrow plasma cells before treatment ( P = 0.04). Multivariate analysis revealed that age was the only factor significantly associated with achievement of VGPR or better (odds ratio, 0.858; 95% CI, 0.753–0.977; P = 0.02).

Peripheral blood stem cell collection and ASCT

Peripheral blood stem cell collection for ASCT was performed in 48 (76.2%) patients. Among them, 38 received granulocyte colony-stimulating factor (G-CSF) alone, and 13 required cyclophosphamide plus G-CSF, including three who underwent rescue mobilization after unsuccessful collection with G-CSF alone. The median number of cells collected was 2.51 × 10 6 /kg (0.03–12.82 × 106/kg), and the target cell dose determined by the attending physician was collected in 46 patients (95.8%).

In the group that received CyBorD induction alone, peripheral blood stem cell collection was performed in 20 patients. Among them, 19 received G-CSF alone, and two received cyclophosphamide plus G-CSF, including one patient who required rescue mobilization after unsuccessful collection with G-CSF alone. The median number of cells collected was 2.51 × 10 6 /kg (1.1–10.57 × 106/kg), and the target cell dose for transplantation was achieved in 18 patients (90%).

Peripheral blood stem cells were collected from 28 patients in the group that received additional LenDex induction. Among them, 19 received G-CSF alone and 11 received cyclophosphamide plus G-CSF, including two patients who required rescue mobilization after unsuccessful collection with G-CSF alone. The median number of cells collected was 2.49 × 10 6 /kg (0.03–12.82 × 106/kg), and the target cell dose for transplantation was achieved in 26 patients (93%).

ASCT was performed in 44 patients, and engraftment was observed in all patients. The median time to engraftment was 12.5 days (range, 10–20 days) overall and 13 days (range, 11–20 days) in patients who received additional LenDex induction.

Response and survival outcomes

The 3-year OS and PFS rates from the date of study enrollment were 90.0% (95% CI, 79.0%–95.4%) and 43.9% (95% CI, 28.1%–58.5%), respectively (Fig. 3 ). Among patients who underwent ASCT, OS and PFS were similar between the group that received CyBorD induction alone ( n = 18) and the group that received additional LenDex induction ( n = 28). Baseline characteristics of the ASCT recipient subgroups are summarized in Supplemental Table 1.

Factors associated with PFS were analyzed in the overall cohort, including age (< 65 vs. ≥ 65), disease stage (ISS), Durie-Salmon (DS) stage, sex (male vs. female), PS (0‒1 vs. ≥ 2), presence of plasmacytoma, high tumor burden (bone marrow plasma cell < 60% vs. ≥ 60%), bone lesion, high-risk CA, and lactate dehydrogenase (Table 3 ). Univariate analysis identified DS stage III and high-risk CA as factors associated with PFS. Although multivariate analysis did not identify any significant factors, the impact of high-risk CA on PFS remained of borderline significance (hazard ratio, 2.311; 95% CI, 0.910–5.871; P = 0.078).

Safety

Twelve clinically meaningful protocol-related adverse events were reported, including heart failure, hyperkalemia, loss of appetite during CyBorD therapy; hyperglycemia, and hypoxemia during LenDex therapy; and pneumonia, pulmonary artery thrombosis, pancreatic cancer, lymphoma, hyperthyroidism, skin rash, and breast cancer during LEN maintenance therapy. Detailed information on serious adverse events and secondary primary malignancies is provided in Supplemental Tables 2 and 3 , respectively.

Discussion

In the present study, LenDex was added before ASCT in patients who did not achieve a sufficient response (VGPR or better) after CyBorD induction. The primary endpoint was the CR-or-better rate at 100 days after ASCT among all enrolled patients. ASCT was performed in 44 of the 63 patients, and six (9.5%) achieved CR or better 100 days after ASCT. Among the 44 patients who underwent ASCT, six (13.6%) achieved CR or better. This CR-or-better rate was not improved compared with the 20% CR rate observed in our previous study using BD induction therapy [ 16 ]. However, a direct comparison between the present PIANO study and the previous TUBA study should be interpreted with caution because of differences in the study population, treatment era, regimen composition, supportive care, and the absence of measurable residual disease (MRD) assessment. One possible contributing factor is the lower BOR dose intensity associated with once-weekly administration in the present study compared with twice-weekly administration used in the TUBA study, although this interpretation remains speculative. In addition, although the addition of LenDex therapy improved responses in approximately half of the patients, the treatment period before ASCT was prolonged to approximately 8 months, and the BOR dose intensity was further reduced. The best response rate after ASCT was also inferior to that reported in a previous study, suggesting a potential role for consolidation therapy in patients without a sufficient response after ASCT.

