Успешное лечение пациента с множественной миеломой во время беременности: отчет по делу и обзор литературы.

Background

Multiple myeloma (MM) is a malignant neoplasm characterised by the clonal proliferation of plasma cells in the bone marrow (BM), accounting for approximately 1% of all cancers and more than 10% of haematological malignancies [ 1 ]. In general, MM mainly affects elderly males between 50 and 70 years of age but less commonly occurs in young people aged younger than 40 years. Cases occurring during pregnancy are extremely rare [ 2 ]. Since it was first reported by Giordano et al. in 1965 [ 3 ], this special entity has been recognised. However, data on the presentation features, clinical course, therapeutic approaches, prognosis, and outcomes of pregnancies complicated by MM are lacking. The diagnosis of MM during pregnancy is easily missed or delayed due to an overlap of the disease and gestation-related symptoms [ 4 ]. Moreover, clinicians experience difficulties in helping, counselling and reassuring pregnant patients with MM, given that there is no existing consensus or guidelines to follow. Therapy-attributable risks for mothers and foetuses increase the degree of caution when a therapy is initiated. In the absence of large-scale clinical trials, it is important to obtain evidence from reviewing a large number of similar cases. Herein, we present a case in which a patient was diagnosed with MM during pregnancy and successfully managed, in conjunction with a narrative review of the existing cases aimed at providing a practical reference and insights to aid in the diagnosis and management of this disease.

Methods

Data on the demographics, medical history, clinical presentation, disease course, and treatment of a 37-year-old primigravid woman who was diagnosed with MM during pregnancy in our hospital were collected from the hospital information system (HIS). The outcomes of the mother and infant were followed up through outpatient visits and phone calls. Written informed consent was obtained from the patient. MM was diagnosed in accordance with the International Myeloma Working Group (IMWG) criteria, including a BM infiltration exceeding 10% of clonal plasma cells and the presence of at least one of the CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions) or biomarkers of imminent organ damage.

For the literature review, we used “multiple myeloma”, “pregnancy”, “gestation”, “pregnancy complications”, “pregnancy outcomes”, “prenatal”, “maternal”, “foetal”, and “neonatal” as keywords by searching the PubMed, ScienceDirect, Web of Science, Medline, Foreign Medical Retrieval System (FMRS), China National Knowledge Infrastructure (CNKI) and Wanfang databases from 1965 to 2025. The following inclusion criteria were utilised: online case reports or case series with content regarding clinical presentation, diagnosis, and treatment occurring before, during, and/or postpartum, as well as outcomes of both the mother and foetus. The following exclusion criteria were utilised: animal studies, reviews and nonoriginal articles. A total of 223 articles were initially retrieved. Two reviewers screened the titles and abstracts, and those that were not deemed to be relevant were removed. The remaining papers meeting the inclusion/exclusion criteria, as well as duplicate studies, were excluded. In total, 39 articles were selected for inclusion, and 52 cases worldwide (including the case presented here) were included in our study for analysis.

