Puig et al. Blood Cancer Journal (2021)11:101 https://doi.org/10.1038/s41408-021-00490-8 Blood Cancer Journal ARTICLE Open Access Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial Noemi Puig1, Miguel T. Hernández 2, Laura Rosiñol3, Esther González4, Felipe de Arriba5, Albert Oriol 6, Verónica González-Calle1, Fernando Escalante7, Javier de la Rubia8, Mercedes Gironella9, Rafael Ríos10, Ricarda García-Sánchez11, José M. Arguiñano12, Adrián Alegre13, Jesús Martín 14, Norma. C. Gutiérrez1, María J. Calasanz 15, María L. Martín16, María del Carmen Couto17, María Casanova18, Mario Arnao19, Ernesto Pérez-Persona20, Sebastián Garzón21, Marta S. González22, Guillermo Martín-Sánchez23, Enrique M. Ocio1, Morton Coleman24, Cristina Encinas25, Ana M. Vale26, Ana I. Teruel27, María Cortés-Rodríguez1,28, Bruno Paiva 15, M. Teresa Cedena16, Jesús F. San-Miguel 15, Juan J. Lahuerta 29, Joan Bladé3, Ruben Niesvizky24 and María-Victoria Mateos 1 Abstract 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0–54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3–4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C- Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C- Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM- CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene. Introduction Multiple myeloma (MM) is a tumor of clonal plasma cells producing a monoclonal immunoglobulin, and fre- quent devastating complications such as bone disease, Correspondence: María-Victoria Mateos (mvmateos@usal.es) 1 hypercalcemia, renal failure, anemia, and infections. Fol- Hematology Department, Hospital Universitario de Salamanca (HUSAL), IBSAL, lowing diagnosis, patients are usually assessed to determine IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain 2 Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain whether they are eligible for high-dose chemotherapy Full list of author information is available at the end of the article © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Blood Cancer Journal Puig et al. Blood Cancer Journal (2021)11:101 Page 2 of 11 (HDC) and autologous stem cell transplantation (ASCT). compared to Rd alone in patients with newly diagnosed However, most of newly diagnosed MM patients are elderly MM deemed ineligible for HDT and ASCT. or unfit and they will receive approved standard regimens until progression or the development of significant toxicity. Methods These regimens are based on a proteasome inhibitor plus Trial design an alkylator and/or an IMiD and more recently, an anti- This multicenter, randomized, open-label, phase 3 trial CD38 antibody, but always a corticosteroid is present in enrolled patients between July 15th, 2015, and May 8th, these combinations. 2019 at 20 centers in Spain selected by the Spanish Clarithromycin is a macrolide antibiotic that through Myeloma Group (GEM/PETHEMA) and at one site in the the inhibition of CYP3A4 isozyme, seems to optimize the US. All patients included in the trial provided written effects of glucocorticoids by increasing the area under the informed consent. Independent ethics committee from curve and their maximum concentration levels1. In each study´s site reviewed and approved the protocol, addition, clarithromycin has immunomodulatory proper- amendments, and informed consent forms. The trial was ties, partially mediated by the suppression of interleukin-6 conducted in accordance with the principles of the and other pro-inflammatory cytokines such as Declaration of Helsinki and the International Conference interleukin-1 and tumor necrosis factor α2. Macrolides on Harmonization-Good Clinical Practice guidelines. Dr. have also been shown to modify the expression of certain Niesvizky and his group at the New York Presbyterian cell adhesion molecules (ICAM-1, LFA antigen, and Hospital-Cornell Medical Center designed the trial and VCAM1), therefore altering the plasma cell-bone marrow BMS/Celgene sponsored its development. Data were stroma interactions, known to be essential in the main- compiled by the GEM/PETHEMA group. tenance of myeloma tumor growth3. Lenalidomide plus dexamethasone (Rd) until progres- Patients sion is a standard of care based on the phase 3 FIRST trial The trial enrolled ≥65 years old patients with newly in which 1623 patients with newly diagnosed MM not diagnosed MM with measurable disease (M-protein in eligible for ASCT were randomly assigned to Rd until serum >0.5 g/dL, involved FLC > 10 mg/dL with abnormal progression, Rd for 18 months or melphalan, prednisone κ/λ ratio, Bence Jones proteinuria >0.2 g/24 h and/or the and thalidomide (MPT) for 18 months. At a median fol- identification of at least a plasmacytoma in a CT or MRI low up of 67 months, when compared with MPT, con- sized ≥1 cm in its longest diameter). Eligible patients had a tinuous Rd resulted in longer PFS (median 26 vs Karnofsky performance status ≥60% and were unsuitable 22 months; hazard ratio [HR] 0.69; 95% confidence for ASCT due to age. Other inclusion criteria were to be interval [CI], 0.59–0.79; p < 0.00001) and superior overall able to receive prophylactic anticoagulation, to have a life survival (OS) (median 59 vs 49 months; HR 0.78; 95% CI, expectancy ≥ 3 months and an absolute neutrophil count 0.67–0.92; p = 0.0023)4,5. ≥1.0 ×109/L, hemoglobin ≥7 g/dL, platelets ≥75.000/mm3 In 2002, Niesvizky et al. reported an overall response (>30.000/mm3 if extensive bone marrow infiltration), rate (ORR) of 93% with the combination of clari- GOT/AST and GPT/ALT <3 times the upper limit of the thromycin, low-dose thalidomide and dexamethasone (C- normal range, and a total bilirubin level <2 mg/dL. Rd) in patients with MM in a phase 2 trial6. The same The trial excluded patients