#30714: Multiple Myeloma

Of the five immunoglobulin isotypes found in mammals, the most common is IgG, which comprises 75% of Ig in blood [6]. IgG is detected in blood and tissues and is the antibody responsible for fetal and infant immunity during the time before an infant develops its own immunity [31,32].

IgA is the second most common Ig and is formed as a dimer, a more complicated structure. In general, IgA is found in the mucous membranes in the mouth, saliva, tears, nose, digestive tract, and lungs. It provides defense against micro-organisms by preventing antigens from attaching to epithelial cell surfaces [31,32].

The third most common antibody is IgM. IgM is a huge structure compared to the other isotypes, as it is formed as a pentamer of five molecules joined together. This isotype is detected in the blood [31,32]. IgM (rarely myeloma) is typically associated with Waldenström macroglobulemia [6].

IgG and IgM are the only immunoglobulins able to fix complement. Complement is a series of approximately twenty proteins able to complete opsonization, which consists of coating antigens for recognition and providing binding sites for phagocytes. A first encounter with an antigen produces an immediate primary response. If there has been a recent exposure to sepsis, high levels of antibodies will be detected. Secondary antibody response occurs when previously encountered antigens are re-encountered.

IgE is released in reaction specific to a particular antigen. When an allergen is encountered, IgE has primed both basophils and mast cells to release histamine in blood. Atopic individuals have increased IgE levels. This type of antibody may also be released in cases of parasitic infestation.

The final antibody is IgD, which is detected in the blood. The function of IgD has recently begun to be elucidated [33,34]. Mature B cells undergo alternative mRNA splicing to express IgD and IgM receptors with identical antigenic specificity. Studies have shown that IgD helps the peripheral accumulation of physiologically autoreactive B cells through its functional unresponsiveness to self-antigens and prompts readiness against foreign antigens. Other studies have clarified how and why certain mucosal B cells become plasmablasts or plasma cells that specialize in IgD secretion. Secreted IgD enters the circulation to "arm" basophils and mast cells with IgD antibodies that are reactive against mucosal antigens and to stimulate the release of immunoactivating, proinflammatory, and antimicrobial mediators [33,34].

Bone homeostasis under the normal physiologic process is achieved when there is a balance between bone resorption and bone formation. The cells responsible for remodeling (i.e., osteoblasts, osteocytes, and osteoclasts) participate in three phases of bone homeostasis:

Resorption

As noted, osteoclasts are the bone cells responsible for resorption or removing fatigued mineralized bone to prepare the bone surfaces for osteoblasts to lay down new bone matrix. Osteoclasts originate from hematopoietic stem cells, specifically the monocyte/macrophage lineage. In order to differentiate and become activated, cytokines produced by bone marrow stromal cells and by osteoblasts produce macrophage colony-stimulating factor (M-CSF). Osteoclasts express receptor activator of nuclear factor kappa B (RANK) on their surface; its ligand, RANKL, is expressed on marrow stromal cells and osteoblasts. When RANK and RANKL interact, promoting the differentiation of osteoclasts, the resorption process begins.

Osteoclasts have a life expectancy of three to four weeks. They are large, multi-nucleated cells found on the surface of cortical bones, forming Howship lacunae, or tunneling into trabecular bone, forming Haversian canals. Osteoclasts adhere firmly to bone surface engulfed in a membrane that seals off the area, over a "ruffled border," and begin resorption. Osteoclasts can remove only a limited area of mineral and matrix before the next step, the reversal process, begins. How osteoclasts receive the signal to halt the process is unknown; the possibility that elevated calcium triggers this halt has been suggested, or the matrix itself may secrete a substance. One very important established factor in this process is the osteoprotegerin (OPG) decoy receptor. Osteoprotegerin prohibits RANK/RANKL binding, preventing osteoclast development. Therefore, OPG and RANKL regulate how much bone is broken down, maintaining a necessary balance [35,36,38,39,40,41].

Reversal

With the completion of bone resorption, mononuclear cells, presumed to be monocyte/macrophages located on the bone surface, lay down material on which the osteoblasts will adhere. It is possible that osteopontin may play a major role here; there is still much research underway in this area [42,43,44,45].

Formation

The third and final phase of the growth of new bone occurs during formation. Osteoblasts, the major component of formation, arise from pluripotent stem cells, which differentiate into fibrous tissue, adipocytes, cartilage, or muscle. The periosteum and marrow stromal cells have osteoblast progenitor cells; these cells are committed to differentiate into osteoblasts and are instrumental in acting as receptors for bone growth factors and remodeling. In a slow process over time, the bone matrix fibers introduced by the osteoblasts strengthen and completely fill in the area cleared away by osteoclasts. Flattened lining cells then cover this new area, and a resting phase ensues until the cycle repeats itself.

Bone Maintenance

Calcium stored within bone promotes calcium homeostasis. Decreased serum calcium prompts a signal to the parathyroid hormone to allow the release of calcium from bone, which results in an increase in the level in blood. Conversely, with an elevated serum calcium, the thyroid releases calcitonin to counteract the effects of the parathyroid and promote the storage of calcium within bone. Parathyroid hormone, in its role as calcium regulator, is essential to promote absorption of calcium from the gastrointestinal tract and maintain the balance within the kidneys [36,41]. This becomes disrupted in patients with hypercalcemia.

Bone and bone marrow, while having very distinct functions, also work interdependently. Along with the process of skeletal changes, bone marrow undergoes its own changes. The hematopoietic (red) marrow of infancy is replaced gradually by yellow or fatty marrow. For every 10 years of life, the cellularity of marrow decreases by approximately 10%. In adults, red marrow is found in the sternum, ileum, ribs, and vertebra [35].

The destruction of bone caused by the invasion of plasma cells produces a multitude of problems. In MM, homeostasis is lost or uncoupled, and this results in destroyed bone, with osteolytic lesions leading to fractures, pain, and the release of calcium into the circulation, perpetuating renal insufficiency and hypercalcemia. The pathology of bone destruction in those with MM begins by MM cells expressing RANKL, prompting osteoclasts to resorb bone. MM cells then secrete macrophage inflammatory protein 1α (MIP 1α), which stimulates osteoclast formation. A gene (dickkopf1) and protein (DKK1) are expressed, inhibiting osteoblasts. Vascular endothelial growth factor (VEGF) mimics M-CSF to help in the differentiation of osteoclasts, thereby increasing resorption. MM cells are in close proximity to marrow stromal cells, which induces release of cytokine IL-6. IL-6 promotes MM cell survival, either by promoting growth or blocking apoptosis. Finally, bone matrix is destroyed, releasing IL-6 and promoting MM cloning. Plasma cells release PTH-related protein, which increases bone resorption [19,35,36,41,46].

Advances in technology (e.g., high-throughput sequencing) and the associated shift toward precision medicine in oncology have revolutionized the diagnosis and treatment of MM in the last decade. Modern diagnostic workups are incomplete without cytogenetic testing, including interphase fluorescence in situ hybridization (FISH) in purified plasma cells or in combination with immunofluorescent detection of light-chain-restricted plasma cells (cIg-FISH) [29,51,52]. Standard cytogenetic testing uses samples grown in the lab from bone marrow (or blood) plasma cells, a process that takes weeks [53]. FISH testing uses the actual biopsied plasma cells and fluorescent dyes that attach to specific areas of particular chromosomes to identify abnormalities, and the results are available within one or two days.

In respect to MM, there are several specific gene mutations that can help to predict a patient's prognosis and response to a particular type of therapy. Cytogenetic irregularities seen in MM are of two main types: immunoglobulin heavy-chain (IgH) translocations and genomic imbalances (i.e., chromosomal gains and losses) (Table 1)[52,53]. IgH translocations are found in approximately 40% of MM cases, but abnormal cytogenetic findings are not necessarily indicative of poor prognosis. In fact, a t(11;14) translocation is associated with a positive or neutral prognosis [52,53].

Monosomy 13/13q deletions are found in 50% of malignancies [54,55,56]. Although these are linked with short survival (even with chemotherapy), 80% of patients with monosomy 13 also have t(4;14), another strong factor for poor outcome. Armed with data from clinical trials that show patients with the t(4;14) translocation have more favorable outcomes when treated with proteasome inhibitors, clinicians can now make better informed treatment decisions for this cohort [57,58]. Rare chromosomal deletions (e.g., 17p deletions) are associated with extremely poor prognoses; mean survival after diagnosis is four months [59].

Other genetic tests used in research or clinical trial settings include comparative genomic hybridization, mapping arrays based on single nucleotide polymorphisms, and gene expression profiling. However, these tests are typically unavailable in clinical settings due to technologic limitations [51]. Although the molecular markers currently lack validation, these whole-genome techniques are expected to become an important feature of diagnosis and treatment in the near future.

Bone marrow aspiration and biopsy are performed for diagnostic purposes. They are initially performed as part of the plasma cell dyscrasia workup and then periodically to monitor the response to treatment and disease progression [6]. Investing time in preparing the patient for bone marrow aspiration and biopsy and obtaining a good specimen with the first endeavor is time well spent. A signed informed consent form must be obtained, and patients should be prepared for the procedure, including the fact that they will be positioned on their stomachs.

