Each year, more and more multiple myeloma patients must consider an issue which, in years past, was not even viewed as relevant to people with myeloma.

That issue is pregnancy.

It is true that the co-occurrence of multiple myeloma and pregnancy re­mains relatively rare, given that myeloma typically affects older in­di­vid­u­als.  The median age at myeloma diagnosis is 69 years, and only 4 percent of my­e­lo­ma cases occur in in­di­vid­u­als younger than 45 years.

Likewise, only about 30 cases of pregnancy in women with myeloma have been reported in the medical literature so far.

Yet a number of factors are making pregnancy an increasingly relevant issue among myeloma patients.

Women in the United States and elsewhere are delaying their first pregnancies until they are older.  In addi­tion, myeloma patients are living longer, and survival among myeloma patients is typically the longest among those diagnosed when they are young.

As a result, pregnancy and multiple myeloma as a single topic is receiving increasing attention in the medical literature.  Several articles on the subject have appeared in medical journals in just the last six months.

Thus, it seems an appropriate time to review what is known – and not known – about multiple myeloma and pregnancy.  The literature on the subject is still limited, and there are no consensus recommendations or clinical trial findings that patients can turn to.

There is, however, evidence that should be helpful to the increasing number of myeloma patients with questions about their disease and pregnancy.

Pregnancy After Chemotherapy And Myeloma Remission

In a recent report ^[1], French researchers described a case in which a 38 year-old woman with multiple my­e­lo­ma became pregnant 10 years after she achieved remission through intensive chemotherapy.

During initial diagnosis and disease relapse, the patient received treatment with a number of che­mo­ther­a­peutic agents including high-dose cyclophosphamide ^[2] (Cytoxan) and high-dose melphalan ^[3] (Alkeran). She also underwent two autologous (own) stem cell transplants.

Based on this case, and a number of cases reported for other blood cancers such as leukemia and lymphoma, the French researchers note that fertility may be preserved even in women who receive high-dose chemotherapy and more than one stem cell transplant.

In general, chemotherapy is associated with reduced function of reproductive organs and lower fertility. For instance, a recent German study ^[4] showed that women at least 30 years of age were particularly susceptible to changes in menstrual activity upon chemotherapy for Hodgkin lymphoma.  Women below 30 years of age and those with early stage disease were more likely to retain menstrual activity.

Male fertility, on the other hand, did not appear to be affected by chemotherapy for Hodgkin lymphoma.

In 2011, the Center for International Bone and Marrow Transplant Research reported a large case series ^[5] of pregnancies that occurred after autologous and donor stem cell transplantation. The researchers analyzed 83 pregnancies in female stem cell transplant recipients and 95 pregnancies in female partners of male recipients, reported to the center between 2002 and 2007. (Note that only 1 of the 178 patients underwent stem cell transplantation for myeloma.)

According to this report, fertility was most frequently preserved in recipients who were young adults (15 years to 30 years) at the time of stem cell transplantation. Most patients who maintained fertility had not received total body irradiation.

The majority of pregnancies occurred between five years and ten years after stem cell transplantation, but a few occurred within the first year after transplantation.

The results also show that chronic graft-versus-host disease, high doses of total body irradiation, and high doses of cyclophosphamide do not always impair fertility.

One approach that can be used to preserve fertility in female myeloma patients is embryo cryopreservation. In this method, eggs are harvested from the myeloma patient prior to chemotherapy. These eggs are fertilized under laboratory conditions (by a technique called in vitro fertilization or IVF), and embryos that are between five days and six days old are stored at sub-zero temperatures.

Cryopreserved embryos can subsequently be thawed and implanted, once the patient achieves remission and is ready for pregnancy. It is currently believed that embryos can remain viable in this frozen state for up to 10 years. Embryo cryopreservation offers myeloma patients an opportunity to store healthy embryos without damage from chemotherapeutic agents.

Women who do not have a partner can freeze unfertilized eggs. However, this technology is relatively new and has a lower success rate than embryo cryopreservation.

Cryopreservation of semen is currently thought to be the best method of fertility preservation for men.

Myeloma Diagnosis And Treatment During Pregnancy

British researchers recently reported several important observations from three cases ^[6] in which myeloma was diagnosed during pregnancy.

First, the myeloma symptoms seen in pregnant women are similar to those observed in patients who are not pregnant.

Most of the regular tests for myeloma diagnosis can be performed in pregnant women, except the skeletal survey, which is a series of X-rays of all bones in the body. The researchers state that skeletal surveys should not be used for pregnant women, in order to avoid exposing the fetus to X-rays.

Findings from a 2011 French review ^[7] show that myeloma is most frequently detected in the third trimester of pregnancy. The investigators suggest that both the non-specific nature of myeloma symptoms (bone pain and anemia) and the rare occurrence of myeloma in younger individuals make it unlikely that medical teams would initially consider this diagnosis.

The cases in the British report support previous findings that pregnancy in women with myeloma generally results in a healthy newborn. A majority of cases of myeloma presenting during pregnancy, though, were associated with delivery by caesarean section, often due to concerns regarding bone disease and pelvis stability.

Based on treatment outcomes of the three British patients and previously published data on the side effects of various myeloma drugs, the British researchers made the following recommendation:

They suggest that myeloma diagnosed during pregnancy be managed with steroids until delivery, at which point induction therapy with novel agents can commence. However, the researchers caution that a different approach may be required if the disease stage is more advanced during diagnosis or if the disease symptoms constitute an emergency.

These researchers and others have noted that chemotherapy is considered particularly risky during the first trimester of pregnancy, when vital organs of the fetus are initially developing.