with unmeasurable disease, group published in 2013 the long-term results of the other cancers within 5 years before enrollment (except for combination of C-Rd as a therapy for treatment-naïve squamous-cell and basal-cell carcinomas of the skin, symptomatic MM patients. After a median follow-up of carcinoma in situ of the cervix or breast and localized 6.6 years, ORR was 93% with a very good partial response prostate cancer with Gleason score <7 and stable PSA), (VGPR) or better rate of 68%. Median progression-free significant cardiopathy, HIV, hepatitis B and C, throm- survival (PFS) was 49 months and no increase of sec- boembolic events in the last 4 weeks before inclusion or ondary primary malignancies was detected7. In a matched AL amyloidosis. case-control study of 72 patients treated with C-Rd or with lenalidomide and dexamethasone (Rd) alone, the Randomization and trial treatment clarithromycin arm showed higher response rates, Eligible patients were randomly assigned in a 1:1 ratio, including complete response (CR) (45,8% vs 13,9%, p < to receive clarithromycin plus lenalidomide and dex- 0.001) and VGPR or better (73.6% vs 33.3%, p < 0.001), as amethasone (C-Rd group) or lenalidomide and dex- well as a higher PFS (median 48.3 vs 27.5 months, p = amethasone alone (Rd group). 0.044) on intention-to-treat (ITT) analysis8. The method used to generate the random allocation In this study, we have evaluated in a randomized and sequence was an Excel macro and the mechanism used to prospective way the efficacy and safety of clarithromycin implement it was an interactive web response system plus lenalidomide and dexamethasone (C-Rd) as integrated in the electronic case report form. A data Blood Cancer Journal Puig et al. Blood Cancer Journal (2021)11:101 Page 3 of 11 manager from the GEM-PETHEMA group generated the The safety population comprised patients who received allocation sequence; principal investigators and sub- any dose of treatment trial. Continuous variables were investigators from the participant centers enrolled the analyzed with descriptive statistics, and categorical vari- patients and patients were randomly assigned to one of ables were summarized in frequency tables. The primary the two treatment arms as detailed above. end point of PFS was compared between the treatment All patients received oral lenalidomide (25 mg/day on groups with a stratified log-rank test, and the treatment days 1 through 21) and oral dexamethasone (40 mg effect (HR and corresponding 95% CI) were determined weekly on days 1, 8, 15, and 22) until disease progression by using a stratified Cox regression model, with treatment or unacceptable toxicity. For those patients with impaired as the only explanatory variable. Other time-to-event end creatinine clearance, a reduced dose of lenalidomide was points were calculated similarly. Time-to-event variables recommended: 10 mg/day (days 1–21) if CrCl (mL/min) were summarized with the Kaplan–Meier method. Binary was between 30 to 60, 15 mg/48 h (days 1–21) if CrCl <30 endpoints, such as response rate, were assessed with a but not requiring dialysis and 5 mg/24 h (days 1–21) after Fisher exact test, and an odds ratio and two-sided 95% CI the procedure in cases requiring dialysis. Patients 75 years were calculated. old and older received 20 mg of weekly dexamethasone. Considering the results of the FIRST trial, the median Patients assigned to the C-Rd group received oral Clari- PFS for patients receiving Rd was expected to be thromycin 500 mg/12 h continuously. ~25.5 months. Thus, the target median PFS for patients assigned to the experimental arm was hypothesized to be End points and assessments 44.6 months (target hazard ratio = 1.75). To achieve 90% The primary end point of the study was PFS, defined as power to detect a 75% increase in median PFS (44.6 vs the time from randomization to either disease progression 25.5. months), at the two-sided 0.05 significance level and or death. Secondary end points included response rates, assuming 10% drop out rate, the required sample size was event free survival, time to progression (TTP), OS, dura- of 286. tion of response, PFS2, quality of life and toxicity. TTP was defined as the time from randomization to the Results documented first disease progression and PFS2 as the Patients and treatment time from randomization to the documented second Between December 15th, 2015 and December 31st, disease progression. Response rates were calculated fol- 2018, a total of 286 patients were randomly assigned: 143 lowing the International Myeloma Working Group to the C-Rd group and 143 to the control group. Demo- (IMWG) criteria and the overall response rate (ORR) graphic and clinical characteristics of the two groups are included the sum of PR, VGPR, CR and sCR rates. detailed in Table 1. In the overall population, the median Minimal residual disease (MRD) was evaluated in bone age was 76 years (range, 65–93), and more than half of the marrow aspirates by next-generation flow cytometry fol- patients (56.6%) were 75 years of age or older. lowing the IMWG recommendations, and achieved a Among patients who were randomized, 275 (135 [94%] median limit of detection of 2 × 10−6 9. in the clarithromycin group and 140 [98%] in the control Urine and serum samples were obtained every 28 days group) received at least one cycle of the corresponding (before starting a new cycle of treatment) and analyzed at treatment arm. At the time of the data cutoff for this the local laboratories of the participating centers to deter- analysis (February 7th, 2020), a total of 108 (75.5%) mine the presence of monoclonal proteins and the con- patients in the C-Rd group and 82 (57.3%) patients in