Results

Case presentation

A 37-year-old primigravid woman with no relevant medical history was observed to have elevated serum protein and globulin levels in routine blood tests at 14 + 6 weeks gestation at the outpatient antenatal clinic. She reported no discomfort. The total protein (TP) concentration was 105.9 g/L (normal range: 60–80 g/L), and the globulin (GLB) concentration was 77.0 g/L (normal range: 18–32 g/L) in the serum. The haemoglobin (Hb) concentration was 8.3 g/dL, whereas it was 10.3 g/dL at 8 weeks gestation. Serum creatinine levels, lactate dehydrogenase (LDH) levels and electrolyte levels were within normal ranges. Additionally, the blood pressure measurement was normal. A urine dipstick test revealed proteinuria (+). Molecular analysis of thalassaemia confirmed -- SEA /αα. The peripheral blood film did not demonstrate atypical cells. Tests for anti-nuclear (ANA), extractable nuclear (ENA), and anti-neutrophil cytoplasmic (ANCA) antibodies were negative. Thyroid and liver function tests were normal. Notably, non-invasive prenatal testing (NIPT) of the patient revealed an abnormal phenomenon of multiple non-specific genomic imbalances. A maternal tumour was suspected, and further investigations revealed a serum IgG concentration of 70.1 g/L (normal range: 7.0–16 g/L), a serum β2-microglobulin concentration of 5.6 mg/L (normal range: 0.8–2.2 mg/L), an M protein concentration of 54.9 g/L, a urinary lambda light chain (LAMBDA) concentration of 3360 mg/L, and a urinary kappa light chain (KAPPA) concentration of 32.1 mg/L. Immunofixation revealed the presence of lambda-type IgG in the blood. BM biopsy revealed multifocal solitary lesions of clonal plasma cell plasmacytoma (Fig. 1 ). Cytogenetic analysis revealed a normal karyotype of 46,XX. BM fluorescence in situ hybridisation (FISH) analysis revealed del (RB1), del (D13S319) and breakage of IGH. The diagnosis of MM was established. A multidisciplinary team (MDT) meeting was held to discuss the treatment protocol. Due to the fact that the patient was asymptomatic and strongly desired to proceed with the pregnancy, a plan was implemented for close observation of symptoms, physical examinations and laboratory tests for organ damage in terms of bone disease, progressive anaemia, hypercalcaemia, and renal failure. A complete blood count test‌, renal liver function test, electrolyte test, coagulation assay, routine urinalysis, serum β2-microglobulin test, and serum and urinary free light chain assays were regularly performed (Fig. 2 ). At 20 weeks gestation, amniocentesis was performed, and chromosomal microarray analysis (CMA) of the amniotic fluid was determined to be normal. The patient’s haemoglobin concentration was 8.1 g/dL, and the serum β2-microglobulin concentration was 6.9 mg/L. Additionally, the serum IgG concentration was 76.8 g/L, the LAMBDA concentration was 18.5 g/L, and the KAPPA concentration was 0.8 g/L. Moreover, the urinary LAMBDA concentration was 1730 mg/L, and the urinary KAPPA concentration was 24.0 mg/L. Serum creatinine and calcium levels were normal. Subsequent foetal ultrasonography revealed no structural anomalies. At 24 weeks gestation, the patient began to experience pain and fatigue. At this time point, the haemoglobin concentration was 6.8 g/dL, and serum tests revealed a β2-microglobulin concentration of 10.1 mg/L, an IgG concentration of 77.3 g/L, a LAMBDA concentration of 21.3 g/L, a KAPPA concentration of 0.6 g/L, a creatinine concentration of 51.9 µmmol/L and a calcium concentration of 2.3 mmol/L. Additionally, the urinary LAMBDA concentration was 3250 mg/L, and the urinary KAPPA concentration was 15.0 mg/L. The test results led to a suspicion of active MM. Based on the toxicity of chemotherapy and the survival limit of the infant born at this gestational age (GA), as well as the mother’s good tolerance for bone pain, normal calcium levels and good renal function, a decision was made for expectant observation with supportive care. She received red blood cell transfusions and plasma exchange as supportive care. At 26 weeks gestation, the pain was not relieved. A magnetic resonance imaging (MRI) scan of the spine showed a compression deformity of the T9 vertebra (Fig. 3 ). The serum calcium concentration was 2.9 mmol/L (which was slightly higher than the normal range), and the serum creatinine concentration was within normal limits. Ultrasound foetal biometry and Doppler assessment revealed an optimal condition, thus indicating no foetal growth restriction (FGR). Thus, the patient was diagnosed with Durie-Salmon stage IIIA and International Staging System III λ light chain myeloma. Given that the MM progressed quickly, the MDT suggested the initiation of chemotherapy, but the patient refused. At 27 + 3 weeks gestation, the patient experienced severe systemic pain that was unbearable. Cytoreductive chemotherapy with CD (cyclophosphamide + dexamethasone) was proposed by the MDT. Given that methylprednisolone exhibits a relatively weaker capacity to penetrate through the placenta, the MDT replaced dexamethasone with methylprednisolone for chemotherapy (cyclophosphamide at 700 mg + methylprednisolone at 40 mg). Moreover, enoxaparin was administered to prevent thrombotic events. Tests involving foetal movement, foetal heart rate monitoring, and foetal ultrasonography were performed on a daily basis during chemotherapy. At 28 weeks gestation, the patient’s myeloma burden was not relieved. Additionally, the serum calcium concentration increased to 3.1 mmol/L, and the creatinine concentration increased to 132 µmol/L, with a peak being detected throughout the disease course. The proteinuria status of (+) persisted in the urinalysis and demonstrated no increasing trend compared to the previous measurements. All of the platelet and liver enzyme levels were within the normal ranges. Moreover, the blood pressure measurements remained normal. A foetal birth weight of 1090 ± 459 g was estimated via ultrasound. Doppler measurements of the pulsatility index (PI), resistive index (RI) of the umbilical artery (UA), and foetal middle cerebral artery (MCA) were normal (UA-PI: 1.00; UA-RI: 0.66; MCA-PI: 2.29; MCA-RI: 0.87). As the survival and quality of life significantly improved with good neonatal care in this GA, the MDT suggested termination of the pregnancy to initiate intensive anti-myeloma chemotherapy. Dexamethasone phosphate was administered in a regimen of four 6-mg maternal intramuscular injections every 12 h to accelerate foetal lung maturation. At 28 + 3 weeks gestation, the patient delivered a female infant weighing 1100 g via Caesarean section, with Apgar scores of 5 and 7 being observed at 1 min and 5 min, respectively. The newborn developed mild respiratory distress syndrome, and she was admitted to the neonatal intensive care unit (NICU). She was fed via donated breast milk and recovered well after a 50-day hospital stay.