Although the addition of LenDex therapy to CyBorD induction did not improve the CR rate after ASCT, it improved responses in 17 of 32 patients (53%) before ASCT. In addition, PFS and OS after ASCT were similar between patients treated with CyBorD alone and those treated with CyBorD followed by LenDex, although the latter group had an insufficient response to initial CyBorD. The observed 3-year OS of 90.0% appeared favorable compared with the 4-year OS of 80% reported in our previous TUBA study; however, direct comparison is limited by differences in the treatment era and therapeutic strategies. Furthermore, recent studies evaluating contemporary VCD/CyBorD- or VRd-based induction strategies have reported heterogeneous post-ASCT outcomes depending on treatment intensity and regimen composition [ 9 – 11 ], underscoring the difficulty of direct cross-study comparisons. Recent quadruplet induction studies, such as PERSEUS and GMMG-HD7 [ 5 , 8 ], have also demonstrated highly favorable outcomes in transplant-eligible patients with NDMM, although OS data are not yet mature. However, this study was not designed as a randomized comparison between the two strategies, and the post-ASCT survival analyses were restricted to patients who successfully underwent transplantation. Therefore, the effect of LenDex intensification on long-term outcomes remains unclear.

Multivariate analysis of factors associated with response 100 days after ASCT revealed that age was the sole factor associated with achieving VGPR or better, and ISS, an established prognostic factor in multiple myeloma, was not significantly associated with response. Furthermore, high-risk CA showed a borderline association with PFS ( P = 0.078). This finding may be attributable to the limited number of patients with high-risk CA. Chromosomal data were available at diagnosis for 53 patients, of whom nine had high-risk abnormalities.

Only one patient (3%) discontinued treatment owing to adverse events during LenDex therapy. Regarding the impact on stem cell collection, the LenDex group more frequently required mobilization with high-dose cyclophosphamide therapy. However, sufficient numbers of stem cells were collected from 93% of these patients, a rate similar to that in the CyBorD-alone group. Plerixafor was approved for clinical use in Japan in 2016 during the latter portion of this study's enrollment period. However, it was not incorporated into the present protocol, which was designed in 2014, and therefore was not used for stem cell mobilization in this cohort. Future use of plerixafor may further reduce the negative effects of LEN on stem cell collection [ 21 , 22 ].

In this study, 12 clinically meaningful protocol-related adverse events were reported: three during CyBorD, two during LenDex, and seven during LEN maintenance therapy. All were known treatment-related adverse events, and none occurred frequently. Therefore, the tolerability of the treatment protocol was considered acceptable. However, three cases of secondary primary malignancies occurred during LEN maintenance, and patients receiving LEN maintenance should be monitored carefully. Previous studies have suggested an association between LEN maintenance therapy and an increased risk of secondary primary malignancies after ASCT [ 23 , 24 ]. In addition, although adverse events during treatment were routinely monitored, the comprehensive reporting of all grade ≥ 3 adverse events, including less clinically relevant toxicities, was limited in this investigator-initiated study and should be considered when interpreting the safety results.