the centration of free light chains in serum. MRD was evaluated control group had discontinued treatment, most com- centrally in the three reference laboratories of the Spanish monly due to progressive disease (31.4% in the C-Rd Myeloma Group (Madrid, Pamplona and Salamanca) and group and 47.5% in the control group), adverse events was assessed following the recommendations of the Euro- (25% in the C-Rd group and 19.5% in the control group) Flow group in bone marrow samples obtained at the and death (22.2% in the C-Rd group and 12.2% in the moment of achieving suspected CR and yearly afterwards9. control group). Individuals who discontinued treatment Quality of life was assessed through the FACIT fatigue for reasons different than progressive disease but agreed scale. Toxicity analysis was based on the identification of to remain in the trial were monitored for the primary end adverse events (clinically, on physical examination and/or point. A patient flow diagram has been included in the in laboratory or other complementary tests) graded in Supplementary Material (Fig. 1). accordance with the NCI CTCAE (version 4). The median duration of treatment was 15.0 months (range, 0.2–44) in the C-Rd group and 15.9 months Statistical analysis (range, 0.4–46) in the control group, and the median The primary analysis population was the intention-to- number of treatment cycles was 10 (range, 1–48) in the C- treat group of all patients who underwent randomization. Rd group and 14 (range, 1–47) in the control group. Blood Cancer Journal Puig et al. Blood Cancer Journal (2021)11:101 Page 4 of 11 Table 1 Demographic and clinical characteristics in the clarithromycin group and 61.9% (95% CI, 53.5–70.3) in intention-to-treat population at baseline. the control group. The median PFS was 23 months in the Characteristic C-Rd Group (n = 143) Rd Group (n = 143) clarithromycin group (95% CI 15.3–30.6) and 29 months (95% CI, 22.4–35.5) in the control group. The HR for Age disease progression or death in the clarithromycin group Median (range)—yr 75 (65–91) 76 (65–93) as compared to the control group was 1.293 (95% CI, Distribution—no. (%) 0.919–1.818, p = 0.14) (Fig. 1A). <75 yr 65 (45.5) 59 (41.3) ≥75 yr 78 (54.5) 84 (58.7) Prespecified subgroup analyses of PFS (Table 2) showed Sex—no. (%) that the clarithromycin group was statistically inferior as Male 71 (49.7) 64 (44.8) compared to the control group in patients 75 years of age Female 72 (50.3) 79 (55.2) or older (HR, 0.64; 95% CI, 0.41–1.0), with ISS III (HR, ECOG performance status—no. (%) 0.60; 95% CI, 0.34–1.07), R-ISS III (HR, 0.26; 95% CI, 0 36 (25.9) 41 (29.3) 0.09–0.71); ECOG ≥2 (HR, 0.50; 95% CI, 0.29–0.88), and 1 68 (48.9) 66 (47.1) with a high-risk cytogenetic profile (HR, 0.46; 95% CI, 2 33 (23.7) 29 (20.7) 0.20–1.04). ISS disease stage—no. (%) In the ITT population, median TTP was 39 months in I 36 (25.1) 33 (23.0) both arms (p = 0.962) (Fig. 2A). Among patients <75 years II 53 (37.0) 59 (41.2) of age, median TTP was not reached in the clarithromycin III 54 (37.7) 51 (35.6) R-ISS disease stage—no. (%) group and was 39 months in the control group (p = 0.601) I 15 (12.8) 17 (14.4) (Fig. 2B), while in ≥75 years old patients median TTP was II 79 (67.5) 83 (70.3) 35 months in the clarithromycin group and not reached in III 23 (19.6) 18 (15.2) the control group (p = 0.559) (Fig. 2C). Type of measurable disease—no. (%) The percentage of patients with a CR or better was sig- IgG 74 (52.1) 84 (58.7) nificantly higher in the clarithromycin group than in the IgA 47 (33) 37 (25.8) control group (22.6% vs 14.4%, p = 0.048). Among 29 Bence Jones 21 (14.7) 17 (11.8) patients achieving CR in whom MRD was evaluated (15 Cytogenetic profile—no./total no. (%) from the C-Rd group and 14 from the Rd), there were no Standard risk 106/131 (80.9) 108/130 (83.1) significant differences in undetectable MRD rates (4/15 High risk 25/131 (19.1) 22/130 (16.9) [27%] of patients from the C-Rd group and in 5/14 [36%] The intention-to-treat population was defined as all the patients who underwent from the Rd group). There were no statistically significant randomization. Eastern Cooperative Oncology Group (ECOG) performance status is scored from differences in the percentage of patients achieving VGPR or 0 to 5, with 0 reflecting no disability and higher scores indicating increasing better (52.9% vs 46.1%) between the two groups (Table 3). disability. The International Staging System (ISS) disease stage, which is obtained on the The ORR was 71.5% in the clarithromycin group and 76.4% basis of the combination of serum β2-microglobulin and albumin levels, consists in the control group. The median time to first response was in three stages: I (β2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL), II (neither stage I nor stage III) and III (β2-microglobulin ≥ 5.5 mg/L). Higher stages indicate 28 days in both groups, and the median time to a CR or more advanced disease. better was 5.5 months in the clarithromycin group and The R-ISS is obtained on the basis of the combination of ISS, chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after 5.4 months days in the control group. CD138 plasma cell purification and serum lactate dehydrogenase (LDH). R-ISS I At a median follow-up of 19 months, 84 patients had includes ISS stage I, no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III including died, 46 (32.1%) in the clarithromycin group and 38 ISS stage III and high-risk CA or high LDH level; and R-ISS II, including all other (26.5%) in the control group. The median OS has not been possible combinations. Other types include IgD (one case), IgM (one case), non-secretory (two cases), reached yet in either group (Fig. 3A–C). and