Fig. 1 Bone marrow biopsy of the patient showing multifocal solitary lesions of clonal plasma cells ( A ) that were positive for 38 ( B ), CD138 ( C ), and LAMBDA ( D ) and negative for KAPPA ( E ) at diagnosis, along with demonstrating normal cellularity after treatment ( F ) (HE×200)

Fig. 2 Graphs of laboratory indicators of the patient at diagnosis, during pregnancy and after the delivery

Fig. 3 Spinal MR image of the patient at 26 weeks gestation showing compression deformity of the T9 vertebra (white arrow). Left: T1WI, Middle: T2WI, Right: T2WI-FS

After the delivery, a PET/CT scan confirmed multiple bone lesions in the skull, pelvis and metaphysis of the long bones (Fig. 4 ). The patient underwent chemotherapy immediately after delivery with alternating VRd (bortezomib at 1.3 mg/m 2 , lenalidomide at 25 mg, and dexamethasone at 40 mg) and Vd (bortezomib at 1.3 mg/m 2 and dexamethasone at 40 mg) regimens (involving 2 cycles of VRd followed by 4 cycles of Vd, along with a subsequent 2 cycles of VRd) designed for subsequent autologous stem cell transplantation (ASCT). Serum calcium levels quickly decreased to the normal range, and creatinine levels did not subsequently increase (Fig. 2 ). Six months postpartum, a very good partial response (VGPR) was achieved. The patient underwent ASCT with pretreatment involving melphalan. Two months after ASCT, a BM biopsy revealed normal cellularity (Fig. 1 ). No obvious monoclonal bands were observed on serum and urine immunofixation. Furthermore, the VRd regimen was maintained in the outpatient setting. The infant remained healthy, with no neurodevelopmental disorders being observed after a 2.5-year follow-up.

Fig. 4 99Tcm-MDP-PET/CT scan of the patient postpartum showing hypermetabolic bone lesions in the skull, pelvis and metaphysis of the long bones

Literature review

Ultimately, a literature review identified 52 cases of MM associated with pregnancy, including the current case. Ten cases were reported before the year 2000, and 42 cases were reported after 2000, thus indicating an increasing trend. Forty-five cases (86.5%) were reported in European and American countries, with six cases (11.5%) being reported in Asian countries and only one case (1.9%) being reported in African countries, thereby indicating that the incidence of MM may be related to regions and races (being relatively high in European and American countries but lower in Afro-Asian countries). The affected age ranged between 21 and 44 years. Ten patients (19.2%) were diagnosed prior to pregnancy, 38 patients (73.1%) were diagnosed during pregnancy, and 4 patients (7.7%) were diagnosed postpartum. One patient was diagnosed with undetermined monoclonal gammopathy of undetermined significance (MGUS) 6 years before becoming pregnant, after which they developed symptomatic MM during the postpartum period.

The initial complaints of the patients were often concealed and non-specific in nature. In summary, bodily pain (53.8%) was mentioned as the most common perceptible symptom, which was mostly attributed to bone lesions. Rare causes included pancreatitis, neuralgia and lumps on the forehead. Other symptoms included anaemia (13.5%), hypercalcaemia (7.6%), proteinuria/kidney failure (11.5%), lethargy/hyperemesis/dyspnoea (7.6%), spontaneous abortion (3.8%), cytopenia (3.8%) and breast lumps (1.9%) (Fig. 5 ).

Fig. 5 Initial presentation of the patients with multiple myeloma during pregnancy in the literature review

Among the 10 patients who were diagnosed prior to pregnancy, 9 patients received chemotherapy. The adopted regimens included velcade, cyclophosphamide/thalidomide, and dexamethasone (VCd/VTd); thalidomide and dexamethasone (Td); or vincristine, azithromycin and dexamethasone (VAd). After achieving complete remission, 3 patients received ASCT. Moreover, two patients progressed or relapsed during pregnancy.

Among the 48 patients who were diagnosed before or during pregnancy, 25 patients (52.0%) received chemotherapy during pregnancy. Two patients used cyclophosphamide (CTX), with these cases being reported in the 1960s and 1970s. Eleven patients exclusively used steroids; among them, seven patients used dexamethasone (mostly involving 40 mg daily for 4 days each week), one patient used prednisolone (50 mg every second day), two patients used methylprednisolone (high dosage), and 1 case did not mention the type of steroid that was utilised. Eight patients were treated with different chemotherapeutic combinations, including cyclophosphamide, dexamethasone/prednisone, melphalan, vincristine or interferons. Moreover, one patient was treated with IFN-α solely during the first trimester. Three cases did not clearly describe the chemotherapy regimens.

A total of 48 live infants were delivered, including 16 full-term births (33.3%), 26 preterm births (55.3%), and 6 births with unmentioned GA. Twenty-four infants (50.0%) were delivered via Caesarean section, 6 infants were delivered via vaginal delivery, and the remaining infants underwent undescribed delivery mood. Three patients chose to terminate the pregnancy. Additionally, one case ended in foetal death at 24 weeks gestation. One newborn died during the neonatal period. Forty-seven (97.9%) infants remained symptom-free during the follow-up until the publication date. Among the reported GAs, our case represents the tiniest. The infant is now 2.5-years-old and has exhibited normal development.

