Patients with RRMM and serious complications admitted to our hospital from January 2005 to October 2021 were included in this study. The inclusion criteria were (1): Patients met the diagnostic criteria of RRMM according to the International Myeloma Working Group (16) (2); Age >18 years old (3); Patients were ineligible to receive traditional chemotherapy due to at least one of the following conditions, heart failure NYHA (New York Heart Association) III ~ IV, lung function impairment with a grade of III ~ IV (17), coronary heart disease (CHD), hypertensive heart disease (HHD), hydropericardium, pleural effusion, seroperitoneum, Eastern Cooperative Oncology Group (ECOG) performance score ≥ 3 points or Karnofsky (KPS) score ≤ 40 points (4); Patients received at least one line (1–4) regimen for 1 to 8 courses before receiving low-dose CP regimen. Physical performance was assessed based on the ECOG standards (18). CD138 immunomagnetic beads were used to separate myeloma cells after 2015. MM risk stratification was performed according to Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013 (19). In detail, the patients were divided into high risk, intermediate risk and standard risk groups.

All patients were given continuous oral administration of low-dose CP (cyclophosphamide, 50 mg/d; prednisone,15 mg/d). Novel drugs including bortezomib, lenalidomide, thalidomide or ixazomib was given on the basis of CP (CP+X group) if the patients achieved improvements in organ failure (NYHA grade or lung function grade improved ≥ 1) or physical performance (ECOG score improvement ≥1 point or KPS score improvement ≥20 points) following CP regimen. Consideration of the general condition of the patient being poor, we reduced the therapeutic dose of novel drugs, specifically, bortezomib was given at a dose of 1.3 mg/m² through intravenous infusion every week for all time, lenalidomide was given at a dose of 10 mg orally on day1-21, thalidomide was given at a dose of 100 mg orally every day for all time, and Isazzomib was given 3 mg orally 3 times every month (1 time/week). Patients were continued to receive CP regimen if the drugs were effective and no obvious adverse reaction was occurred, while the CP regimen was discontinued when the number of neutrophils and platelets decreased to 0.5×10⁹/L and 30×10⁹/L, respectively, or the patients failed to achieve disease stability (SD) after 3 months of standard therapy. Meanwhile, the patients were administered with granulocyte colony-stimulating factor (G-CSF) and apheresis platelets. The patients continued to receive CP regimen when neutrophils and platelets restored at the levels of >1.0×10⁹/L and 30×10⁹/L, respectively.

The treatment response was assessed according to the International Myeloma Working Group consensus criteria for response (20), including complete response (CR), very good partial response (VGPR), partial response (PR), SD and progressive disease (PD). The changes of B-type natriuretic peptide (BNP)/pro-BNP and left ventricular ejection fraction (LVEF) in patients with cardiac insufficiency were assessed. AEs were evaluated according to the National Cancer Institute Standard for Common Toxic Events (NCICTCAE) 3.0. The ORR refers to the proportion of patients with sustained tumor shrinkage, including patients achieved CR and PR, in detail, ORR (%) = (CR+VGPR+PR)/(CR+VGPR+PR+SD+PD)×100%.

SPSS 21.0 software was used for statistical analysis. Wilconxon matched test was used to compare the BNP/pro-BNP levels of patients before and after treatment. Differences of the clinical features and the incidences of AEs in the CP and CP+X groups were compared using the χ² tests or Fisher’s exact tests. Kaplan-Meier curves with log-rank tests were used to analysis the influencing factors of progression-free survival (PFS) and OS. Univariate Cox was used to assess the prognostic influencing factors. P<0.05 was considered as statistical significance. PFS was defined as the time from diagnosis to the occurrence of PD, recurrence, death or the end of follow-up. OS was defined as the time from diagnosis to death from any cause or the end of follow-up.

A total of 130 RRMM patients with seven complications were enrolled in this study, among which 89 patients received CP regimen and 41 patients received CP+X regimen following CP treatment. Among the 130 patients, 73 patients (56.6%) were male, 92 patients (71.3%) aged >65 years, and the immunoglobulin type of 20 patients (15.4%) were light chain type. In addition, most of the patients (95.3%; 122/128) were diagnosed at a stage of DS (Durie-Salmon) III, and 98 patients (76.6%) were diagnosed at a stage of III according to the ISS (International Staging System). Among the 130 patients, 72 patients had available FISH results, with 60 patients (83.3%) of standard-risk group, 5 patients (6.9%) in the intermediate-risk group and 7 patients (9.7%) in the high-risk group according to the mSMART 2013. The detailed clinical information of patients was demonstrated in Supplementary Table 1 .