biclonal (one case). Cytogenetic risk was based on the results of fluorescence in situ hybridization performed on CD138 + enriched bone marrow samples obtained at diagnosis. Safety High risk was defined by the presence of at least one of the following Table 4 summarizes the most common adverse events abnormalities: del17p, t(4;14), or t(14;16). (AEs) of any grade (Table 4a) and the most common AEs of grade 3 or 4 (Table 4b) during treatment in the safety Efficacy population, globally and across age groups. The most At a median follow-up of 19.0 months (range, 0–54), common AEs of grade 3 or 4 were neutropenia (12% vs disease progression or death was observed in 132 patients, 19% in de C-Rd and Rd groups, respectively [p = ns]), (71 of 143 patients [49.6%] in the clarithromycin group asthenia (11% vs 3%, [p = 0.009]) and steroid-related (15% and 61 of 143 patients [42.6%] in the control group). The vs 6%, [p = 0.021]). Among steroid-related adverse events, Kaplan–Meier estimate of the percentage of patients who we included tremors, anxiety, insomnia, nervousness, were alive without disease progression at 19 months was myopathy, hyperglycemia, confusion, cataracts, facial 53.4% (95% confidence interval [CI], 44.5–62.2) in the edema, and aphonia. Overall, the incidence of infections Blood Cancer Journal Puig et al. Blood Cancer Journal (2021)11:101 Page 5 of 11 Fig. 1 Progression-free survival. A In the overall cohort, (B) In patients <75 years old, (C) In patients ≥75 years old. of any grade was 54%; the incidence of grade 3 or 4 The median relative dose intensity for clarithromycin infections was 30% in the clarithromycin group and 25% was 80% (Table 5). The median relative dose intensity for in the control group (p = ns). When we analyzed toxicity lenalidomide was 72.1% in the clarithromycin group and dividing the cohort by age, we found out that among 83.3% in the control group; 14 patients (9.7%) in the patients ≤75 years old, grade 3–4 adverse events were clarithromycin group and 19 patients (13.2%) in the almost equally reported in the two arms; in contrast, control group received 10 mg or less as a starting dose of among patients >75 years old, the rates of asthenia (14% lenalidomide. The percentage of patients that required vs 3% in C-Rd and Rd respectively, [p = 0.024]), steroid- dose modifications of lenalidomide (including lenalido- related AEs (19% vs 5%, [p = 0.006]) and infections (33% mide discontinuations) were 54.5% in the clarithromycin vs 25%, [p = ns]) were higher in the clarithromycin group group and 51% in the control group; as per dex- with neutropenia being more frequently identified in the amethasone, the percentage of patients that required dose Rd group (14% vs 25%, [p = ns]). modifications (including discontinuations) were 49.6% in Serious AEs were reported in 55.9% of the patients in the clarithromycin group vs 46.5% in the control group. the clarithromycin group and in 47.6% of the patients in One patient discontinued lenalidomide in the clari- the control group. The most common serious AEs in both thromycin group; 6 patients in the clarithromycin group groups were infectious, 24% in the clarithromycin group and 4 in the control group discontinued dexamethasone and 28% in the control group. The percentage of patients and 16 patients discontinued clarithromycin. The median who developed adverse events leading to discontinuation relative dose intensity for dexamethasone was 62.8% in of the trial treatment was 25% in the C-Rd group and the clarithromycin group and 84.3% in the control group. 19.5% in the control group. Trial discontinuation due to infection occurred in 1 patient in each group. Discussion Adverse events resulting in death were observed in 36 Retrospective and single-arm studies performed in patients (25%) in the clarithromycin group and in 22 relapsed/refractory and newly diagnosed MM patients patients (15%) in the control group. The most frequent reported better outcomes when clarithromycin was adverse events were infections, which resulted in death in combined with immunomodulatory drugs, either thali- 10% (14/143) and 5% (7/143) of the patients, respectively. domide, lenalidomide and pomalidomide. In this phase 3 Invasive second primary cancers occurred in 4 patients trial for patients with newly diagnosed MM who were (3%) in the clarithromycin group (solid tumors in 4 cases ineligible for HDT and ASCT, the combination of clari- [2%] and hematologic cancers in 1 case [1%]) and in 1 thromycin, lenalidomide and dexamethasone resulted in a patient (1%) in the control group (solid tumor). rate of CR or better significantly higher than that obtained Blood Cancer Journal Table 2 Prespecified subgroup analysis of progression-free survival. Subgroup Clarithromycin Group Control Group Clarithromycin Group Control Group Hazard ratio (95% CI) no. of progression events or deaths/total no. median progression-free survival (mo) Blood Cancer Journal Sex Male 37/71 32/64 23 26 1.24 (0.77–1.98) Female 33/71 29/79 35 39 1.38 (0.84–2.27) Age <75yr 26/64 26/59 NR 33 1.02 (0.59–1.75) ≥75yr 44/78 35/84 19 28 1.56 (1.00–2.42) ISS I 10/36 11/33 NR 33 0.90 (0.38–2.13) II 32/52 31/59 15 25 1.35 (0.82–2.20) Puig et al. Blood Cancer Journal (2021)11:101 III 28/54 19/51 17 NR 1.67 (0.94–2.98) Baseline creatinine clearance >60 ml/min 63/131 56/132 23 29 1.29 (0.90–1.84) ≤60 ml/min 7/11 5/11 9 NR 1.65 (0.52–5.20) Type of MM IgG 29/74 32/84 35 39 1.06 (0.64–1.74) Non-IgG 41/68 29/59 16 28 1.50 (0.93–2.40) Cytogenetic profile High risk 17/25 9/22 12 NR 2.16 (0.96–4.86) Standard risk 48/106 43/108 27 33 1.22 (0.81–1.84) ECOG score 0 11/32 18/41 39 33 0.60 (0.28–1.27) 1 30/64 22/61 26 NR 1.36 (0.79–2.36) ≥2 29/46 21/41 