Among the total number of included cases, 41 women (78.8%) survived up to the publication date, whereas 10 women (19.2%) died. The causes of death involved active MM (7 patients), sudden cardiac arrest attributed to light chain deposition disease (LCDD) associated with MM (1 patient), metastasis of concurrent colorectal cancer (1 patient) and infection caused by neutropenia (1 patient). A summary and details of the cases are shown in Tables 1 and 2 .

Table 1 Summary of the cases included in the literature review Parameter Number of cases ( N = 52) Age range (years) 21–44 Diagnosed before pregnancy 10 (19.2%) Diagnosed during pregnancy 38 (73.1%), including 7 cases in the first trimester, 24 cases in the second trimester, and 7 cases in the third trimester Diagnosed postpartum 4 (7.7%) Not mentioned, 1 case (1.9%) Anti-myeloma treatment during pregnancy Yes, 26 cases (50.0%) No, 25 cases (48.0%) Not mentioned, 1 case (1.9%) Anti-myeloma treatment postpartum Yes, 45 cases (86.5%) No, 1 case (1.9%) Not mentioned, 6 cases (11.5%) Mother’s survival status Alive, 41 cases (78.8%) Died, 10 cases (19.2%) Not mentioned, 1 case (1.9%) Foetal status Healthy, 47 cases (90.4%) Stillbirth, 1 case (1.9%) Termination, 3 cases (5.8%) Newborn died, 1 case (1.9%)