Red marrow is the target for biopsy. Realizing that the marrow will have decreased by approximately 50% in adults, with the remainder being adipose tissue, there is little to be gained from sampling marrow from various sites for comparison [21,60]. The iliac crest is usually selected for the aspiration and biopsy and is reportedly the least uncomfortable from all the sites [21,60]. The posterior iliac crest is the preferred site; the anterior iliac crest is an alternative if the patient is unable to lie prone or is obese [21,60]. In patients with MM, the sternum is never the optimum site for the bone marrow aspiration because the bones are too fragile and the procedure would present a heightened risk of perforating the sternum and damaging the underlying organs.

Prior to the procedure, the lab will have been notified in order to have a technician available at the bedside. The technician will set up the slides for the marrow smears, as the aspirate and biopsy specimens clot quickly. The screening of the marrow will include cellularity, morphology, maturation, cytogenetic testing, immunophenotyping, and molecular analysis [21,60].

Approximately 10 to 15 minutes prior to the bone marrow biopsy, the patient will be administered an analgesic and possibly an anxiolytic. A nail imprint or indentation with a pen (no ink) will mark the area selected. The area is cleansed, draped, and numbed with local anesthetic, and the bone marrow biopsy is performed. The patient may experience pain when the needle penetrates the periosteum and cortical bone; a more intense discomfort occurs when the marrow is aspirated [60].

A pressure dressing will be applied to the bone marrow site, and the patient will be instructed to lie on their back (a rolled up towel works well to reinforce pressure) for at least one hour. Periodic checks to assess for any bleeding, ensuring the site remains dry and the dressing intact, for 48 hours will help to reduce the risk of infection [21,60].

Glucocorticoids act in several ways. They reduce inflammation by inhibiting cytokines and suppress the action of immune system. This prevents white blood cells (WBCs) from migrating to a site of infection, in turn reducing swelling and pain and increasing circulation to the area. The agents also potentiate the effects of chemotherapy and immunomodulators.

Patients taking glucocorticoids should be monitored closely, as the drugs may mask underlying infections. They also decrease the body's ability to fight infection, as WBCs remain in the circulation rather than at the site of inflammation.

Unfortunately, the side effects associated with glucocorticoids can negatively influence patients' quality of life. As with any medication, responses differ; some patients tolerate steroids well, while others find the side effects intolerable. The longer the period patients remain on the steroids, the more pronounced the side effects become. Possible side effects associated with glucocorticoids include [22]:

When patients are educated regarding their medications and possible side effects and have an awareness of what to expect, this invariably guides their attitude and willingness to comply with their treatment. Patients should be encouraged to take steroids after a meal or with food to reduce the risk of gastric irritation; steroids should never be ingested on an empty stomach. Taking the medication as early as possible in the day may help to relieve feelings of hyperactivity and promote a good night's sleep.

Daily weight should be monitored and recorded; patients are instructed to report any sudden weight increase, shortness of breath, or edema to their healthcare provider immediately [22]. When nurses administer dexamethasone as an IV push, it is best to administer the drug slowly to avoid the unpleasant (although transient) perineal irritation that occurs with too rapid administration of this agent.

Patient education is vital for patients with MM taking bisphosphonates. Regular oral hygiene should be stressed. A thorough dental check-up prior to starting bisphosphonate treatment is strongly recommended, with extraction of unsalvageable teeth [52,75]. Invasive dental work while taking bisphosphonates should be avoided or completed before treatment begins [83,88].

Patients should be advised that blood work will be monitored for creatinine and albumin. The findings of this blood work will guide dose adjustments. Oral supplements of calcium and vitamin D should be continued per the physician's recommendation [87].

Thalidomide was originally used in Europe during the 1950s and early 1960s as a treatment for morning sickness and insomnia in pregnant women. Thalidomide did not appear to present any risks. Respiratory depression was not an issue; the belief that the placenta acted as a protective barrier between mother and fetus supported the safety aspect. For approximately five years, women in Europe and Canada could obtain this over-the-counter drug. The FDA never approved the use of thalidomide due to concerns related to peripheral neuropathy, and it was not available in the United States. In the 1960s, it began to become evident that the drug was linked to severe teratogenic side effects. Thalidomide produced at least 10,000 infants born with deformed internal organs, missing arms and legs, and flipper-like attachments at shoulder and hip areas that replaced digits (phocomelia) [89].

These fetal deformities heightened the awareness of the need for improved and adequate drug safety regulations, including the realization that the effects for animals and humans are not always the same. In this case, a medication that appeared to be safe in animals proved teratogenic in humans [89,90,91]. However, thalidomide was also found to have anti-inflammatory and immunomodulatory properties. Both of these mechanisms make the drug useful in medicine today.

Thalidomide reappeared in the medical arena in the late 1990s. In July 1998, the FDA initially approved thalidomide to treat the skin disease erythema nodosum leprosum, which is associated with Hansen disease (leprosy). The anti-inflammatory properties also make thalidomide a useful medication for rheumatoid arthritis. Oncology nurses may be familiar with this immunomodulator for its use in the treatment of advanced breast cancer, hepatocellular tumors, Kaposi sarcoma, and renal cell cancer. Patients with acquired immunodeficiency syndrome (AIDS) receive thalidomide as palliation for cachexia, as it can reportedly stimulate appetite and promote sleep. For hematologic malignancies, thalidomide is generally prescribed for Waldenstöm macroglobulinemia and myelodysplastic syndrome (MDS) [75,92,93,94,95].

With the introduction of thalidomide for myeloma treatment in 1997, the options for treatment expanded and additional novel agents followed soon after [6]. Nearly all patients in the United States receive induction therapy that includes at least one novel agent. Most patients receive combination bortezomib/lenalidomide/dexamethasone [6]. The NCCN guideline states that combination regimens that include thalidomide may be useful in certain circumstances [52]. However, the agent is no longer widely used in the United States due to the availability of next-generation immunomodulatory drugs and their relatively favorable side effects profile compared to thalidomide [6,52].

Safety Regulations Related To Thalidomide

Since 1998, at least 130,000 patients in the United States have received thalidomide under the strict governance of the System for Thalidomide Education and Prescribing Safety (STEPS) program—now called Thalidomide REMS [96]. The Thalidomide REMS program mandates safety practices in the prescription, administration, and monitoring of patients taking thalidomide. Thalidomide may be prescribed to women of childbearing age and men who are still possibly sexually active, which means the risk for severe fetal defects exists. Patients, prescribing practitioners, and pharmacists are all required to register with Thalidomide REMS, undergo an education process, and their verbal understanding and written consents are obtained. Only registered practitioners who complete the mandated training receive an authorization number; pharmacists are required to follow up with a verification number when prescriptions are filled. Patients are allowed a maximum of seven capsules before a new prescription can be filled. These capsules are considered a 28-day supply and no refills are permitted [96]. On the casing of every thalidomide capsule is a warning related to risks to pregnancy. One 50-mg capsule is sufficient to cause the teratogenic side effects of phocomelia during fetal limb formation. This could potentially occur during the first 20 to 35 days of pregnancy.

Women who take thalidomide must use two acceptable forms of birth control (as directed by their physician) for four weeks before beginning thalidomide, during their treatment, and for four weeks after treatment. The woman must have two negative pregnancy tests prior to beginning thalidomide and will need to be tested for pregnancy in a lab at certain times during her treatment [96]. Women who are two years postmenopausal or have undergone a hysterectomy may be excused from meeting these requirements [96]. Men receiving thalidomide treatment who are sexually active should be counseled to use a condom during treatment or completely avoid any sexual contact with a woman who is pregnant or may become pregnant while taking this medication and for four weeks after completing treatment. Women taking thalidomide cannot breastfeed, and men cannot donate sperm; neither is permitted to donate blood [92,96,97,98].

Mechanism of Action

Within the bone marrow, myeloma cells produce growth factor, known as vascular endothelial growth factor (VEGF), to promote their own existence (neovascularization). VEGF exerts its influence upon marrow cells to secrete cytokines IL-6 and tumor necrosis factor-alpha (TNF-α) [75]. These factors attract additional myeloma cells. With an increased number of cells attached to endothelial cells, a vicious cycle continues, with an increase in VEGF producing a more aggressive disease.

Thalidomide produces several actions to combat the effects of myeloma cells [89,90,94]:

Dosing

Thalidomide is poorly soluble in water and therefore is not manufactured in the IV form. Within four hours of oral ingestion, the maximum serum concentration is reached and the kidneys excrete the breakdown of metabolites [75,99]. Capsules are produced in 50-mg, 100-mg, 150-mg, and 200-mg doses [75].

In most cases, the goal is to reach a target dose within 14 days of initiating the medication, but each treatment plan is individualized. Patients may have comorbidities that do not accommodate rapid titration of the drug. The usual dose increases are by increments of 50 mg or 100 mg, and the maximum dose is usually 800 mg [75]. The average daily dose is in the range of 200–400 mg. Higher doses may produce a better response, but the toxicities may outweigh the benefits [82]. Routine blood work should be ordered to monitor protein levels and plasma cell counts in order to assess the response to therapy.