Among the 130 patients with RRMM, 41 patients received CP+X regimen because they achieved improvements in organ failure or physical performance following CP treatment. The gender, age, immunoglobulin type, DS stage, ISS stage, mSMART, and B2MG (β2-microglobulin) level at the time of CP treatment showed no obvious difference between the 2 groups, while the proportion of patients with NYHA I-II grade in the CP+X group was higher than that of the CP group (57.9% vs. 19.8%, P<0.001) ( Table 1 ). This result indicated that NYHA grade maybe a factor of organ failure or physical performance improvement following CP regimen in RRMM patients.

The therapeutic response of 128 of the 130 patients were evaluated as 2 patients were lost to follow up at the time of efficacy assessment, among which 6 patients (4.7%) achieved CR, 19 patients (14.8%) achieved VGPR, 50 patients (39.1%) achieved PR, 19 patients (14.8%) achieved SD, with the remaining 34 patients (26.6%) achieved PD following CP regimen. The CRR and ORR were 4.7% and 58.6%, respectively. The drug onset time which refers to the time from the start of using CP regimen to the time of disease being controlled was 1-4 months, with a median drug onset time of 2 months. In addition, we assessed the effect of CP treatment on the heart function of patients with RRMM. The BNP level, a marker of heart function (21), was detected in 73 patients before CP treatment and after CP treatment. Also, we tested the level of pro-BNP in 23 patients before and after CP regimen. Compared with those before CP treatment, the levels of pro-BNP ( Figure 1A ) and BNP ( Figure 1B ) were significantly decreased after CP treatment. In addition, the LVEF was significantly increased following the treatment ( Figure 1C ). These results suggested that CP treatment could improve the heart function of MM patients.

All 41 patients in the CP+X group were evaluated for therapeutic response to CP and CP+X regimens. Among them, 1 patient (2.4%) achieved CR, 11 patients (26.9%) achieved VGPR, 18 patients (43.9%) achieved PR, 8 patients (19.5%) achieved SD, and 3 patients (7.3%) achieved PD following CP regimen. The CRR and ORR were 2.4% and 73.2%, respectively. Following CP+X regimen, 10 patients (24.4%) achieved CR, 14 patients (34.1%) achieved VGPR, 10 patients (24.4%) achieved PR, 4 (9.8%) and 3 patients (7.3%) achieved SD and PD, respectively. The CRR and ORR rate of CP+X were 24.4% and 92.9%, respectively. The CRR was significantly increased following CP+X regimen as compared with that before CP+X regimen (24.4% vs. 2.4%, P=0.007) ( Figure 2 ).

During the treatment period, 41 (31.5%) of the 130 patients occurred AEs, including 10 cases (7.7%) of hyperglycemia, 8 cases (6.2%) of pneumonia, 7 cases (5.4%) of Cushing’s syndrome, 6 cases (4.6%) of gastritis, 4 cases (3.1%) of infection, 1 case (0.8%) of hypokalemia, 1 case (0.8%) of osteonecrosis of the femoral head (ONFH), 1 case (0.8%) of paronychitis combined with osteomyelitis, 1 case (0.8%) of limb numbness, 1 case (0.8%) of hemoptysis, and 1 case (0.8%) of gastrointestinal bleeding.

In addition, we compared the incidence of AEs between CP and CP+X groups during the treatment period. AEs were found in 20 patients (48.8%) of the CP+X group, which was significantly higher than that of the CP group (23.6%; 21/89) (P=0.004), especially for hyperglycemia (17.1% vs. 3.4%, P=0.011), Table 2 .

The median follow-up time for all of the 130 patients was (110.0 ± 6.6) months, with a 9-year OS and PFS rates of (12.4 ± 3.4)% and (21.3±3.8), respectively. The time to last full examination was 17 July 2022, and 2 of the 130 patients (1 of the CP group and 1 of the CP+X group) were lost to follow up during the study. The median OS and PFS time were (38.0 ± 3.6) months and (22.9±5.2) months, respectively.

Also, we compared the survival of patients received CP only (CP group) and CP+X following CP regimen (CP+X group). The median follow-up time for patients in the CP+X group was (93.87 ± 19.68) months, with a 9-year survival rate of (27.5 ± 10.1)%, and the median survival time of (94.37 ± 15.67) months, respectively. For the CP group, the 9-year survival rate was (6.8 ± 2.8)%, and the median survival time was (31.5 ± 3.7) months. Both the OS and PFS rates of the CP+X group significantly higher than those of the CP group ( Figures 3A, B ).

Moreover, we analyzed the prognostic influencing factors of RRMM using the univariate Cox analysis. Among the factors of gender, age, globulin type, DS, ISS and B2MG level, number of complications (4–7), heart failure, lung function (III-IV), CHD, HHD, arrhythmia, diabetes, hydropericardium, lung infection and pleural effusion at the time of CP treatment, the light chain type of globulin was a protective factor (P=0.037) while heart failure was a worse factor of PFS (P=0.024) for patients with RRMM ( Table 3 ).