This study has some limitations. First, there was substantial treatment attrition during the study period. Of the 63 enrolled patients, only 44 underwent ASCT and 39 received LEN maintenance therapy, whereas only 15 completed the planned 24 months of maintenance treatment. This attrition may have influenced the interpretation of the response and survival outcomes, particularly because the post-ASCT analyses were restricted to patients who successfully completed the earlier treatment phases. Currently, anti-CD38 monoclonal antibody-based induction regimens are increasingly used for transplant-eligible patients with NDMM [ 3 – 5 , 8 ]. However, this study was conducted prior to the approval of these agents. Therefore, the sequential strategy of CyBorD followed by the response-adapted LenDex evaluated in this study should not be interpreted as a current standard induction approach in the anti-CD38 monoclonal antibody era. Rather, the present study should be regarded primarily as a historical benchmark and a proof of concept for the feasibility of response-adapted treatment intensification strategies in transplant-eligible patients with NDMM. In addition, such adaptive approaches may retain clinical relevance in settings where access to anti-CD38 monoclonal antibodies remains limited owing to regulatory, financial, or resource-related constraints. Moreover, a negative MRD has emerged as one of the most powerful prognostic factors for PFS and OS [ 25 , 26 ]. However, MRD was not analyzed in this study. Therefore, caution is warranted when interpreting CR/sCR rates as surrogate markers of treatment efficacy, because responses assessed according to the IMWG 2016 criteria [ 18 ] may not fully reflect the depth of response currently considered clinically relevant in the modern treatment era. Future studies using contemporary quadruplet induction regimens and MRD-guided adaptive strategies are required to determine whether response-adapted intensification can improve long-term outcomes in the modern treatment era. Despite these limitations, the results of the present study support the feasibility of response-adapted second-line induction for patients with an insufficient response to the initial induction therapy and may help guide the design of future clinical studies in patients with NDMM.

In conclusion, although response-adapted LenDex intensification improved responses before ASCT in a subset of patients and resulted in similar post-ASCT survival outcomes to those observed in patients with a sufficient response to CyBorD alone, the primary endpoint of CR or better at 100 days after ASCT was not improved compared with the 20% CR rate observed in our previous BD-based TUBA study. Given the current treatment landscape incorporating VRd-based and anti-CD38 antibody-containing induction therapies, this study should primarily be regarded as a historical benchmark and hypothesis-generating study. Nevertheless, the present results provide proof of concept for response-adapted treatment intensification in transplant-eligible patients with NDMM and may remain relevant in settings with limited access to anti-CD38 monoclonal antibodies. Future studies using contemporary induction regimens, MRD-guided adaptive strategies, and larger patient cohorts are warranted to determine whether response-adapted intensification strategies improve long-term outcomes.

Supplementary Information

Supplementary Material 1

Supplementary Material 2

Supplementary Material 3

Acknowledgments

Clinical trial registration

Yes (UMIN000012465).

Authors’ contributions

D.M. and G.Y. contributed equally to this work. D.M. collected the data and wrote the manuscript; G.Y. contributed to data collection, interpretation, and wrote the manuscript; S. Kako, Y. Hiroshima, S. Ota, T. Handa, A. Wake, A. Meguro, K. Usuki, N. Tsukada, and H. Nakasone reviewed the manuscript, contributed to data interpretation, and approved the final version. Y. Kanda supervised the project, reviewed and wrote the manuscript, and served as the corresponding author.

Funding

This study was funded by Bristol Myers Squibb. The funder had no role in the design, data collection, data analysis, and reporting of this study.

Data availability

We confirm that the data supporting the findings of this study are available within the article.

Declarations

Ethics approval and consent to participate

This study was initially approved by the Institutional Review Board of Toranomon Hospital (approval date: March 11, 2014), and subsequently reviewed and approved as a specified clinical trial by the Certified Review Board of Jichi Medical University Saitama Medical Center (approval number: jRCTs031180335; approval date: February 25, 2019). Written informed consent was obtained from all participants before enrollment.

Competing interests

Funding statement: This study was supported by funding from Bristol Myers Squibb.

Conflict of interest disclosure: S.K., N.T., D.M., and H.N. have received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen Pharmaceutical and Bristol Myers Squibb (BMS); S.K. and H.N. have also received such payments from Sanofi. K.U. has received research grants or contracts from BMS, Ono, Sanofi, and Takeda, and payment or honoraria from BMS, Ono, Pfizer, Sanofi, and Takeda. All other authors declare no conflicts of interest.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Daisuke Minakata and Go Yamamoto contributed equally to this manuscript.

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Associated Data

Supplementary Materials

Supplementary Material 1

Supplementary Material 2

Supplementary Material 3

Data Availability Statement

We confirm that the data supporting the findings of this study are available within the article.