There is a great deal of flexibility with thalidomide dosing, which is one benefit of its use. If the side effects warrant dose reduction, the drug may be stopped for a short period and reinstituted at a lower dose [75]. Reportedly, patients have been maintained on thalidomide for two to three years. However, it is not clear if there is a maximum length of time patients can continue to stay on this drug [82].

Side Effects

In addition to teratogenicity, thalidomide is associated with several side effects, including [2,9,66,75,87,94,96,97,98,99]:

Reversing or minimizing the side effects of thalidomide is generally achievable with a few simple measures. However, if side effects are not addressed in a timely manner, patients are at risk for long-term effects, such as peripheral neuropathy with the potential for permanent residual damage, especially if neuropathy was a prior issue. Problems identified early in the treatment plan may be ameliorated by interruption or reduction of the thalidomide dose, allowing for the addition of medications to counteract the side effects [20].

To reduce the incidence of adverse sedative effects, patients are advised to take thalidomide at bedtime [75,94,96]. For patients prescribed higher doses, the recommendation is to take half of the dose at 7:00 p.m. and the remainder at bedtime. It is important to remember that, for patients who are required to make an early start in the morning, safety and the ability to function are paramount. As trivial as this may sound, it adds significantly to patients' quality of life when they are able to achieve as much normalcy as possible.

Constipation, orthostatic hypotension, and skin problems may also arise. Constipation can be remedied by advising patients to take stool softeners or laxatives and to drink plenty of fluids on a regular basis. Patients should also be encouraged to consume a high-fiber diet.

For reports of dizziness or syncope, education similar to that provided to patients who are taking medications for hypertension is applicable. Changing position slowly, sitting on the side of the bed for at least a minute or more before standing, and avoiding sudden movements that could precipitate a rapid drop in blood pressure will help to prevent falls and subsequent injuries.

Dry skin usually requires emollients. Patients should be advised to avoid soaking in hot baths; applying lotion directly after a shower will help to keep skin moist. Light, loose-fitting clothing and staying cool will alleviate some of the symptoms of pruritus [9,90,94].

Patients taking lenalidomide are often encountered in an emergency setting as a result of hospitalization caused by the side effects of this immunomodulatory drug. Common admitting diagnoses in these patients include neutropenia, thrombocytopenia, DVT, or pulmonary embolism [82]. Obtaining a patient's admission history may reveal inclusion of peripheral blood stem cell (PBSC) transplant in the treatment plan, as lenalidomide is prescribed as part of maintenance therapy for these patients [52,100]. Most patients who have undertaken such a procedure are good historians; many will relate the entire history of their disease, and this personal account of their journey provides valuable and insightful information. In addition, family members often have useful information about disease and treatment histories.

In 2006, lenalidomide combined with dexamethasone (RD or Revlimid/Dex) was approved by the FDA for the treatment of relapsed/refractory MM in patients previously treated with at least one other treatment modality [6]. The FDA expanded approval of lenalidomide in combination with dexamethasone as frontline therapy for patients newly diagnosed with MM [6]. The combination also has been shown to be effective in relapsed or refractory MM [101]. In 2017, Revlimid received FDA approval as maintenance therapy after autologous stem cell transplant. Revlimid is part of standard of care regimens [6,101]. For previously treated MM, the NCCN recommends the combination lenalidomide/dexamethasone/carfilzomib [52]. Greater numbers of patients are now receiving lenalidomide (or bortezomib) combinations for induction therapy, and, as noted, fewer are receiving thalidomide combinations.

It has been well established that the immunomodulatory actions of thalidomide reduce tumor burden. However, the dose-limiting toxicities associated with thalidomide, such as neuropathy, excessive sedation, and constipation, prompted researchers to formulate a drug with comparable actions but with fewer side effects. Lenalidomide, a derivative of thalidomide, is the result of this research. Lenalidomide is reportedly 50,000% more potent than thalidomide when analyzed in the laboratory [87]. Comparable responses with lenalidomide at lower doses to those of thalidomide have been established; furthermore, lenalidomide displays a different side effect profile [9,10].

Revlimid REMS Program

The teratogenic properties of lenalidomide are unknown; however, with the lessons learned from thalidomide, there is no margin for error. Therefore, a program has been established to monitor patients who take lenalidomide [102].

The Revlimid REMS program has the same governing principles as the Thalidomide REMS program. Registration of prescribers, pharmacists, and patients is required. Contraception (with two forms of contraception or abstinence) for women of childbearing age is mandated four weeks prior to initiating the drug, during any interruption, and four weeks after discontinuing lenalidomide. After treatment begins, weekly pregnancy tests are required for the first four weeks of use, followed by monthly tests in women with regular menstrual cycles. Pregnancy testing should occur every two weeks in women with irregular menstrual cycles [102].

Lenalidomide is present in semen. For men who are sexually active with women of potential childbearing age (even if the men have had a vasectomy), condoms are required during treatment and for four weeks after completing the therapy. Additionally, men should not donate sperm during and for four weeks after treatment or during therapy interruptions [75,102].

Mechanism of Action

Lenalidomide acts in several beneficial ways to combat the MM process. Most importantly, the drug [9,10,75,91]:

Dosing

The general dosing regimen for lenalidomide is 25 mg daily for 21 days. Dexamethasone 40 mg is added on days 1–4, 9–12, and 17–20. This is repeated for four cycles. In the fifth cycle, lenalidomide is given for 21 days, but dexamethasone is administered on days 1–4 only [75,81,87].

Lenalidomide is rapidly absorbed. It is available only in the oral form, and the drug is produced in 2.5-mg, 5-mg, 10-mg, 15-mg, 20-mg, and 25-mg capsules. A daily aspirin is prescribed in addition to the lenalidomide and dexamethasone as prophylaxis against thromboembolic events. For patients with an implanted central venous access device, the standard therapy of warfarin 1-mg or 2-mg tablet daily will also be prescribed [75].

For the first three cycles of lenalidomide, lab work, including a CBC with manual differential, will be monitored twice weekly and then on a monthly basis thereafter. Monthly lab work includes creatinine, LFTs, and a thyroid function test. For patients taking warfarin, monitoring the prothrombin ratio/international normalized ratio (PT/INR) is essential. Additional lab work will vary depending on the overall performance of the patient and any existing comorbidities [75,87].

Side Effects

The major side effects with lenalidomide, all of which require dose reduction or interruption, are the myelosuppressive effects of neutropenia, anemia, and thrombocytopenia. For patients with a combination regimen including doxorubicin and erythropoietin, the heightened risk of thromboembolic events bears very close monitoring. The GI symptoms of constipation, loss of appetite, and diarrhea are usually less significant than the myelosuppressive effects [9,75,87]. Side effects may be treated as follows [10,87]:

Presence of unacceptable side effects calls for dose reduction, interruption, or discontinuation. One very important factor to consider in this equation is the willingness of the patient to accept and deal with the side effects. What one patient may tolerate relatively easily may seem monumental to another. The patient's goal is survival. For some patients, the realization that this is the last treatment option available leaves them little choice; they make the decision to do their best to get through each day.

The FDA warns that patients who receive lenalidomide are at an increased risk of developing additional malignancies, including acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma [103]. While the overall risk is low, patients should be warned of this risk, and physicians should closely monitor those who have been treated with lenalidomide [75].

Bortezomib is a proteasome inhibitor and one of the more recently developed targeted therapies available for relapsed or refractory MM. Due to the improved survival seen with this drug, it was approved by the FDA as a first-line/induction treatment in 2008. Bortezomib is approved for use alone or in combination with melphalan and prednisone (VMP) [75]. Other combinations used, though not specifically approved for use in the United States, include lenalidomide/bortezomib/dexamethasone (RVD) and bortezomib/melphalan/prednisone/thalidomide (VMPT) [75].

Mechanism of Action

Proteasomes are essential to cellular metabolism and are present in every cell in the human body. The proteasome/ubiquitin system regulates cell proliferation and apoptosis; damaged cells are broken down, and undamaged proteins are used to make new proteins. In order to destroy cancer cells and prevent cancer cell division, bortezomib as a proteasome inhibitor produces the following actions [2,72,93,104,105]:

Bortezomib is well tolerated in patients with renal dysfunction; creatinine clearance does not affect the pharmacokinetics of this drug [66].

Dosing and Monitoring

Bortezomib is administered in the outpatient setting as an IV push over three to five seconds. On days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day treatment cycle, 1.3 mg/m2 IV is administered for four cycles, followed by 1.3 mg/m2 IV on days 1, 8, 22, and 29 of a 42-day treatment cycle for five cycles [75]. A 72-hour timed interval between administrations is given to allow proteasome activity within the cells to return to normal. If after two cycles there is evidence of progressive disease or after four cycles there is stable disease, dexamethasone may be added. In these cases, dexamethasone 40 mg oral is given on days 1 to 4 and days 9 to 12; bortezomib is administered on days 1, 4, 8, and 11. The cycle is repeated every 21 days for cycles 1 and 2. On cycles 3 and 4, bortezomib 1.3 mg/m2 IV is administered on days 1, 4, 8, and 11; dexamethasone oral 40 mg is administered on days 1 to 4 [75]. A total of eight cycles are given [75].