11 29 1.99 (1.13–3.51) R-ISS I 3/15 6/17 NR 29 0.68 (0.17–2.74) II 42/79 36/83 23 29 1.21 (0.77–1.88) III 16/23 5/18 7 NR 3.89 (1.41–10.7) Clarithromycin Beer Control Beer Shown are the results of an analysis of progression-free survival in prespecified subgroups of the intention-to-treat population that were defined according to baseline characteristics. The experimental group was treated with clarithromycin, lenalidomide and dexamethasone; the control group received lenalidomide and dexamethasone. The International Staging System (ISS) has three stages defined as follows: I (serum β2-microglobulin level < 3.5 mg/L and albumin level ≥ 3.5 g/dL; stage II, neither stage I nor III; and stage III serum β2-microglobulin level ≥ 5.5 mg/L. A high-risk cytogenetic profile was defined by a funding of t(4;14), t(14;16), or del17p on fluorescence in situ hybridization testing. The R-ISS is obtained on the basis of the combination of ISS, chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH). R-ISS I includes ISS stage I, no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III including ISS stage III and high-risk CA or high LDH level; and R-ISS II, including all other possible combinations. Eastern Cooperative Oncology Group (ECOG) performance status is scored on a scale from 0 to 5, with higher scores indicating increasing disability. Page 6 of 11 Puig et al. Blood Cancer Journal (2021)11:101 Page 7 of 11 Fig. 2 Time-to progression. A In the overall cohort, (B) In patients <75 years old, (C) In patients ≥75 years old. Table 3 Summary of response rates. trials, the median PFS reached by the group of patients receiving lenalidomide and dexamethasone was 26.0, 34.4 C-Rd Rd P value and 28.9 months, respectively. Importantly, the percentage Group Group of patients 75 years of age or older in our study (56.6%) was (n = 143) (n = 143) higher than the reported in these three trials (43%, 43% and 48% ≥65 years old in each of them, respectively). Overall response—no. (%) 71.5 76.4 Furthermore, the ORR observed in the control arm of Best overall response – no (%) our study (76.4%) is comparable to what has been reported Complete response or better 33 (22.6) 21 (14.4) 0.048 in the above trials with continuous Rd as control arm Stringent complete response 31 (21.3) 18 (12.4) 0.029 (FIRST trial, 75%, MAIA, 82% and SWOG, 78.8%)4,10–13. However, the addition of clarithromycin to the standard Complete response 2 (1.3) 3 (2.0) 0.500 Rd did not result into a significant benefit in PFS in our Very good partial response or better 77 (52.9) 67 (46.1) 0.144 trial. This contrasts with previous retrospective and Very good partial response 44 (30.3) 46 (31.7) 0.449 single-arm studies performed in relapsed/refractory and Partial response 27 (18.6) 44 (30.3) 0.014 newly diagnosed MM patients reporting better outcomes when clarithromycin was combined with immunomodu- Stable disease 27 (18.6) 31 (21.3) 0.330 latory drugs, either thalidomide, lenalidomide and Progressive disease 1 (0.6) 1 (0.6) 0.751 pomalidomide. Niesvizky et al. published in 2013 the Response could not be evaluated 0 (0) 3 (2.0) 0.124 long-term results of C-Rd in NDMM patients7. After a Response was assessed following the guidelines of the International Myeloma median follow-up of 6.6 years, ORR was 93% with a VGPR Working Group. The P value was calculated with the use of the Fisher´s or better rate of 68% and a median PFS of 49 months. In exact test. our study, the ORR rates were also comparable in both arms although the percentage of patients with a CR or with lenalidomide and dexamethasone alone (22.6% vs better was significantly higher in the clarithromycin group 14.4%, p = 0.048); however, the observed median PFS was than in the control group (22.6% vs 14.4%, p = 0.048)7. not significantly different between the two groups of This can be due to the increased activity achieved by patients (23 months in the C-Rd arm vs 29 months in the adding clarithromycin to Rd as it has been previously Rd arm). described in the setting of newly diagnosed MM using the To contextualize our results, the median PFS observed in same schedule8. Furthermore, a phase 2 trial evaluating the control group was comparable to that reported by other the safety and efficacy of clarithromycin, pomalidomide studies performed in newly diagnosed MM patients ineli- and dexamethasone in relapsed or refractory MM repor- gible for ASCT.4,10–13. In the FIRST, MAIA and SWOG ted an ORR of 60% (23% ≥VGPR), which is significantly Blood Cancer Journal Puig et al. Blood Cancer Journal (2021)11:101 Page 8 of 11 Fig. 3 Overall survival. A In the overall cohort, (B) In patients <75 years old, (C) In patients ≥75 years old. higher than that reported in patients treated with Poma- arm and 40% (16/40) in the Rd arm. Therefore, a higher lidomide and dexamethasone alone in the MM-002 study number of patients ≥75 years old dying without asso- (32.7%)14, in MM-003 (31.4%)15, in STRATUS (32.6%)16, ciated PD in the C-Rd arm (26 vs 16 in the Rd arm) was and in IFM- 2009-02 (34.5%)17. responsible for the shorter PFS observed in this group. Importantly, as stated above, more than half of the When we analyzed the most common AE of grade 3–4, patients in our trial were ≥75 years old. In depth analysis neutropenia and infections were the most frequently of our results showed that, whereas in patients <75 years reported in both arms (19% and 25% [10% of pneumonia] old, PFS was comparable in both arms (NR, 33 months; p in Rd vs 12% and 30% [7% pneumonia] in C-Rd, respec- = ns), in the group of patients 75 years old and older, tively). As compared to the Rd arm, a slightly higher median PFS was shorter in the C-Rd group (19 vs percentage of cases presented