Table 2 Details of the cases included in the literature review Case Year of publication Author Nationality Age of onset (years) Initial presentation Medical history Onset or diagnostic time GA at the onset (weeks) Anti-myeloma treatment before pregnancy Successful delivery GA at delivery (weeks) Foetal status Anti-myeloma treatment during pregnancy Delivery mode Anti-myeloma treatment postpartum Outcomes of the mother to the date of publication 1 1965 Giordano [ 3 ] Portugal 40 Bone pain N Pregnancy Second trimester N Y 38 Newborn died 20 days after delivery CTX n.a. Y n.a. 2 1966 Kosova [ 5 ] America 35 Back pain Similar pain experienced 6 months earlier Pre-pregnancy Exacerbated pain at 6 weeks gestation Y Y Term Healthy Y Vaginal CTX Died of PD 3 1968 Rosner [ 6 ] America 42 Headaches and a lump on the forehead N Pre-pregnancy - Y Y Term Healthy N n.a. MP Died of PD 4 1971 Talerman [ 7 ] Jamaica 39 n.a. Sickle cell anaemia Pregnancy Third trimester N Y 35 Healthy N n.a. n.a. Died of PD 5 1974 Lergier [ 8 ] America 21 Bone pain N Pre-pregnancy - MP, CTX Y Term Healthy CTX at 50 mg on alternate days C-section CTX, MP Alive 6 1987 Harster [ 9 ] America 29 Hypercalcaemia N Postpartum - N Y n.a. Healthy N n.a. Y Died of PD 7 1987 Harster [ 9 ] America 30 Bone pain N Postpartum - N Y n.a. Healthy N n.a. Y Alive 8 1990 Michael[ 10 ] America 32 Anaemia Anaemia Postpartum 20 N Y 38 Healthy N n.a. MP Alive 9 2017 Rehman[ 11 ] India 32 Body ache N Pregnancy 8 N Medical termination - - N n.a. Td Alive 10 1991 Pajor [ 12 ] America 27 Anaemia N Pregnancy Second trimester N Y 39 Healthy N n.a. VMP Alive 11 1995 Hideyuld [ 13 ] America 41 Anaemia N Pre-pregnancy - VAd Y 38 Healthy IFN-α in the first trimester n.a. n.a. Alive 12 2003 Maglione [ 14 ] Italy 34 Signs of spontaneous abortion N Pregnancy 6 N Y 34 Healthy N C-section MPT, ASCT Alive 13 2004 Forthman [ 15 ] America 41 Back, right arm and pelvic pain N Pregnancy 28 N Y 34 Healthy Dexamethasone C-section Dexamethasone, radiotherapy, melphalan, ASCT Alive 14 2007 Lee [ 16 ] Britain 32 Nausea, vomiting, weight loss, back pain, and lumps on the forehead and right side Diagnosed as MGUS at age 25 Presentation appeared quickly during postpartum and worsened 3 months later during postpartum - N Y n.a. Healthy N n.a. VAd Dead 15 2006 Malik [ 17 ] Britain 34 Severe vomiting, light-headedness and lethargy N Pregnancy 15 N N Termination at 19 weeks gestation - N n.a. PAd, radiotherapy, CTd Alive 16 2008 Zun [ 18 ] Korea 32 Back pain N Pregnancy 31 N Y 32 Healthy N C-section VAd, VTd Alive 17 2010 Dabrowska [ 19 ] Britain 42 Proteinuria and anaemia Pregnancy with preeclampsia and intrauterine FGR Pregnancy 28 N Y 35 Healthy N C-section Chemotherapy, ASCT Alive 18 2010 Willmott [ 20 ] Britain 33 Right hip pain, anaemia and thrombocytopenia Polycystic ovaries, endometriosis and hypothyroidism Pregnancy 15 N Y 33 Healthy Dexamethasone at 20 mg on days 1–4, enoxaparin at 40 mg daily C-section CTd, ASCT Alive 19 2011 Avilés [ 21 ] America 32 Bone pain N Pregnancy Early pregnancy N Y 36 Healthy CMOP, MP n.a. n.a. Died of PD 20 2011 Avilés [ 21 ] America 37 Bone pain N Pregnancy Mid-pregnancy N Y 38 Healthy CMOP-D, MP n.a. n.a. Died of PD 21 2011 Avilés [ 21 ] America 24 Bone pain N Pregnancy Early pregnancy N Y 33 Healthy CMOP-I, MP n.a. ASCT Alive 22 2011 Avilés [ 21 ] America 35 Bone pain N Pregnancy Early pregnancy N Y 34 Healthy DAI, MP n.a. ASCT Alive 23 2011 Avilés [ 21 ] America 32 Anaemia and fractures N Pregnancy Late pregnancy N Y 39 Healthy CMOP n.a. ASCT Alive 24 2011 Avilés [ 21 ] America 39 Bone pain N Pregnancy Mid-pregnancy N Y 38 Healthy DAI n.a. n.a. Alive 25 2011 Kasenda [ 22 ] Germany 34 Back pain N Pregnancy 23 N Y 32 Healthy Prednisone at 50 mg every second day C-section VCd, ASCT Alive 26 2011 Borjade [ 23 ] France 33 Asymptomatic proteinuria N Pregnancy 12 N Y 34 Healthy N Vaginal VRd, ASCT Alive 27 2009 Quinn [ 24 ] Britain 39 Back pain and spinal cord compression N Pregnancy 32 N Y 32 Healthy Emergency C-section, spinal decompression surgery C-section Radiotherapy, ID, ESHAP, peripheral blood stem cell rescue, Vd Alive 28 2013 Brisou [ 25 ] France 26 Neuralgia N Pre-pregnancy - VAd, ASCT Y 37 Healthy n.a. C-section VCd, ASCT Alive 29 2013 Bouzguenda [ 26 ] Tunisia 39 Breast lumps N Pregnancy 26 N Y 34 Healthy Dexamethasone at 20 mg/m 2 daily on days 1–4 C-section Td, radiotherapy, ASCT Alive 30 2014 Smith [ 27 ] Britain 34 Proteinuria N Pregnancy 24 N Y 