Pegylated liposomal doxorubicin may also be combined with bortezomib [106]. In this combination regimen, bortezomib 1.3 mg/m2 IV push is administered on days 1, 4, 8, and 11. Pegylated liposomal doxorubicin 30 mg/m2 IV is added on day 4. The cycle is repeated every 21 days [75,81].

Prior to each treatment of bortezomib, baseline vital signs and a neurologic assessment should be performed to monitor for potential side effects. Any evidence of hypotension, exacerbated even further by dehydration, will be corrected with a bolus of IV saline prior to the treatment.

Routine lab work will include a CBC, CMP, and measurement of folate and vitamin B levels. Patients with a high tumor burden require close monitoring as there is the potential for tumor lysis syndrome to occur [22,72,81,105].

Side Effects

Bortezomib inhibits megakarocyte formation, which may cause thrombocytopenia. However, platelet counts will recover by the next cycle. Other possible side effects include [22,72,104]:

It should be noted that approximately 15% of patients experience severe (grade 3 or 4) neuropathy with the VMP combination [75]. Supplements such as the amino acids L-carnitine and L-glutamine and vitamins B6 and B12 may offer some neuroprotection. Additionally, an mRNA test is in development that would identify patients with MM at risk for bortezomib-induced peripheral neuropathy. The incidence of neuropathy has been demonstrated to be significantly less with subcutaneous bortezomib than with IV administration [75]. Neuropathy can be reversed in the majority of patients with gabapentin.

Patient Education

Providing patients with calendars that map out the dates for treatment will help prevent any miscommunication regarding appointments. Educating patients and caregivers regarding possible side effects, warning signs, and when to contact a healthcare provider positively impacts the delivery of treatment as planned [72,105]. It is important that patients divulge any supplements they may be taking to address side effects, as these can interfere with renal function and cause diarrhea [105].

Patients should be instructed to report nausea, vomiting, or diarrhea not controlled by their prescribed medications, as this can quickly lead to dehydration. Patients invariably wait too long to notify their providers when these side effects are an issue. Patients require reminders that it is easier to correct dehydration before it becomes severe.

The neuropathy associated with MM and its treatment is usually sensory as opposed to motor in nature. Any previous treatment regimens should be carefully considered for cumulative side effects, especially related to peripheral neuropathy. If symptoms are severe, a reduction in the dose may be necessary until the neuropathy subsides. Peripheral neuropathy may be treated with pregabalin (150–600 mg/day) for at least three months or gabapentin starting with doses of 100 mg three times per day and increasing to a maximum of 600 mg three times per day. Duloxetine (30–60 mg/day) is considered a valid second-line option [107]. Creams such as capsaicin or cocoa butter have also been reported to be helpful [105]. In patients with suspected disease related to peripheral neuropathy, it is important to rule out amyloidosis in patients presenting with nephrotic syndrome or unexplained cardiac problems [52]. If fatigue is an issue, patients should be advised not to drive and to avoid operating heavy machinery. Hyponatremia has been reported as a side effect after several cycles of bortezomib.

Carfilzomib is a novel, highly selective proteasome inhibitor approved by the FDA for the treatment of MM in 2012 [75,108]. It is specifically indicated for patients previously treated with at least two other therapies, including bortezomib and an immunomodulatory agent, whose disease progressed within 60 days after the last treatment. It may now be used at first relapse [6].

Mechanism of Action

Like bortezomib, carfilzomib inhibits proteasome, which is responsible for intracellular protein homeostasis. Specifically, it is a potent, selective, and irreversible inhibitor of chymotrypsin-like activity of the 20S proteasome, leading to cell cycle arrest and apoptosis [75]. The high selectivity of this agent leads to fewer adverse systemic effects, such as peripheral neuropathy, that may arise with the use of bortezomib [108].

Dosing and Monitoring

Carfilzomib should be administered intravenously over 2 to 10 minutes, on two consecutive days weekly for three weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (days 17 to 28) [75; 108]. The recommended dose in the first cycle is 20 mg/m2, and, if tolerated, the recommended dose for the second and succeeding cycles is 36 mg/m2 [75]. It is important that patients are well hydrated when taking carfilzomib. An infusion of 250–500 mL normal saline (or other appropriate IV fluid, such as 5% dextrose in water) should be given before and after (if needed) each dose in the first cycle and additional cycles, if necessary [75]. Premedication with dexamethasone is recommended prior to all doses in cycle 1, all doses during first dose escalation cycle, and as needed with future cycles to reduce the incidence and severity of infusion reactions [75]. Patients should be monitored for infusion-related reactions, dehydration, tumor lysis syndrome, heart failure, peripheral neuropathy, and pulmonary symptoms.

Side Effects

Anemia, thrombocytopenia, fatigue, nausea, dyspnea, diarrhea, and pyrexia are among the most common side effects associated with carfilzomib [75,108]. Other serious adverse effects include [75,108]:

In 2013, the FDA approved pomalidomide, an immunomodulator in the same class as lenalidomide and thalidomide [109]. Like carfilzomib, it is approved for the treatment of patients previously treated with at least two other therapies, including lenalidomide and bortezomib, whose disease progressed within 60 days after the last treatment [75].

Mechanism of Action

Pomalidomide acts in many of the same ways as other drugs in its class. It has been shown to induce cell cycle arrest and apoptosis directly in MM cells; enhance T cell- and natural killer cell-mediated cytotoxicity; inhibit production of proinflammatory cytokines; and inhibit angiogenesis [75].

Dosing and Monitoring

Pomalidomide should be administered orally (either alone or in combination with dexamethasone) at a dose of 4 mg on days 1 through 21 of repeated 28-day cycles [75,109]. Cycles are repeated until disease progression or unacceptable toxicity. The absolute neutrophil count should be ≥500 cells/mcL and platelets ≥50,000 cells/mcL prior to initiating new cycles of therapy [75]. For each subsequent drop of neutrophil count to <500 cells/mcL and/or platelets <25,000 cells/mcL, therapy should be interrupted. When counts rise back to appropriate levels, resume dosing at 1 mg less than the previous dose.

Side Effects

In clinical trials of pomalidomide, the most common side effects included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper respiratory tract infections, back pain, and pyrexia [75,109]. Boxed warnings regarding the risk for embryo-fetal toxicity and venous thromboembolism have also been issued [75,109]. Due to the significant embryo-fetal risks, pomalidomide is only available to those registered with the POMALYST Risk Evaluation and Mitigation Strategy (REMS) Program. Patients of childbearing age are required to use two forms of reliable contraception to prevent pregnancy, and women must have two negative pregnancy tests prior to initiating treatment. Pregnancy prevention should continue for at least four weeks after cessation of therapy. To address the risk of thromboembolic events, individualized anticoagulation therapy should be considered [75].

Panobinostat was approved in 2015 for the treatment of patients with MM [110]. This agent is indicated for patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent [75].

Mechanism of Action

Panobinostat acts by inhibiting histone deacetylase (HDAC), causing cell cycle arrest and/or apoptosis [75]. At the time of its approval, it was the only HDAC inhibitor approved for the treatment of MM [110].

Dosing and Monitoring

Oral panobinostat is administered as part of a multi-agent regiment with bortezomib and dexamethasone. The initial dose is 20 mg once every other day for three doses each week during weeks 1 and 2 of a 21-day treatment cycle (rest during week 3) for up to eight cycles, or 16 cycles in patients experiencing clinical benefit and acceptable toxicity [75,111]. If dose reduction is necessary to manage toxicity, the same schedule should be kept, but the dose should be reduced in increments of 5 mg [75].

Side Effects

The most common side effects of panobinostat are diarrhea, fatigue, nausea, edema in the extremities, decreased appetite, fever, vomiting, and weakness [75,110]. The most common laboratory abnormalities include hypophosphatemia, hypokalemia, hyponatremia, increased creatinine, thrombocytopenia, leukopenia, and anemia [75]. The drug also carries a boxed warning due to the increased risk of severe diarrhea and severe and fatal cardiac events, arrhythmias, and electrocardiogram changes [75,110].

In 2020, the FDA approved isatuximab, in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor [75,112]. Isatuximab is a CD38-directed cytolytic antibody that promotes apoptosis and immunomodulatory activity. In studies, patients who received isatuximab in combination with pomalidomide and low-dose dexamethasone had a 40% reduction in the risk of disease progression or death compared with patients who received only pomalidomide and dexamethasone [112]. In 2021, the FDA approved isatuximab in combination with carfilzomib and dexamethasone (isatuximab-irfc) for the treatment of relapsed/refractory MM in patients who have received one to three prior lines of therapy [113].

There are two chimeric antigen receptor (CAR) T-cell therapies approved by the FDA and included as preferred options by the NCCN Panel for relapsed/refractory MM after at least four prior therapies: idecabtagene vicleucel and ciltacabtagene autoleucel [20].

