Pregnancy has been reported in patients with hematological malignancies, such as acute leukemia, Hodgkin and malignant lymphoma and chronic myelocytic leukemia. Only 12 cases of pregnancy occurring in patients with multiple myeloma (MM) have been reported. The present report describes 6 additional cases of this rare association that received chemotherapy during pregnancy, including in the first trimester. The newborns were 3 male and 3 female with weight >2500 g and without evidence of fetal malformations. Longer follow-up (>3 years) did not give evidence of late complications in the children. Three mothers received stem cell transplantation.
Multiple myeloma (MM) is a malignant disease characterized by an abnormal proliferation of plasma cells, with a mean age at time of diagnosis of 62 years (1, 2). It is a disease affecting elderly people, more often men between 50 to 70 years. Thus the presence of pregnancy during MM is very rare; until now, only 13 cases of this association have been reported (2–16). Most of these were reported as single cases, without longer follow-up of mother and newborn; thus, adequate treatment has not been defined and the effect of pregnancy on the disease process has remained unknown until now.
Between 1992 and 2006, we diagnosed and treated 6 cases of MM associated with pregnancy, In this report we describe the specific treatment given during pregnancy, and the longer follow-up results and compare our cases with the patients reported in the literature.
In five cases MM was diagnosed before pregnancy, and because all were symptomatic of myeloma, we began treatment with different therapeutic schedules according to the time of diagnosis. Interferon is not considered useful in the treatment of MM, but when case 3 was diagnosed, this drug was common in therapeutic decisions. The combination of interferon and all trans retinoic acid is not common in MM either, but between 1998 to 2005 this combination was the first line of treatment in our Institution with good results (17). One case was diagnosed concomitant with the pregnancy, but she had an aggressive disease with severe anemia, renal insufficiency, fracture of the femur and vertebral collapse, thus the decision was to start treatment. Taking into consideration that all patients had bone lesions in different body parts, a cesarean was performed in all patients for delivery. Chemotherapy was stopped 3 to 4 weeks before the delivery to avoid presence of hematological toxicity in the newborn.
During pregnancy, an expert gynecologist followed the mothers and they received nutrimental support.
All newborns were carefully examined for any congenital abnormalities, and laboratory tests were performed: complete blood and platelets counts, careful review of blood smears, serum chemistry, determinations of immunoglobulin (and if they showed any abnormalities: we performed protein electrophoresis), and cytogenetic studies (18, 19). The children were reviewed every three months for the first two years, every 6 months for the following 5 years, and every year until the last follow-up (December 2008) or when they were >21 years old. If they presented clinical indications, additional studies were performed. Laboratory tests were performed at each medical evaluation. At 3, 6 and 12 years psychological and neurological evaluation were performed. Academic progress was monitored by an medical assistant and the corresponding teachers.
The study was begun in 1988 (HO-88-010) to evaluate cancer and pregnancy, including long term follow-up. Parents gave their informed consent to participate in the study and also the studies in the children when corresponding children were <7 years of age and assenting to participate in the analysis.
Table I shows the main clinical characteristics of pregnancy and MM, including the present 6 cases. Different schedules of chemotherapy were administered according to the time of diagnosis. Cases 3, 4 and 6 after chemotherapy achieve complete remission and were allocated to received autologous stem cell transplant (ASCT), 6 to 9 months after delivery. All are alive and completing responding 7, 7 and 2 years after pregnancy. Case 4 died early with active MM. Cases 1 and 2 were treated with different chemotherapeutic combinations, case 1 achieved complete remission, and case 2 achieved partial remission, but they showed progression disease and died 4 and 6 years after pregnancy, respectively.
|Ref||Age (years)||Trimester at diagnosis||Treatment during pregnancy (trimester of pregnancy)||Delivery (week/weight)||Current status Mother/Newborn|
|3||40||2°||Cy, 800 mg (total dose) (1°)||(38/3000)||NA||alive, 3 months|
|4||35||1°||RT, 1.5 G, lumbar spine Urethane, 2 g/day (1°)||(38/3100)||dead, 3 months||NA|
|5||42||1°||Urethane, 2 g/day, 1 month (1°)||(38/NA) (1°)||dead, 6 months||alive, 6 months|
|7||21||2°||Cy, 50 mg/day, until delivery||(39/2523)||alive 3 months||alive, 3 months|
|8||32||3°||None||(38/3000)||alive 2 months||alive 2 months|
|9||33||2°||None||(36/NA)||alive 2 months||alive 2 months|
|10||41||1°||IFN, 3.0 MU, three times a week for 2 months (1°)||(38/NA)||alive (?)||NA|
|11||34||1°||None||(38/3000)||alive (?)||alive (?)|
|12||41||3°||None||(32/2270)||alive 2 months||NA|
|14||39||3°||None||(32/NA)||alive 1 month||NA|
|32||1°||CMOP (6) MP (2)||(36/2900)||dead (6a)||alive 19a|
|37||2°||CMOP-D (3) MP (3)||(38/3100)||dead (4a)||alive 15a|
|24||1°||CMOP-I (3) MP (5)||(33/2850)||alive 10a||alive 10a|
|35||1°||DAI (6), MP (5)||(34/2500)||alive (7a)||alive 10a|
|39||2°||DAI (6)||(38/2750)||alive (5a)||alive 5a|
|32||3°||CMOP (6)||(39/3050)||alive (4a)||alive 4a|
At delivery, all newborns showed an Apgare score >9, weight was normal, according to the specific week of pregnancy; and in all cases, no congenital abnormalities were observed, and all laboratory tests were negative. During the follow-up the physical, neurological and psychological development of newborns were considered normal. All were alive, without any evidence of any cancer. The placenta was examined in cases 2–6, in all cases without evidence of infiltration.
Pregnancy in the presence of MM occurs rarely, only 15 cases have been reported in the world literature. Haster reported two additional cases diagnosed after delivery (15). In reviewing the literature we found that 7 cases were diagnosed during second and third trimester of pregnancy and 4 during the first trimester. In most cases the use of chemotherapy was considered dangerous to the fetus and they did not receive any specific therapy. Two patients received urethane and interferon during the first trimester; but this was stopped when pregnancy was confirmed. One mother received radiotherapy 1.5 G to the lumbar area and urethane 2 g/day during the first 3 months of pregnancy. Two mothers received cyclophosphamide during the second and third trimester. In the present cases, five were diagnosed during the first and second trimester, when treatment for MM as already underway, because the pregnancy had not been suspected. Taking into consideration that chemotherapy was given during early pregnancy we considered the possibility of fetal damage, but careful evaluation did not show any evidence of fetal damage, Thus, according to the parents wishes we decided to continue the same treatment, (moreover three patients were candidates to SCT). (Table I).
The newborns reported in the present paper and literature review were normal, no congenital abnormalities were observed and five children were noted alive 2 to 6 years after birth, but 7 children were not mentioned in any follow-up. One child showed an elevation of gamma-globulin, but it disappeared at 6 months; further studies were not mentioned. Although children were exposed to chemotherapy in utero, including in two cases all trans retinoic acid, all were normal with and remain no evidence of any physical or psychological alteration, with normal physical development and scholar degree appropriate to their ages. Based in this small number of cases, it appears that the use of chemotherapy regimens that were employed as cytoreductive therapy before ASCT did not affect the fetal development and survival.