35 Healthy Dexamethasone at 20 mg daily on days 1–4 C-section Vd Alive 31 2014 Smith [ 27 ] Britain 38 Back pain N Pregnancy 32 N Y 32 Healthy N C-section CID, ESHAP, radiotherapy, ASCT, Vd, VRd Died of neutropenic sepsis 32 2014 Smith [ 27 ] Britain 33 Cytopenia, anaemia and hypercalcaemia N Pregnancy 14 N Y 33 Healthy Dexamethasone at 20 mg every two weeks C-section CTd, ASCT, VAd Alive 33 2014 McIntosh [ 28 ] America 22 Hypercalcaemic pancreatitis Anaemia Pregnancy 32 N Y 33 Healthy N C-section n.a. Alive 34 2016 Cabañas-Perianes [ 29 ] Spain 37 Anaemia N Pregnancy 27 N Y 34 Healthy N C-section VRd Alive 35 2014 Kho [ 30 ] Australia 30 Spontaneous abortion N Pre-pregnancy - VAd, ASCT Y Term Healthy N C-section Td Alive 36 2014 Khot [ 30 ] Australia 32 n.a. N Pregnancy 14 N N Termination at 14 weeks gestation - N - VAd, Cd, ASCT, Vd, VRd, VCd Alive 37 2016 Jurczyszyn [ 31 ] Poland and America 43 Pneumonia and hypercalcaemia N Pregnancy 28 N Y 30 Healthy High dose of methylprednisolone C-section VRd Alive 38 2016 Jurczyszyn [ 31 ] Poland and America 39 Back pain N Pregnancy 26 N Y 36 Healthy Dexamethasone at 40 mg on days 1–4 C-section Vd, ASCT, Pd Died of colorectal cancer 39 2016 Jurczyszyn [ 31 ] Poland and America 34 Mild cytopenia N Pre-pregnancy - N Y n.a. Healthy Y n.a. N Alive 40 2016 Jurczyszynr[ 31 ] Poland and America n.a. n.a. N Pregnancy First trimester N Y n.a. Healthy N n.a. Y Alive 41 2016 Jurczyszyn [ 31 ] Poland and America n.a. n.a. N Pregnancy - N Y n.a. Healthy N n.a. Y Alive 42 2018 Kim [ 32 ] Korea 34 Proteinuria and renal deterioration N Pregnancy 20 N N 24 Stillborn Y - VRd Died due to cardiac arrest 43 2021 Garg [ 33 ] India 29 Weakness and back pain Voluntary MTP Pre-pregnancy - VAd, Td Y 37 Healthy N Vaginal VCd, ASCT Alive 44 2021 Magen [ 34 ] Britain 40 Hypertension and acute kidney failure Previous gestational hypertension Pregnancy 25 N Y 36 Healthy CD, dexamethasone at 40 mg daily on days 1–4, CTX at 500 mg/m 2 weekly C-section VRd, ASCT Alive 45 2015 Meng [ 35 ] China 38 Pain N Pregnancy Second trimester N Y Term Healthy N C-section Y Alive 46 2024 Mullanfiroze [ 36 ] Britain 37 Thoracic pain and malignant spinal cord compression N Pregnancy 28 N Y 32 Healthy Methylprednisolone at 250 mg twice weekly C-section DVd, radiotherapy, ASCT Alive 47 2023 Elgabryd [ 37 ] Britain 35 Back pain N Pre-pregnancy Recurrence at 22 weeks gestation VCd/VTd, ASCT Y 40 Healthy N, but LMWHs Vaginal IRd, Isa-Pd, ASCT Alive 48 2022 Chory [ 38 ] America 43 Severe flank pain N Pregnancy 24 N Y 30 Healthy Steroid C-section Chemotherapy Alive 49 2014 Quigley[ 39 ] Britain 43 Dyspnoea Polycystic ovarian syndrome Pregnancy 16 N Y 35 Healthy Dexamethasone at 10 mg, tinzaparin Vaginal CTd, ASCT Alive 50 2022 Thuyle [ 40 ] France 40 Hypercalcaemia N Pregnancy 34 N Y 34 Healthy N C-section VRd, ASCT Alive 51 2024 Sanjeev[ 41 ] Spain 44 Back pain and fatigue MTP and spontaneous abortion Pre-pregnancy - VAd, Td Y 37 Healthy N Vaginal VRd, KPd, ASCT Alive 52 The current case, 2026 Lin China 37 Albuminuria and anaemia N Pregnancy 14 N Y 28 Healthy Plasma exchange and blood transfusion, CD, methylprednisolone at 40 mg daily on days 1–4, CTX at 500 mg/m 2 weekly C-section VRd, Vd, ASCT, DRd Alive Abbreviations : GA Gestational age, Y Yes, N No, n.a. Not available, C-section Caesarean section, ASCT Autologous stem cell transplantation, MTP Medical termination of pregnancy, PD Progression of disease, CD Cyclophosphamide+ dexamethasone; VRd=bortezomib+lenalidomide+dexamethasone, Vd bortezomib+dexamethasone, CTX Cyclophosphamide, CID Cyclophosphamide+idarubicin+dexamethasone, MP melphalan+prednisone, Pad bortezomib/velcade+ adriamycin+dexamethasone, VAd Vincristine+adriamycin+dexamethasone, MPT Melphalan+prednisone+thalidomide, VTd bortezomib+thalidomide+dexamethasone, Td Thalidomide+dexamethasone, CTd Cyclophosphamide+thalidomide+dexamethasone, VCd bortezomib+cyclophosphamide+dexamethasone, ID Idarubicin+dexamethasone, IRd Isatuximab+lenalidomide+dexamethasone, Isa-Pd Isatuximab+pomalidomide+dexamethasone, KPd carfilzomib+pomalidomide+dexamethasone, DVd Daratumumab+bortezomib+dexamethasone, VMP Vincristine+melphalan+methylprednisolone, ESHAP Etoposide+cisplatin+cytarabine+methylprednisolone, CMOP Cyclophosphamide+melphalan+vincristine+prednisone, CMOP-D CMOP + doxorubicine, CMOP-I CMOP + IFN, DAI Dexamethasone + all trans-retinoic acid + interferon, Pd Pomalidomide+dexamethasone, LMWHs Low-molecular-weight heparin