Idecabtagene Vicleucel

In 2021, the FDA approved idecabtagene vicleucel, the first cell-based gene therapy to treat adult patients with multiple myeloma [114]. The agent is reserved for patients who have not responded to, or whose disease has returned after, at least four prior lines of therapy. Idecabtagene vicleucel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor T-cell therapy. Severe adverse effects have been associated with use, including cytokine release syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, neurologic toxicity, and prolonged cytopenia [114]. Because of this, it was approved with a REMS plan requiring that dispensing facilities and their involved staff be specially certified and trained and that patients be informed of the potential serious side effects.

Ciltacabtagene Autoleucel

A second (BCMA)-directed genetically modified autologous chimeric antigen receptor T-cell therapy, ciltacabtagene autoleucel, received FDA approval in 2022 [115]. The safety and efficacy of this agent were evaluated in an open label, multicenter clinical trial that included 97 patients with relapsed or refractory MM who had received at least three prior lines of therapy. Eighty-two percent of patients had received four or more prior lines of therapy [115]. Efficacy was established based on overall response rate and duration of response. The overall response rate was 97.9%. Among the 95 patients who responded to treatment, the median duration of response was 21.8 months. Ciltacabtagene autoleucel carries the same boxed warning for adverse effects as idecabtagene vicleucel and also includes a REMS plan [75,115].

There are three bispecific antibodies approved by the FDA and included as preferred options by the NCCN Panel for relapsed/refractory MM after at least four prior therapies: elranatamab, teclistamab, and talquetamab [20].

Elranatamab

In August 2023, the FDA granted accelerated approval to elranatamab, the first fixed-dose subcutaneous BCMA-directed agent for treatment of relapsed/refractory MM [6,75,116].

Teclistamab

Teclistamab-cqyv is a first-in-class bispecific BCMA-directed T-cell engager [6,75]. It received FDA approval in 2022 for the treatment of relapsed/refractory MM in patients who have received at least four prior lines of therapy [117]. Teclistamab binds to the CD3 receptor on the surface of T-cells and to BCMA expressed on the surface of MM cells, resulting in T-cell activation, the release of various proinflammatory cytokines, and the lysis of BCMA-expressing MM cells [75]. Teclistamab has a boxed warning for life threatening or fatal cytokine release syndrome (CRS) and neurologic toxicity. Because of these risks, the agent is available only through Tecvayli REMS [117].

Talquetamab

Talquetamab received FDA approval in 2023 for treatment of relapsed/refractory MM [6,75,118]. Due to the boxed warning risks of CRS and neurologic toxicity, patients should be hospitalized for 48 hours after all doses within the talquetamab dosing schedule. One to three hours prior to receiving all doses of talquetamab, patients should be premedicated with a corticosteroid, a histamine H1 antagonist, and an antipyretic [75]. Talquetamab is available only through Tecvayli-Talvey REMS [118].

Selinexor is a first-in-class selective nuclear export inhibitor. It reversibly inhibits nuclear export of tumor suppressor proteins, growth regulators, and mRNAs of oncogenic proteins, resulting in accumulation of suppressor proteins in the nucleus, cell cycle arrest, and cancer cell apoptosis [75]. Selinexor received FDA approval in 2019 (in combination with dexamethasone) for the treatment of relapsed/refractory MM in patients who have received at least four prior therapies. In 2020, the FDA approved the agent (in combination with bortezomib and dexamethasone) for treatment of MM in patients who have received at least one prior therapy [6,119]. The NCCN Panel included selinexor/dexamethasone under other recommended options for patients with relapsed/refractory MM. Selinexor/bortezomib/dexamethasone once weekly is a category 1 recommendation for previously-treated MM [52]. Adverse reactions reported in approximately 20% of patients include nausea/vomiting, fatigue, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, and cataract. Selinexor is available in tablet form [6,75,119].

With preliminary testing completed, the first phase of the transplant procedure is induction, with the goal of reducing the number of plasma cells and M protein levels. Depending on the stage of the disease and taking into account any prior treatments administered, the following chemotherapy, immunomodulators, and/or glucocorticoids may be ordered [20]:

The most successful, induction therapy options for transplant-eligible patients include [20]:

The current consensus is that three-drug regimens that include bortezomib are considered standard treatment in the absence of a clinical trial [52]. Three-drug regimens have shown improved efficacy compared with two-drug combinations [132]. Combination therapies have been shown to produce rapid and high response rates [52]. A review of 40 studies of various induction therapy regimens found varying levels of safety and efficacy among two- and three-drug regimens and emphasized the importance of individualized treatment approaches for transplant-eligible patients with MM [133].

Total body irradiation was once a component of the preparative regimen for transplant, but these regimens have been abandoned [52]. Newer, potentially less toxic radiation techniques that deliver total marrow irradiation while reducing toxicities to nontarget organs are undergoing evaluation in clinical trials [52].

The NCCN recommends that response to the induction be assessed after each cycle [52]. Assessment of induction treatment response includes scans, bone marrow biopsy, and blood work. If there is a 50% reduction in plasma cells, the patient is eligible to proceed with the transplant. If there is a less than 50% response, consideration will be given to whether to continue with the current induction or switch and/or alter the therapy. As an example, if a patient is receiving thalidomide plus dexamethasone, the oncologist may add bortezomib in an attempt to produce a more favorable response. Induction therapy with bortezomib/dexamethasone combination has been found to significantly improve response rates in patients undergoing autologous transplantation [134,135,136]. A systematic review found improved overall survival rates in trials of bortezomib versus no bortezomib with the same and with different background therapy [137].

Patients preparing for an autotransplant should not receive melphalan prior to harvesting their own stem cells, as melphalan is an alkylating agent. The damage to stem cells in the marrow can manifest in the future (usually in several years) as leukemia [22,52,131].

During the induction phase, which can take up to several months, the patient's day-to-day routine will include anticoagulant prophylaxis (especially for patients who are prescribed thalidomide or lenalidomide) and antibiotic prophylaxis [73]. The most common antibiotic prophylaxis is sulfamethoxazole and trimethoprim (Septra DS) 800 mg two or three times a week [52]. Steroid therapy is also continued, and blood glucose levels will be monitored for adverse effects. It is also important to monitor for opportunistic infections, such as herpes zoster, as patients will be at a heightened risk while immunocompromised. Patients should be instructed on when to report signs or symptoms of infection, including redness, swelling, or any drainage from the catheter site. Fever (a temperature of 100.4° Fahrenheit or greater), chills, sore throat, productive cough, or the inability to eat or drink sufficient fluids to maintain hydration should be reported promptly [82].

Only 1% of marrow cells are stem cells, and an even smaller percentage exist in the peripheral blood. Stem cells require mobilization to enable sufficient cells for collection. Colony growth stimulating factors is prescribed and given on a daily basis, boosting the number of WBCs and mobilizing them by approximately 18-fold [138]. Patients or care providers will be instructed regarding administration of the subcutaneous injection. Alternatively, patients may receive the injections at an outpatient clinic or infusion center. Most patients and caregivers, however, are able to inject the medication.

Chemotherapy mobilization (chemomobilization) is also used to increase the number of stem cells and has the ability to increase the number of cells by as much as 60-fold [138]. Chemotherapy is often used simultaneously with growth factors. The decision to use chemomobilization will depend on the success of the induction and the reduction of tumor burden. Although cyclophosphamide is an alkylating agent, it is commonly used with granulocyte macrophage colony-stimulating factor (GM-CSF) as a mobilizing agent [75,82]. Clinical trials comparing granulocyte colony-stimulating factor (G-CSF) with GM-CSF have shown better mobilization with G-CSF in fewer apheresis (collection) sessions. Common side effects of G-CSF include bone pain, malaise, headache, chills, and fever [123].

Plerixafor, an inhibitor of chemokine receptor 4 (CXCR4), was approved by the FDA in 2008 for peripheral stem cell mobilization [75,123]. Results of some clinical trials indicate that use of plerixafor in addition to G-CSF could lead to an increased mobilization and release of stem cells, thereby facilitating effective apheresis. The aim of one systematic review was to evaluate the efficacy and safety of additional plerixafor to G-CSF for stem cell mobilization in patients with MM [139]. Two trials evaluated 600 patients with MM or non-Hodgkin lymphoma. In both studies, the experimental group received G-CSF plus plerixafor. The control group received G-CSF plus placebo. With regard to successful stem cell collection, the analysis showed an advantage for participants randomized to the plerixafor group. There was insufficient evidence to determine whether additional plerixafor affects survival or adverse events [139]. A literature review also showed that the addition of plerixafor to G-CSF is well tolerated and resulted in a greater proportion of patients reaching optimal cell collections with fewer number of apheresis [140].

In 2023, the FDA approved motixafortide in combination with filgrastim for peripheral stem cell mobilization [141,142]. The approval is based on results from the GENESIS trial. The GENESIS trial enrolled 122 people with multiple myeloma, ranging from 18 to 78 years of age. Trial participants with MM were randomly assigned to receive G-CSF plus motixafortide or G-CSF plus a placebo for stem cell mobilization. Motixafortide plus G-CSF enabled 92.5% of patients to successfully meet the primary endpoint (3–5 x 10⁶ CD34+ cells/kg) [123,141,142].