with infections in the C-Rd 28 months; p = 0.05) (Fig. 1B-C). TTP was then analyzed arm, but also with more frequent asthenia (11% vs 3%) as a secondary endpoint: no differences were observed and steroid-related AEs (15% vs 6%). The most frequent when analyzing the ITT population and similar results AEs reported in the group of patients receiving Rd in the were obtained in the group of patients <75 years (NR in MAIA and FIRST trials were neutropenia and infections, C-Rd and 39 months in Rd) and in those ≥75 years old as presented in the Rd arm in our study. On the other (35 months in C-Rd vs NR in Rd). Thus, in the ≥75 years hand, the most common grade 3 or higher non- old cohort, PFS was longer in the control group with no hematologic adverse events reported in the BiRd trial differences in TTP between the two arms, thus suggesting included myopathy (11.1%), neuromood (4.2%) and tre- that the higher treatment-related mortality in these older mor (4.2%), all of them attributable to steroids and also patients could be explaining our results. more frequently developed by the C-Rd arm in our We then analyzed the 90 documented deaths, 50 in the study18. Similarly, in the ClaPd trial for relapsed and C-Rd group and 40 in the Rd group. Whereas the number refractory MM patients, the most common non- of patients dying in the context of PD was similar in both hematologic grade 3 or higher toxicities were fatigue groups (14 patients in the C-Rd group and 18 in the Rd (15%), pulmonary infection (13%), and hyperglycemia group), there were 36 cases in the C-Rd arm vs 22 in the (15%)3. Importantly, the median age in these two studies Rd arm who died in the absence of PD (14 vs 7 due to was significantly lower than in ours: 63 (range, 36–83) in infections, 5 vs 3 of cardiovascular origin and 3 vs 0 due the BiRd trial, 63 (range, 42–87) in the ClaPd trial and 76 to secondary primary malignancies, respectively; in 8 (range, 65–93) in our trial.3,18. In fact, whereas among cases in each group, the exact cause of death was patients ≤ 75 years old, we found that grade 3–4 adverse unknown). The percentage of patients ≥75 years old events were almost equally reported in the two arms, in dying without associated PD was 52% (26/50) in the C-Rd patients >75 years old, the rates of asthenia (14% vs 3% in Blood Cancer Journal Puig et al. Blood Cancer Journal (2021)11:101 Page 9 of 11 Table 4 a Most common adverse events and second primary malignancies reported during treatment in the safety population. b Most common adverse events of grade 3–4 reported during treatment in the safety population. No. (%) All Age ≤ 75 Years Age >75 Years TEAE or SPM C-Rd (n = 143) Rd (n = 143) p C-Rd (n = 65) Rd (n = 59) p C-Rd (n = 78) Rd (n = 84) p a Hematologic TEAEs, any grade Neutropenia 34 (24) 51 (36) 0.038 15 (23) 14 (24) 1 19 (24) 37 (44) 0.013 Anemia 26 (18) 28 (20) 0.880 7 (14) 8 (14) 0.784 19 (24) 20 (24) 1 Thrombocytopenia 21 (15) 22 (15) 1 9 (14) 7 (12) 0.794 12 (15) 15 (18) 0.833 Nonhematologic TEAEs, any grade Astenia 40 (28) 44 (31) 0.697 17 (26) 12 (20) 0.526 23 (29) 32 (38) 0.319 Steroid-related 58 (41) 40 (28) 0.034 28 (34) 17 (29) 0.134 30 (38) 23 (27) 0.180 Infections 78 (55) 76 (53) 0.906 32 (49) 28 (47) 0.859 46 (59) 48 (57) 0.874 Pneumonia 11 (8) 19 (13) 0.176 6 (9) 7 (12) 0.771 5 (6) 12 (14) 0.127 DVT and EP 9 (6) 11 (8) 0.817 5 (8) 5 (8) 1 4 (5) 6 (7) 0.748 Diarrhea 22 (15) 24 (17) 0.872 10 (15) 10 (17) 1 12 (15) 14 (17) 0.834 Invasive second primary cancer 4 (3) 1 (1) 0.371 1.(1) 0 (0) 1 3 (4) 1 (1) 0.353 b Hematologic TEAEs, any grade Neutropenia 17 (12) 28 (19) 0.104 6 (9) 7 (12) 0.771 11 (14) 21 (25) 0.114 Anemia 4 (3) 10 (7) 0.169 1 (2) 5 (8) 0.101 3 (4) 5 (6) 0.721 Thrombocytopenia 7 (5) 4 (3) 0.541 2 (3) 1 (2) 1 5 (6) 3 (3) 0.483 Nonhematologic TEAEs, any grade Astenia 16 (11) 4 (3) 0.009 5 (8) 1 (2) 0.211 11 (14) 3 (3) 0.024 Steroid-related 22 (15) 9 (6) 0.021 7 (11) 5 (8) 0.766 15 (19) 4 (5) 0.006 Infections 43 (30) 36 (25) 0.428 17 (26) 15 (25) 1 26 (33) 21 (25) 0.299 Pneumonia 10 (7) 14 (10) 0.523 6 (9) 6 (10) 1 4 (5) 8 (9) 0.373 DVT and EP 2 (1) 6 (4) 0.282 0 (0) 4 (7) 0.049 2 (2) 2 (2) 1 Diarrhea 4 (3) 5 (3) 1 2 (3) 2 (3) 1 2 (2) 3 (3) 1 Invasive second primary cancer 4 (3) 1 (1) 0.371 1 (1) 0 (0) 1 3 (4) 1 (1) 0.353 C-Rd and Rd respectively), steroid-related AEs (19% vs intensity of 62.8% vs 84.3%) than patients treated with Rd. 5%) and infections (33% vs 25%) were higher in the Thus, the similar PFS between the two groups in our study clarithromycin group. might also be related to the lower treatment compliance The median treatment duration was similar in the two observed in the clarithromycin group. groups (15.0 vs 15.9 months) but, the median number of Recent trials have explored the clinical impact of spar- treatment cycles was lower in the C-Rd group vs the Rd ing steroids in elderly patients with MM. In the study group (10 vs 14 months). Besides, due to the higher inci- presented by Larocca et al. at the EHA2020, 199 dence of grade 3–4 AEs, patients in the C-Rd group received intermediate-fit patients were randomized 1:1 to receive less lenalidomide (median relative dose intensity of 72.1% vs standard continuous Rd or 9 cycles of Rd followed by 83.3%) and less dexamethasone (median relative dose maintenance with lenalidomide (10 mg po od days 1–21), Blood Cancer Journal Puig et al. Blood Cancer Journal (2021)11:101 Page 10 of 11 Table 5 Treatment exposure in the safety population. results. Further investigations modifying the dose of both clarithromycin and steroids based on age and frailty status C-Rd Group Control could be of interest to exploit the benefits of this com- (n = 143) Group bination. The results of our trial also highlight