Recent studies have supported, however, the possibility of administering chemotherapy during the second and third trimesters without damage to the developing fetus.

If an aggressive form of myeloma, for instance with damage to multiple organs, necessitates chemotherapy during the first trimester, researchers note that pregnancy termination should be discussed with the patient to allow for optimal treatment.

Thalidomide ^[8] (Thalomid), Revlimid ^[9] (lenalidomide), and Pomalyst ^[10] (pomalidomide, Imnovid) are structurally related myeloma drugs.  Exposure to thalidomide in utero can cause severe birth defects or death.  Therefore, none of these drugs are prescribed during pregnancy.

Thalidomide can also be transmitted from mother to infant through breast milk. It is not known whether Revlimid and Pomalyst are also secreted in human breast milk. Therefore, these drugs are not prescribed for nursing mothers.

The effects of Velcade ^[11] (bortezomib) on fetal development are not clear, since there have been no clinical studies on this subject. While some animal studies suggest that Velcade may not affect fetal development, the subject still remains controversial. For this reason, the British researchers recommend that Velcade should not be prescribed during pregnancy. The French researchers, on the other hand, suggest that Velcade-based treatment could be considered during the second and third trimesters for aggressive or refractory forms of myeloma.

Cyclophosphamide ^[2] (Cytoxan), which works by slowing or stopping cancer cell growth, is also thought to be potentially harmful to the developing fetus. The British researchers recommend that it should not be used during the first trimester. They note that the use of cyclophosphamide during the second and third trimesters is controversial, with some studies suggesting that it may be safe and others suggesting that it may retard growth of the fetus and cause fetal death.

Steroids, such as dexamethasone ^[12] (Decadron) and prednisone ^[13], are considered to be safe during pregnancy. Steroids reduce immune function, in general, and are associated with side effects including maternal weight gain and high blood sugar. However, the British researchers note that the benefits of steroid treatment outweigh the risks when treating pregnant women with myeloma.

Bisphosphonates are a class of drugs that prevent the breakdown of bone. Myeloma patients may receive bisphosphonates to decrease bone pain and prevent the development of bone fractures. Studies have shown that bisphosphonates can be used safely during pregnancy, without any effects on the developing fetus. Zometa ^[14] (zoledronic acid) and Aredia ^[15] (pamidronate) are the two bisphosphonates commonly used in multiple myeloma.

In a 2011 study ^[16], Mexican researchers reported six cases of myeloma patients who received chemotherapy during pregnancy. In five of these cases, the patients began chemotherapy for myeloma because pregnancy was not suspected at that point.  In one case, the patient was diagnosed with myeloma and pregnancy at the same time, but had aggressive disease (with severe anemia, kidney disease, and fractures) that prompted physicians to begin chemotherapy. Three patients received chemotherapy during the first trimester.

Four of the six patients received a regimen that included cyclophosphamide, melphalan, vincristine ^[17] (Oncovin), and prednisone, while two others received dexamethasone, tretinoin (all-trans retinoic acid, Vesanoid), and interferon.

All six newborn infants were healthy, with no defects seen at the time of birth. All children had normal physical, neurological, and psychological development throughout follow up, with an average follow-up period of 10 years and a maximum follow-up period of 19 years.

The researchers note that, in this limited number of cases, induction therapy with chemotherapeutic agents did not affect fetal development and survival.

Pregnancy And Myeloma Progression

Whether pregnancy can contribute to myeloma progression remains controversial.

Certain changes in the mother's body that occur during pregnancy are also typically believed to affect myeloma progression.

For instance, levels of certain proteins in the body – such as interleukin-6, insulin-like growth factor 1, and vascular endothelial growth factor – are elevated during pregnancy.  These proteins are known to promote the growth and survival of myeloma cells in the bone marrow.

In addition, perturbations in immune responses mounted by white blood cells called T helper cells occur during both pregnancy and myeloma.

These findings have led researchers to speculate that pregnancy may create a suitable environment for myeloma progression.

However, a French analysis of 27 cases of myeloma in pregnant women showed that pregnancy did not have an adverse effect on myeloma progression in these women.

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For readers interested in researching further on their own the issue of multiple myeloma and pregnancy, The Beacon has composed a list of potentially useful journal articles (see below).   There also are a number of postings ^[18] on the subject of pregnancy and myeloma in the Beacon's discussion forum.

Recent Publications Regarding Multiple Myeloma And Pregnancy

Smith et al, “Myeloma presenting during pregnancy ^[6],” Hematological Oncology, September 2013 (purchase required).

Brisou et al, “Pregnancy and multiple myeloma are not antinomic ^[1],” Leukemia & Lymphoma, April 2013 (purchase required).

Behringer et al, “Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials ^[4],” Journal of Clinical Oncology, January 2013 (abstract).

Brenner et al, “Haematological cancers in pregnancy ^[19],” The Lancet, February 2012 (abstract).

Borja de Mozota et al, “Multiple myeloma and pregnancy: a case report and literature review ^[7],” Archives of Gynecology and Obstetrics, October 2011 (abstract).

Kasenda et al, “Management of Multiple Myeloma in Pregnancy: Strategies for a Rare Challenge ^[20],” Clinical Lymphoma Myeloma and Leukemia, April 2011 (abstract).

Loren et al, “Pregnancy after Hematopoietic Cell Transplantation: A Report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR) ^[5],” Biology of Blood and Marrow Transplantation, February 2011 (full text).

Avilés and Neri, “Multiple myeloma and pregnancy ^[16],” American Journal of Hematology, January 2011 (purchase required).

Rizack et al, “Management of hematological malignancies during pregnancy ^[21],” American Journal of Hematology, December 2009 (abstract).