Apheresis, or stem cell collection, is performed as an outpatient procedure for both the patient (autologous transplant) and the donor (allogeneic transplant). A blood sample is obtained prior to harvesting in order to count the number of cells. If the count is determined to be inadequate, additional daily doses of the colony-stimulating factor will be given. The actual stem cell collection takes place over several days, with a two to four hour procedure time. The blood is removed in a manner similar to donating blood, except the white cells are centrifuged, separated, and bagged, and the remaining blood is returned to the donor. During cell collection, the donor may experience some dizziness or tingling in their face, hands, or feet, but the extreme symptoms of chills, tremors, or cramps are unlikely. The number of cells required for PBSC transplant equates to 2 million CD34+/kg. Sufficient cells are harvested to allow for two transplants [82,123,142].

Stem cells have reportedly been stored for as long as 10 years. Dimethyl sulfoxide is used to prepare the cells for freezing; stem cells are stored in liquid nitrogen and remain frozen until required for the transplant [123].

Prior to an autologous transplant, after admission to the transplant unit, the patient will receive high-dose chemotherapy. Melphalan is the standard conditioning agent and is used in the vast majority of centers [6,143]. The dosing is 200 mg/m² IV alone two days prior to transplantation, or 140 mg/m² IV two days prior to transplantation in combination with busulfan 9.6 mg/kg IV [6,75]. A reduced dose may be necessary if the patient is elderly [75,122].

The bags containing the stem cells are thawed in warm water baths; reportedly, a smell similar to garlic is often detected as the cells thaw [122]. Patients are infused with the stem cells in a similar manner to a blood transfusion. Each bag is infused over a period of one to four hours with close observation for any signs and symptoms of reaction. Patients' urine may be pink tinged for a short period of time after the procedure.

In the 10 to 14 days following the procedure, the staff at the transplant center will monitor the patient very closely. This is termed the engraftment phase, during which time the cells begin to appear in sufficient numbers in the circulation. Engraftment can occur as early as 10 days after the transplant, but is more likely to take place after 15 to 20 days. Daily blood cell counts will monitor the absolute neutrophil count (ANC). For three consecutive days, the ANC must be 500 or more to signify that engraftment has occurred [122].

Having received the high-dose chemotherapy just prior to the transplant, the patient's nadir will be supported with antibiotic therapy, blood, and platelet transfusions as warranted per the transplant protocol. GM-CSF will be continued. Mucositis, which can often be severe, causing pain and an inability to eat, is an expected side effect and should be treated appropriately.

The amount of time until the patient can be transitioned from the transplant center to pre-arranged accommodation within close proximity will depend on the patient's recovery time and the results of the daily lab work. Every patient is individual; many patients recover sufficiently to be discharged to home within three to four weeks of the transplant [82,122].

Having undergone the PBSC transplant, patients may be placed on maintenance therapy with immunomodulators and/or prednisone. One study has shown that bortezomib increases progression-free and overall survival, and it is particularly beneficial for patients with 17p deletions [144]. Lenalidomide as maintenance therapy after autologous transplantation has been evaluated in two independent randomized phase III studies [52]. In one study, 231 patients were randomized to maintenance therapy with lenalidomide versus 229 patients randomized to placebo after autologous transplantation. Maintenance therapy was initiated at day 100 following transplantation. At a median follow-up of 34 months, 37% of the patients who received lenalidomide versus 58% who received placebo had disease progression or died. The median time to progression in the lenalidomide group was 46 months versus 27 months in the placebo group. Second primary cancers occurred in 18 patients who received lenalidomide (8%) and in 6 patients who received placebo (3%) [145]. In the second study, 614 patients younger than 65 years of age were randomly assigned to maintenance treatment with either lenalidomide (10 mg/day for the first 3 months) or placebo until relapse [146]. The primary end point was progression-free survival. Lenalidomide maintenance therapy improved median progression-free survival (41 months vs. 23 months with placebo). With a median follow-up period of 45 months, more than 70% of patients in both groups were alive at 4 years. The incidence of second primary cancers was 3.1 per 100 patient-years in the lenalidomide group versus 1.2 per 100 patient-years in the placebo group. Median event-free survival (with events that included second primary cancers) was significantly improved with lenalidomide 175]. Routine follow-up appointments are scheduled to monitor the patient's progress and remission and to identify any indication of a relapse.

Despite the vigilance of caregivers and patients following instructions to drink plenty of fluids and remain as mobile as safety permits, the onset of hypercalcemia may be insidious, with early subtle changes in mentation and increases in urine output going unnoticed. Increasing drowsiness may be attributed to the introduction of new pain medications, with the patient's attention focused in this direction. Consideration should be paid to any new additions to the treatment regimen, previous cancer treatment, drug disease-state interactions, and comorbid pathologies, as these could potentially account for changes seen in the patient [149].

Presenting signs and symptoms of hypercalcemia result from an increase in the values of the serum calcium. Hypercalcemia is defined as serum calcium levels greater than 10.4 mg/dL or ionized serum calcium greater than 5.2 mg/dL [149]. In mild hypercalcemia, patients are often asymptomatic. If present, symptoms may include constipation, anorexia, nausea, vomiting, and polyuria [149]. When serum calcium levels are greater than 12 mg/dL, lethargy advances to confusion, lability, delirium, psychosis, and stupor; polyuria slows; and oliguria develops [149]. Changes in cognition may vary depending on previous baseline mentation and accompanying comorbidities. Cardiac contractility is adversely affected, with changes observed on EKG. If hypercalcemia is not effectively treated and reversed, continued rising levels may progress to coma and death [1,41,66,149]. In many cases, early detection will result in positive outcomes, as it is reasonable to expect mild hypercalcemia to be corrected in a timely manner.

The ultimate goal in the treatment of hypercalcemia is to address the underlying disease. Being chronic and multifactorial, MM poses a challenge, as there is no "quick fix." Hypercalcemia may be a reflection of worsening disease; patients may require more frequent hospitalizations with shorter times between admissions. Any mild hypercalcemia may be treated by the administration of IV fluids in the office, or daily fluids may be prescribed in the outpatient clinic for two to three consecutive days. Taking into consideration the skills of the caregiver and the home situation, an inpatient hospital stay may be averted if adequate fluids can be administered as an outpatient and the elevated calcium corrected [1,27,66,149].

Hypercalcemia is primarily diagnosed based on several laboratory tests. In patients without hypercalcemia, serum calcium and protein bound calcium are in balance. Any abnormality in albumin (usually low in the elderly or debilitated patient) will not accurately reflect ionized calcium. The laboratory will run corrected calcium. The formula for corrected calcium is as follows: measured serum calcium + (4 - measured serum albumin [g/dL]) x 0.8. The number 4 is selected as it lies in mid-range for normal albumin [149].

Urinalysis monitoring will indicate decreased sodium phosphorous, sodium, and potassium. Electrolytes, including BUN, creatinine, and magnesium, should also be analyzed [41,149].

Neurologic Changes

The neurons within the central nervous system are depressed by elevated levels of calcium. A higher level of calcium will correspond to a more exaggerated clinical picture. Patients present with lethargy, changes in mental status, and an inability to concentrate, with inappropriate conversations or behavior. Hyporeflexia, decreased muscle tone, and profound weakness will be manifested as the calcium level continues to rise. A calcium level greater than 12 mg/dL can cause emotional lability, confusion, delirium, psychosis, stupor, and coma. Hypercalcemia greater than 18 mg/dL may cause shock, renal failure, and death [149]. It is important to note that even when hypercalcemia has been corrected, older patients may require a longer recovery time to return to their baseline behavior.

Gastrointestinal Signs and Symptoms

Calcium exerts its effect upon smooth or involuntary muscle in the intestinal tract. When motility slows, gastric emptying is delayed, which results in nausea and vomiting. Anorexia and constipation also become part of these GI symptoms [149].

Cardiovascular Signs and Symptoms

Hypercalcemia affects the contractility of the heart muscle and electrical impulses. Varying levels of elevated calcium affect the heart differently; moderate hypercalcemia causes bradycardia, with a shortened QT interval and possible hypertension. Calcium levels greater than 16 mg/dL produce a prolonged QT wave; levels greater than 18 mg/dL have the potential to cause asystole. If patients are taking digoxin, there is the possibility of digoxin toxicity occurring [1,149].

Renal Manifestations

As a protective mechanism, the kidneys can increase their excretion of calcium fivefold, but this can only be sustained for a very limited time. Elevated calcium affects the efficacy of antidiuretic hormones within the collecting tubules, resulting in polyuria. With the decreased ability to concentrate urine, dehydration occurs. Nausea and vomiting, coupled with depleted fluid intake, add to volume depletion, which in turn decreases the glomerular filtration rate (GFR). With a lowered GFR, sodium and water in the proximal tubule are resorbed, in an effort to retain water. Renal failure will follow. Levels of calcium bound to protein decrease when acidosis occurs, resulting in an increased level in the serum [1,149].

The underlying problems of dehydration, the excessive release of calcium due to bone destruction, and renal insufficiency should be corrected as expediently as possible. Obviously, if the elevated calcium is the result of excessive intake of calcium supplements or vitamin D, these should be discontinued immediately. If the patient is receiving total parenteral nutrition (TPN) with calcium in the formula, the nutritional support team will make adjustments as necessary. Any thiazide diuretics should be discontinued, as these inhibit calcium excretion.