the rele- (n = 143) vance of evaluating phase I/II clinical data in the context Median duration of study treatment—mo 15 (0.2–44) 15.9 (0.4–46) of phase III clinical trials, since such design offers us the (range) strongest scientific evidence regarding efficacy and safety of new treatments as compared to the standard of care. Median total number of cycles received— 10 (1–48) 14 (1–47) no. (range) Acknowledgements We acknowledge the contribution to this study of all members of the GEM/ Median relative dose intensity—% (range) PETHEMA group. The full consortia list is detailed in the Supplementary material. Clarithromycin 80 (35.7–98.4) – Author details Lenalidomide 72.1 (0–98.6) 83.3 (19–97.0) 1 Hematology Department, Hospital Universitario de Salamanca (HUSAL), IBSAL, Dexamethasone 62.8 (0–71.4) 84.3 (0–88.7) IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain. 2Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain. 3Hematology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain. 4Hospital Universitario de Cabueñes, Gijón, Spain. 5Hospital Morales Meseguer, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain. 6Institut Català d’Oncologia and Institut Josep Carreras, Hospital both until progressive disease or intolerance. Best Germans Trias i Pujol, Barcelona, Spain. 7Hospital Universitario de León, León, response rates seemed to favor the experimental arm (≥ Spain. 8Hematology Department, Catholic University of Valencia and Hospital nCR 19% vs 15% and ≥ VGPR 44% vs 35% in Rd-R vs Rd, Doctor Peset, Valencia, Spain. 9Hospital Univeristari Vall d´Hebron, Barcelona, Spain. 10Hospital Universitario Virgen de las Nieves, Instituto de Investigación respectively) and no differences in PFS (43% and 42% at Biosanitaria IBS GRANADA, Granada, Spain. 11Hospital Universitario Virgen de la 20 months in Rd-R vs Rd) and OS (84% and 79% at Victoria, Málaga, Spain. 12Complejo Hospitalario de Navarra, Pamplona, Spain. 13 20 months in Rd-R vs Rd) were observed between the two Hospital Universitario de La Princesa, Sevilla, Spain. 14Hospital Universitario Virgen del Rocío, Sevilla, Spain. 15Clínica Universidad de Navarra, CIMA, groups. However, patients assigned to the continuous Rd CIBERONC, IDISNA, Pamplona, Spain. 16Hospital Universitario 12 de Octubre, treatment presented with more grade 3 or higher non- CIBERONC, Instituto de Investigación, IMAS12 Madrid, Spain. 17Hospital hematological toxicities, higher discontinuation rates and Universitario Virgen de Valme, Sevilla, Spain. 18Hematology Department, Hospital Costa del Sol de Marbella, Marbella, Spain. 19Hematology Department, higher dose reductions due to AEs19. Similarly, in the Hospital Universitario y Politécnico La Fe, Valencia, Spain. 20Bioaraba Health updated results of the EMN01 randomized trial published Research Institute, Oncohematology Research Group; Osakidetza, Álava by Bringhen et al., the authors evaluated maintenance University Hospital, Hematology Department, Vitoria-Gasteiz, Spain. 21Hospital del SAS de Jerez, Jerez de la Frontera, Spain. 22Hospital Universitario de treatment with lenalidomide with or without prednisone Santiago, Santiago de Compostela, Spain. 23Hematology Department, Hospital in 402 patients previously treated with Rd and melphalan Universitario Marqués de Valdecilla, Santander, Spain. 24Division of Hematology or cyclophosphamide as induction. From the start of and Oncology, Weill Cornell Medicine, New York, NY, USA. 25Hospital Universitario Gregorio Marañón, Madrid, Spain. 26CHUAC, A Coruña, Spain. maintenance, there were no differences in PFS between 27 Hospital Clínico Universitario de Valencia, Valencia, Spain. 28Statistics patients treated with lenalidomide-prednisone vs those Department, University of Salamanca, Salamanca, Spain. 29Instituto de receiving lenalidomide alone (22.2 vs 18.8 months, HR Investigación del Hospital Universitario, 12 de Octubre, Madrid, Spain 0.85, p = 0.14), with no differences across frailty sub- Author contributions groups defined as per the IMWG Frailty Score20.Thus, in R.N. designed research. N.P., M.C., and M.V.M. analyzed the data. All authors this group of elderly patients with MM, steroids could be performed the research and wrote the paper. N.P. was responsible for the reduced or avoided without compromising treatment writing of the first version of the manuscript. efficacy of lenalidomide. Also, in steroid sparing regimens, Conflict of interest clarithromycin could be added to test its direct immu- N.P.: honoraria: Amgen, Celgene, Janssen, Takeda, The Binding Site; consulting nomodulatory and anti-tumor properties, but avoiding or advisory role: Amgen, Celgene, Janssen, Takeda; speakers’ bureau: Celgene; the side effects derived from its influence on the kinetics research funding: Celgene, Janssen, Amgen, Takeda; travel, accommodations, expenses: Amgen, Celgene, Janssen, Takeda. M.T.H.: consulting or advisory role: of glucocorticoids. Celgene, Janssen, Amgen, Takeda, GSK; speakers’ bureau: Janssen, Celgene, In conclusion, the addition of clarithromycin to Rd in Amgen. L.R.: honoraria from Janssen, Celgene, Amgen and Takeda. E.G.: no transplant ineligible newly diagnosed MM patients is not COIs to disclose. F.d.A.: honoraria from Janssen, Celgene, Amgen, GlaxoSmithKline and Takeda. A.O.: consultancy and speakers bureau for associated with an improved PFS, despite a significantly Celgene and Amgen, consultancy for Janssen, Sanofi, GSK. V.G.