Discussion

MM during pregnancy is a relatively uncommon event, in addition to malignant lymphoma, Hodgkin’s disease and leukaemia; however, although it is rare, it exhibits clinical significance [42]. As women delay conception until achieving an advanced age, the number of MM cases associated with pregnancy has substantially increased over the past two decades. However, obstetricians often lack familiarity with the pathology, initial investigations, and management of MM. Moreover, current evidence is based on a non-pregnant population. This analysis encompassed almost all reported cases of MM associated with pregnancy (with the largest number of cases reported to date). This analysis can provide an alternative reference for clinicians in the absence of clinical trial data.

As a malignancy of plasma cells, MM is characterised by monoclonal Igs in the serum (M protein) and/or urine (Bence Jones protein), as well as BM plasmacytosis. The typical clinical features of MM include bone pain and pathologic fractures due to the infiltration of the BM with malignant plasma cells. Routine laboratory examinations often reveal anaemia, hypercalcaemia, proteinuria and renal dysfunction. The common symptoms of MM during pregnancy include bone pain (mostly involving the vertebrae, pelvis, ribs and long bones), as well as fatigue, which is usually caused by anaemia. More symptoms can arise, which are associated with extraosseous deposits and effects of the paraprotein on the ultimately affected organs [ 43 ]. The symptoms that are present during pregnancy are not significantly different from those that are present in the non-pregnant population. These symptoms can also be frequently observed in normal pregnancies or attributed to gestational complications. For pregnant women who present with obvious bone pain or protracted constitutional symptoms, in addition to unexplained anaemia, proteinuria, hypercalcaemia, and hyperglobulinaemia on routine tests, suspicion of MM should be maintained. Further investigations to confirm the diagnosis include serum protein electrophoresis, serum-free light chain assays, peripheral blood films, β2-microglobulin assays, whole-body MRI or MRI of the spine or pelvis, BM aspirate and biopsy, flow cytometry, and FISH analysis.

Due to the rarity and lack of guidelines regarding the condition, the management of MM during pregnancy is challenging. For asymptomatic patients, waiting and observation have been preferred approaches, as revealed by the current practices. Evaluation of the mother includes identification of symptoms, along with frequent physical examinations and laboratory tests (performed weekly or every 2 weeks). Foetal status must be monitored via regular ultrasound assessments. For symptomatic patients, prompt treatment is necessary. The use of chemotherapy has improved the survival of patients with MM but may exert detrimental effects on the foetus. The standard strategy for treating MM in the non-pregnant population involves induction via the combination of bortezomib, lenalidomide, and dexamethasone (VRd), followed by ASCT and maintenance therapy with either lenalidomide or bortezomib. However, thalidomide and lenalidomide may induce marked teratogenicity, and data on the safety of bortezomib are very scarce. Hence, prior to initiating treatment of MM during pregnancy, discussion by an MDT comprised of haematologists/oncologists, orthopaedists, anaesthetists, obstetricians and neonatologists is necessary, with the goal of preserving the mother’s health and protecting the foetus. The administration of chemotherapy should be avoided during the first trimester unless the progression of the disease affects maternal outcomes, due to the fact that organogenesis occurs during this time period, and the risk of foetal malformation is high. Second- and third-trimester exposure to chemotherapy is associated with intrauterine FGR, foetal death, preterm delivery, and low birth weight [ 44 ]. Based on observational data, the use of select chemotherapeutics during pregnancy in the second and third trimesters was not associated with an increased rate of congenital malformations or perinatal mortality [ 45 ]; however, the current data were derived from other haematological malignancies treated with similar drugs and not from MM. The risk is reduced when single-agent chemotherapy is used. Corticosteroids have been considered to be the safest treatment and have primarily been used as a monotherapy (including dexamethasone, which is the main preferred choice of treatment, as revealed by the literature review) in a temporal manner for individuals who wish to continue with pregnancy. Steroids are metabolised by the placental enzyme 11 beta-hydroxy steroid dehydrogenase type 2. Compared with dexamethasone and betamethasone, prednisolone and methylprednisolone are highly sensitive to this enzyme, and these drugs can be mostly metabolised by the placenta and exert fewer effects on the foetus [ 46 ]. Based on this scenario, we chose methylprednisolone in our case to treat a pregnant patient with myeloma. Combination regimens consisting of corticosteroids and one or more of the following drugs (CTX, melphalan, or vincristine) were also employed as a cytoreductive therapy, as reported in the literature review. Based on the reported cases, these chemotherapies did not seem to affect foetal development or survival [ 47 ]. Novel agents or immunotherapies have demonstrated promising efficacy in MM patients; however, no data on their use in treating MM during pregnancy are available. For individuals who required more intensive multiagent chemotherapy due to disease progression posing a threat to the mother’s safety, delivery or pregnancy termination was considered. Emergent and life-threatening events caused by MM include hypercalcaemia, acute kidney failure and severe infections. In our case, we decided to discontinue the pregnancy when increasing trends in serum calcium and creatinine levels were detected, in order to avoid the aforementioned adverse complications. Caesarean section was preferred because of either the absolute or potential occurrence of pathological fractures [ 48 ]. Once the baby was delivered, full-dose chemotherapy was administered in most cases.

Supportive therapy is also an indispensable approach in the management of MM during pregnancy. The mother must be encouraged to maintain good nutrient intake and remain hydrated. Calcium and vitamin D supplementation is recommended when serum calcium levels are normal. For pain control, NSAIDs and opioids can be safe to prescribe. Patients with severe symptomatic anaemia should be treated with transfusion or erythropoietin therapy. Pregnancy, high myeloma burden and chemotherapy may cause a hypercoagulable state, which subsequently contributes to placental thrombosis, FGR, and maternal thrombotic events. In accordance with the guidance of the Royal College of Obstetricians and Gynecologists (RCOG), an anti-thromboembolic regimen must be administered to high-risk pregnant women [ 49 ]. Hence, for women who are diagnosed during pregnancy and who need chemotherapy, thromboprophylaxis must be considered. Low-molecular-weight heparins (LMWHs) are recommended as a first-line treatment option. In our case, we used enoxaparin to prevent thrombotic events.