Hydration should be initiated with IV normal saline at a rate of 200–300 mL per hour to inhibit resorption of calcium in the tubules. Corticosteroids will also be administered, initially by IV then orally when the patient is able to tolerate it. Corticosteroids decrease calcium absorption from the intestine and increase urinary calcium excretion. Calcitonin may also be helpful, as it inhibits bone resorption. The action is rapid but short lived. As noted, bisphosphonates are a common treatment for cancer-related hypercalcemia [149]. Diuretics such as furosemide may be ordered but only after the fluid volume has been sufficiently replaced. Laxatives may be administered to correct constipation, and antiemetics are helpful for patients experiencing nausea. In extreme cases, patients may require plasmapheresis or dialysis [1,90,149].

For patients who experience confusion or disorientation as a result of hypercalcemia, safety is an issue. Healthcare providers should reorient the patient frequently to his or her surroundings and leave a call bell within reach. If it is feasible, a family member should stay with the patient until the confusion subsides.

Profound weakness heightens the risk for falls, which in turn may result in fractures. The use of transfer devices with a referral to physical therapy should be made, if appropriate. The patient should be mobilized as early and as frequently as possible to maintain calcium in the bones. Mobilization helps to reduce the risk of DVT and pneumonia.

Nurses should monitor medications; self-administration of supplements or antacids is prohibited. In addition, cardiac monitoring will be necessary if significant EKG changes are observed. Patients prone to congestive heart failure or with compromised cardiac status should also be assessed for fluid overload. Strict intake and output are stressed for all patients. Ideal urine output is 100–150 mL per hour. A Foley catheter may be placed for accurate output.

Laboratory values should be monitored for decreased potassium and magnesium. Skin breakdown related to bed rest and incontinence is a risk, and patients' skin should be regularly assessed. Encourage oral care to protect mucous membranes and alleviate dry mouth [1].

For patients whose hypercalcemia and probable coexisting renal failure are reflective of end-stage disease, this may be an appropriate time to re-examine goals and decide how aggressive the plan of care should be. Consultation with a palliative care specialist or initiating comfort measures may be deemed appropriate at this time.

As many as 70% of patients diagnosed with MM present with back pain due to lytic lesions of the spine upon initial diagnosis, and lytic lesions in bone never repair. Despite standardized treatment with bisphosphonates and encouraging patients to remain as mobile as possible, vertebral bodies fracture and SCC follows. The early onset of SCC may initially go undetected, but the usual pathologic sequence of this disease is [19,27,66,151,152,153]:

The presenting symptoms may vary depending on the level of nerve damage. Injury to the cauda equina creates bilateral sensory loss and pain in the perineal area, thighs, and lateral leg area [19,27,66,151,152].

The definitive diagnosis of SCC is made by CT and/or MRI of the spine [1,47,152]. However, the patient's signs and symptoms are often the first indications. Upon examination, the patient may complain of back pain localized to the affected vertebral body. The constant pain does not subside when the patient lies down; in fact, the reverse is usually true, and the pain is less severe when the patient is standing [151,152]. This pain differs from that associated with a herniated disc, which is relieved by a change in position. Added pressure from abdominal organs may also increase pain when the patient is lying supine [151]. Radicular pain caused by nerve compression is exacerbated by coughing, sneezing, or bowel movements. Patients may be able to trace a path of radiating pain as it travels along the dermatome of the affected nerve root [151]. With involvement in the thoracic region, patients report a tight band sensation around their chest or abdominal area.

Compression of the cord may also cause hyperactivity in deep tendon reflexes. Normal brisk reflexes are decreased with nerve root compression. Straight leg raises or neck flexion increase the pain. When patients' legs are straightened and raised and the foot dorsiflexed, resulting pain radiating from the back down the leg is confirmation of nerve root compression. A positive Babinski sign confirms motor involvement. Sensory involvement is assessed by the ability or inability to determine the sense of touch, vibration, position, and temperature variations [1,66,151,152].

Patients may report symptoms of increasing weakness in their legs, which creates difficulty in walking or climbing stairs [152]. Despite the use of a walker and additional assistance, the ataxia will progressively worsen. Sensory loss can occur over varying periods of time, from hours to days and even months, depending on the disease progression. Patients may report numbness or tingling in their toes. The reported loss of sensation gradually progresses up the legs from the toes, with a feeling similar to that of pulling up stockings or socks. Trying to accurately describe symptoms that could be the progression of pre-existing neuropathies or a new disease entity presents a challenge to the patient and caregiver.

With autonomic involvement, which always coexists with other symptoms, patients may not feel the urge to void and may report incontinence or retention. Patients may report dribbling of urine; it is highly probable that this is incontinence with overflow. Little attention may have been paid to constipation, as it is often a problem patients are accustomed to dealing with on a day-to-day basis as an expected side effect from the prescribed opioids [1,27,66,151,152]. Referrals to a radiation oncologist, neurologist, and orthopedist may be required.

Because plasma cell tumors are very radiosensitive even to a low-to-moderate dose of radiation, the American College of Radiology notes that the most commonly offered treatment for spinal cord compression associated with multiple myeloma is emergent external beam radiation therapy following initiation of steroid therapy.

(https://acsearch.acr.org/docs/3091670/Narrative Last Accessed: March 14, 2024)

Level of Evidence: Expert Opinion/Consensus Statement

The goals of SCC treatment are to manage the pain, stabilize the spine, and halt the underlying disease process to prevent irreversible neurologic damage. Restoring patients to their previous level of functioning (or an improved level, if possible) is the ultimate goal. Approaches to treatment include a combination of [1,152,154]:

In addition, glucocorticoids are prescribed to ameliorate symptoms. Typically, this consists of a loading dose of dexamethasone 16 mg followed by a short course of oral dosing at 16 mg daily while treatment is being planned [75,155]. The loading dose may be given prior to imaging to reduce swelling and increase circulation to the spine. Dexamethasone should be reduced and gradually stopped in patients who do not proceed to surgery or radiotherapy and should be discontinued if neurologic function deteriorates at any time [155]. Bisphosphonates should not be used to treat spinal pain in patients with vertebral involvement from tumor types other than myeloma, breast cancer, or prostate cancer, or with the intention of preventing SCC, except as part of a randomized controlled trial [155].

Radiation may also be part of the treatment of SCC. The number of treatments ordered will depend upon its appropriateness with other modalities that have been ordered in the plan of care. Chemotherapy may be used as an adjuvant therapy with radiation therapy or surgery. The choice of chemotherapeutic agent will depend upon the primary tumor type and patient history [152].

Bed rest will be ordered initially until imaging is completed and it is determined that the patient can be safely mobile without negatively affecting outcomes. Patients maintained on bed rest require assistance to turn and reposition in order to maintain skin integrity. For patients permitted to sit for meals or to be assisted to the bedside commode or to the bathroom, falls are a major issue. Call bells should be within easy reach. Transfer belts and walkers should be used for ambulation, with clear uncluttered pathways to the bathroom. Good fitting shoes or, at the very least, non-skid slipper socks should be worn. When patients can safely be mobilized, activity should be encouraged as much as possible. The mechanical stress of weight bearing will help maintain calcium in the bones. It is also a good opportunity to reiterate the role of mobility in decreasing the risk of developing a DVT.

Pain assessment and pain management are paramount. Prior to any procedure requiring the patient to lie in a supine position or remain still for any length of time, pain medication or anxiolytics should be administered. Some patients may require a patient-controlled analgesia (PCA) pump. Weaning from a PCA to a sustained-release analgesic with breakthrough pain medication should take place after the steroids and radiation therapy have succeeded in decreasing the pain. Uncontrolled pain also prevents deep breathing and increases the risk of patients developing pneumonia. Patients should be encouraged to use their incentive spirometer and to cough and deep breathe as part of their daily routine.

In many cases, radiation therapy is administered to halt the myeloma activity. Radiation departments will often provide patient education materials, and the radiation oncologist will outline the treatment plan. The severity of the cord compression will dictate how many treatments will be necessary. Patients may question why their pain seems to have increased after the first few radiation treatments when the goal was to eliminate the pain. Patients should be reassured this is temporary and the initial inflammation will subside [152]. If a patient is planning to undergo a PBSC transplant in the future and the radiated field includes the pelvic area, the number of radiation treatments may be limited. Patients should be aware that their initial appointment will take longer than subsequent treatments. Radiation treatments are usually planned Monday through Friday; the weekend break between treatments allows time for radiated tissues to heal [75,90].

Bowel management can be a challenge when constipation results from opioids, immobility, and reluctance to bear down due to back pain. Fluids should be encouraged; adding prune juice to the patient's diet along with foods high in fiber provides a natural stimulation of the bowel. The majority of patients with MM are older and not accustomed to drinking as much water as is required. Reiterating in very simple terms the importance of keeping kidneys flushed and supplying patients with water bottles may be a simple solution. Laxatives and stool softeners should be administered routinely. An enema or suppository may be necessary if the patient has not had a bowel movement in several days. Teaching patients to intervene if they have gone longer than three days without a bowel movement prevents the development of obstipation.