-C.: honoraria increase in the CR rate as compared to Rd; this is due to a from Janssen and Celgene; research funding from Janssen (BECA SEHH- higher proportion of toxic deaths in the C-Rd arm, mostly JANSSEN ESTANCIAS DE FORMACIÓN EN EL EXTRANJERO 2016–2017); consulting or advisory role for Prothena and Janssen. F.E.: no COIs to disclose. infectious and concentrated in the group ≥75 years old, J.d.l.R. has served as a consultant and provided expert testimony within the which accounted for half of the recruited patients. In this past 2 years for Amgen, Celgene, Takeda, Janssen, and Sanofi. M.G.: honoraria elderly population, overexposure to steroids due to the for Janssen, Celgene, Takeda and Amgen. R.R.: consulting or advisory role for Janssen and Celgene; R.G.S.: Consulting or advisory role: BMS/Celgene, Janssen, delayed clearance induced by clarithromycin together Amgen, Takeda and GSK and speakers bureau from BMS/Celgene, Janssen, with a lower treatment compliance could explain our Amgen and GSK. J.M.A.: no COIs to disclose. A.A.: Consultancy and membership Blood Cancer Journal Puig et al. Blood Cancer Journal (2021)11:101 Page 11 of 11 on an entity´s Board of Directors or advisory committees for Celgene-BMS, 6. Coleman, M. et al. BLT-D (clarithromycin [Biaxin], low-dose thalidomide, and Amgen, Janssen, Sanofi, GSK and Takeda. J.M.: travel, accommodations and dexamethasone) for the treatment of myeloma and Waldenström’s macro- expenses from Amgen and Sandoz. N.C.G.: honoraria from Janssen-Cilag. M.J.C.: globulinemia. Leuk. Lymphoma 43, 1777–1782 (2002). no COIs to disclose. M.L.M.: no COIs to disclose. M.d.C.C.: no COIs to disclose. 7. Rossi, A. et al. BiRd (clarithromycin, lenalidomide, dexamethasone): An update M.C.: no COIs to disclose. M.A.: consultancy and honoraria for Janssen, Bristol- on long-term lenalidomide therapy in previously untreated patients with Myers Squibb, Celgene, Amgen and Takeda. E.P.P.: speakers bureau for multiple myeloma. Blood. 121, 1982–1985 (2013). Celgene/BMS, Amgen, Janssen, GSK. S.G.: consulting or advisory role for 8. Gay, F. et al. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone Janssen, Amgen, Takeda and Celgene. M.S.G.: no COIs to disclose. G.M.S.: no (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diag- COIs to disclose. E.M.O.: Research funding: Array Pharmaceuticals, nosed myeloma. Am. J. Hematol. 85, 664–669 (2010). Mundipharma, Sanofi; consultancy, honoraria and research funding: Celgene, 9. Flores-Montero, J. et al. Next Generation Flow for highly sensitive and stan- Amgen; consultancy and honoraria: Novartis, Takeda, Janssen; honoraria: B.M.S.; dardized detection of minimal residual disease in multiple myeloma. Leuke- consultancy: AbbVie, Pharmamar, Seattle Genetics. M.C.: no COIs to disclose, mia. 31, 2094–2103 (2017). C.E.: no COIs to disclose. A.M.V.: no COIs to disclose. A.I.T.: no COIs to disclose. 10. Facon, T. et al. Daratumumab plus lenalidomide and dexamethasone for M.C.R.: no COIs to disclose. B.P.: consultancy, honoraria, research funding and untreated myeloma. N. Engl. J. Med. 380, 2104–2115 (2019). speaker’s bureau for Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, 11. Durie, P. B. G. M. et al. Bortezomib with lenalidomide and dexamethasone Roche and Sanofi; unrestricted grants from Celgene, EngMab and Takeda; versus lenalidomide and dexamethasone alone in patients with newly diag- consultancy for Celgene, Janssen and Sanofi; M.T.C.: Honoraria from Janssen, nosed myeloma without intent for immediate autologous stem-cell transplant Celgene, Abbvie. J.F.S.-M.: consultancy or advisory role for Abbvie, Amgen, (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet 389, 519–527 Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, MSD, (2017). Novartis, Roche, Sanofi, SecuraBio and Takeda. J.J.L.: consulting or advisory role 12. Durie B. G. M. et al. Longer term follow-up of the randomized phase III trial for Celgene, Takeda, Amgen, Janssen and Sanofi; travel accommodations and SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide expenses for Celgene. J.B.: honoraria for Janssen, Celgene, Takeda, Amgen and and dexamethasone in patients (Pts) with previously untreated multiple Oncopeptides. R.N.: no COIs to disclose. M.V.M.: honoraria and membership on myeloma without an intent for immediate autologous stem cell transplant an entity´s Board of Directors or advisory committees for Janssen, Celgene, (ASCT). Blood Cancer J. [Internet]. 2020;10. Takeda and Amgen, Adaptive, GSK, Sanofi and Oncopeptides; honoraria from 13. Kumar S. K. et al. Updated analysis of daratumumab plus lenalidomide and membership in Board of Directors or advisory committees for Abbvie, Roche, dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in Pfizer, Regeneron and Seattle Genetics. patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM): the phase 3 Maia study. Blood (2020) 136 (Supplement 1): 24–26. Abstract 2276. Publisher’s note 14. Richardson, P. G. et al. Pomalidomide alone or in combination with low-dose Springer Nature remains neutral with regard to jurisdictional claims in dexamethasone in relapsed and refractory multiple myeloma: a randomized published maps and institutional affiliations. phase 2 study. Blood [Internet] 123, 1826–1832 (2014). 15. Miguel, J. S. et al. Pomalidomide plus low-dose dexamethasone versus high- Supplementary information The online version contains supplementary dose dexamethasone alone for patients with relapsed and refractory multiple material available at https://doi.org/10.1038/s41408-021-00490-8. myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. [Internet] 14, 1055–1066 (2013) . 16. Dimopoulos, M. A. et al. Safety and efficacy of pomalidomide plus low-dose Received: 18 January 2021 Revised: 28 March 2021 Accepted: 30 April 2021 dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood [Internet] 128, 497–503 (2016). 17. Leleu, X. et al. 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