This patient was well managed and achieved a favourable outcome in our hospital. To date, at 2.5 years after the diagnosis, both the mother and her daughter are in good health. This was the first case that we encountered in our hospital. With respect to this case, we organised an MDT consisting of haematologists, orthopaedists, anaesthetists, obstetricians and neonatologists to thoroughly discuss the therapeutic strategies, with the goal of ensuring the safety of both the mother and foetus. We searched the relevant published literature and obtained meaningful knowledge about accessible practical experiences and prognosis, which was crucial in the decision-making process. The encouraging outcomes also provided the patient and her family with confidence in continuing the pregnancy and combatting the disease. This case demonstrates the merits of case reports, case series or reviews of similar cases, wherein pregnant women have been excluded from all major trials investigating different treatment regimens. However, several limitations should be acknowledged. This literature review represents a narrative synthesis rather than a formal systematic review. No comparisons were made for accessing different therapeutic approaches; therefore, no consensus could be obtained. Additionally, there were underreported negative outcomes because of publication bias favouring cases with good outcomes; thus, the actual mortality of MM in association with pregnancy is difficult to estimate. Moreover, the follow-up outcomes after the publication date are highly unknown; thus, it is not clear whether the disease or the selection of therapies during pregnancy has any effect on the later outcomes. To overcome these limitations, collaborative research recruiting all cases of MM in association with pregnancy with continuing follow-up is imperative to obtain the most up-to-date information about the epidemiology, therapeutic approaches, prognosis and outcomes. Furthermore, further research aimed at assessing the safety and efficacy of novel agents for treating MM during pregnancy is warranted.

Conclusion

Pregnant patients with MM exhibited a broad spectrum of manifestations. Clinicians should raise concerns and be aware of which investigations to request for a suspected diagnosis of MM. Prompt diagnosis in our patient ensured targeted monitoring, and an individualised strategy formulated by a multidisciplinary team allowed for acceptable maternal and foetal outcomes. Currently, multidisciplinary team work-up is preferable for management. The number of agents deemed to be safe for treating MM during pregnancy is fairly limited. Corticosteroids were observed to be the mainstay temporising treatment. Further research should focus on collaborative studies and be designed to assess novel therapies.

Abbreviations

Multiple myeloma

Bone marrow

Immunoglobulins

Hospital information system

International Myeloma Working Group

Hypercalcaemia, renal failure, anaemia, and bone lesions

Foreign Medical Retrieval System

China National Knowledge Infrastructure

Total protein

Globulin

Haemoglobin

Lactate dehydrogenase

Anti-nuclear

Extractable nuclear

Anti-neutrophil cytoplasmic

Non-invasive prenatal testing

Chromosomal microarray analysis

Lambda light chain

Kappa light chain

Fluorescence in situ hybridisation

Idiopathic growth hormone

Multidisciplinary team

Gestational age

Magnetic resonance imaging

T1-weighted imaging

T2-weighted imaging

Fat suppression

Foetal growth restriction

Pulsatility index

Resistive index

Umbilical artery

Middle cerebral artery

Neonatal intensive care unit

Very good partial response

Autologous stem cell transplantation

Monoclonal gammopathy of undetermined significance

Light chain deposition disease

Non-steroidal anti-inflammatory drugs

Royal College of Obstetricians and Gynecologists

Low-molecular-weight heparins

Cyclophosphamide+dexamethasone

Bortezomib+lenalidomide+dexamethasone

Bortezomib+dexamethasone

Cyclophosphamide

Melphalan+prednisone

Vincristine+adriamycin+dexamethasone

Melphalan+prednisone+thalidomide

Bortezomib+thalidomide+dexamethasone

Thalidomide+dexamethasone

Cyclophosphamide+thalidomide+dexamethasone

Bortezomib+cyclophosphamide+dexamethasone

Ixazolimib+lenalidomide+dexamethasone

Isatuximab+pomalidomide+dexamethasone

Carfilzomib+pomalidomide+dexamethasone

Daratumumab+bortezomib+dexamethasone

Vincristine+melphalan+methylprednisolone

Etoposide+cisplatin+cytarabine+methylprednisolone

Cyclophosphamide+melphalan+vincristine+prednisone

CMOP+doxorubicine

CMOP + IFN

Dexamethasone + all trans-retinoic acid+interferon

Pomalidomide+dexamethasone

Publisher’s note

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

Authors’ contributions

LXB performed the literature review and wrote the first draft of the manuscript. HXL contributed to the literature review, verified the data and wrote the subsequent drafts. LQW performed the data collection and analysis of the case. CWW conceived the concept of the study and edited the manuscript. ZY designed the study and supervised the process.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Data availability

The datasets generated during the current study are presented in the manuscript. More detailed data are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Institutional Ethical Committee of the Zhangzhou Hospital (no. 2025LWB667). Written informed consent was obtained from the patient.

Consent for publication

Consent for publication was obtained from the patient, and all of the authors approved the publication of the manuscript.

Competing interests

The authors declare no competing interests.

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