If a patient exhibits signs and symptoms of urinary retention upon admission, a bladder scan to check for retained urine is an appropriate initial intervention. Depending on the volume of residual in the bladder, an in-and-out catheter may be ordered or an indwelling Foley catheter placed, if necessary. The patient will then be assessed for the optimum time to remove the catheter and begin a regular toileting schedule.

Blood glucose monitoring is performed in conjunction with steroid therapy [152]. Reassurance should be given to patients who have misunderstandings about the test or believe that they have developed diabetes. Understanding that the hyperglycemia will subside with the tapering and discontinuation of the steroids will alleviate their fears.

Case management should be consulted to assist with discharge planning for any equipment required at home, such as a walker, wheelchair, or three-in-one commode. Physical therapy may be continued at home or patients may continue rehabilitation in a skilled facility, if deemed appropriate [1,27,152]. Hospice referral and palliative care are appropriate for patients who have failed to respond to chemotherapy and conventional radiation therapy and who are not candidates for surgery. Goals of palliative care include the prevention of further injury, pain control, the restoration and maintenance of bowel/bladder function, and the provision of emotional support for both patient and caregiver(s) [152].

Pain is demoralizing and incapacitating and can create a multitude of problems if not adequately addressed and corrected. Percutaneous vertebroplasty (PV) and balloon kyphoplasty (BKP) are two options available to patients to address the pain associated with SCC [6,52,155]. The goal with either procedure is to stabilize the spine, restore height to the vertebral column, and eliminate the pain [154]. Pain relief has reportedly been sustained over long postoperative periods in patients with MM [154]. The International Myeloma Working Group recommends that patients with significant pain at a fracture site be offered either a PV or a BKP procedure and that the procedure should be performed within four to eight weeks unless there are medical contraindications [154]. Early intervention has been demonstrated to improve clinical outcome and quality of life [156,157].

Vertebroplasty

Vertebroplasty is performed either in the outpatient setting or during an inpatient hospitalization, if warranted. Anesthesia in the form of moderate sedation with local anesthesia or general anesthesia is administered [154]. Preprocedure standards for both vertebroplasty and balloon kyphoplasty require:

Either an interventional radiologist or orthopedist will perform the vertebroplasty. To undergo the vertebroplasty, the patient will be required to lie in the prone position; care is required in positioning the patient to prevent rib fractures due to boney disease. Under fluoroscopy, the vertebral body is injected with radiopaque acrylic bone cement. One to three vertebrae may be injected at any one time [154].

During the procedure, there is a potential for cement to leak from the site and migrate to the lungs, with the possibility of minor to more serious side effects occurring [154,158]. However, according to the literature, few adverse events (e.g., pulmonary embolism) have been reported.

Balloon Kyphoplasty

Balloon kyphoplasty requires a more involved procedure than vertebroplasty. It is performed by an orthopedic surgeon using general anesthesia for the sedation; this may require an overnight stay in the hospital. Two small incisions are made in the skin, which allows a pathway to be tunneled into the vertebra and the positioning of a balloon on both sides of the vertebra. The height of the vertebra is restored with the use of a bone tamp, and the cement-filled balloon is then positioned in place. After the space in the vertebra is filled with cement, the balloon can be removed. One of the advantages of the balloon kyphoplasty is a reduced risk of cement leakage. There is, however, the risk that some of the bone marrow may be displaced into the lungs. Again, according to the literature, the risks associated with this procedure appear to be minimal [154,159].

With completion of either vertebroplasty or balloon kyphoplasty, patients are required to remain flat in bed for at least one hour, allowing time for the cement to harden. In addition to routine postoperative vital signs, the operative site should be monitored for any bleeding or swelling; generally, no more than a small bandage covers the site.

If the procedure is successful, patients report that back pain is minimal if not completely resolved [154].

In normal renal function, approximately 50 mg of free light chains, comprised of kappa or lambda chains, are excreted on a daily basis [18]. These light chains are filtered and reabsorbed in the proximal tubule within the nephrons. In patients with MM, a reverse of this process happens; light chains build up when they are not catabolized by lysosomal enzymes and are unable to be resorbed by the proximal tubular cells. Resisting the actions of the enzymes or proteases, the chains are not degraded. Damage from the light chains causes atrophy of the cells within the proximal tubule. Leaving the damaged proximal tubules, the light chains progress to the distal tubule and collecting duct in the nephron. Here, further damage results when light chains precipitate with Tamm-Horsfall mucoprotein (THMP) on the ascending wall of the loop of Henle. The chains and THMP precipitate, forming hyaline casts [163]. Aggregation of casts causes obstruction within the tubules and prevents the flow of urine. THMP is implicated in sodium homeostasis, blood pressure regulation, and a defense molecule against infections in the urinary system. Investigations have focused on the immunomodulatory effects of THMP on immune cells and on THMP as a disease biomarker of acute and chronic kidney diseases [164]. Evidence also indicates that the mucoprotein has an affinity for and binds to Escherichia coli[165].

With damage to the tubules, dehydration subsequently follows. This is compounded even further by underlying hypercalcemia. With nausea and/or an inability to drink adequate fluids, the cycle continues. This perpetuates an even further reduction of the flow of urine through the impaired kidneys created by the casts blocking the tubules [27,28,131].

The Department of Veterans Affairs guideline panel suggests that periodic evaluation for chronic kidney disease be considered in patients with multiple myeloma.

(https://www.healthquality.va.gov/guidelines/CD/ckd/VADoDCKDCPGFinal5082142020.pdf Last Accessed: March 14, 2024)

Level of Evidence: Expert Opinion/Consensus Statement

There may be few physical signs and symptoms exhibited with early renal impairment. When present, they may include:

Several factors may contribute to the development of renal failure in patients with MM, including [18,131]:

Determining the cause of renal failure is of paramount importance in effectively managing the symptoms and preventing additional complications. Assessment of patients should begin with a complete history and physical examination. Additional laboratory and imaging tests may include:

Several referrals may be necessary to effectively address renal failure. The first referral is often to a nephrologist. A referral to interventional radiology may be necessary for placement of a dialysis catheter for plasmapheresis or renal dialysis.

The initial treatment approach for renal failure in patients with MM is treatment of the underlying malignancy. VAD is effective when rapid reduction in the M protein is a priority. Cyclophosphamide or melphalan and prednisone at a reduced dose may be the preferred choice for older patients. The efficacy of bortezomib in relapsed and refractory MM has been discussed. Studies have also shown that bortezomib-based regimens may be effective in patients with MM who present with renal failure [166,167,168,169,170]. If angiotensin-converting enzyme (ACE) inhibitors and diuretics are being taken, they should be discontinued immediately. Diet modification is often also necessary.

Intravenous fluids may be necessary to maintain volume homeostasis. Urine alkalinization should be monitored, and if necessary, IV sodium bicarbonate infusion may be administered.

As with many complications, glucocorticoids are often administered. If anemia is present, erythropoietin or blood transfusion may be ordered [52]. Allopurinol may be included in the medication regimen to prevent hypercalciuria from chemotherapy [75]. If hypercalciuria is present, it may be reduced by the use of IV bisphosphonates [52,75]. Hyperkalemia may be corrected with either oral or rectal sodium polystyrene sulfonate. In severe cases, plasmapheresis or renal dialysis may be required.

If the patient has a central venous access device, astute care is pivotal in preventing line sepsis; conversely, if the central venous access device is deemed to be the source of infection, blood cultures and the initiation of IV antibiotics with subsequent line removal will be ordered [28,131].

Plasmapheresis

If standard treatment is not sufficient to reverse the renal failure, plasmapheresis, or more drastically renal dialysis, may be offered to patients in an attempt to prolong survival [52]. In order to carry out the plasma exchange, a catheter will be placed in interventional radiology after an informed consent has been obtained. A current PT/INR with CBC is required. For patients taking lenalidomide, thrombocytopenia may be an issue. Platelets should be available for administration just prior to this procedure if the platelet count is low. If a patient's mentation does not allow him or her to sign an informed consent, a healthcare proxy or legally designated decision maker will be requested to do so. After the vascular catheter is in place, transfer of the patient to a unit equipped to perform the plasma exchange will be necessary. Most institutions have policies requiring nurses to complete training and/or receive certification in order to flush implanted catheters for plasma exchange and/or renal dialysis [28,52].

Nursing care of patients with MM and renal compromise is relatively involved. Of course, patient safety should be strenuously maintained. Several factors should be continuously monitored to ensure that interventions are effective and that the condition is not worsening. Strict and accurate intake and output measures should be recorded. The patient should also be weighed daily; typically, the dry weight (before patient eats breakfast) is measured. A Foley catheter may be inserted to measure hourly urine output.

Vital signs should be closely monitored. Blood pressure will decrease in cases of hypovolemia, and a fever may indicate sepsis, which may not be reflected with neutropenia. Laboratory results should also be regularly assessed. Bleeding precautions for thrombocytopenia and compromised host precautions for neutropenia should be initiated. In many cases, continuous EKG monitoring for hyperkalemia is necessary.

Skin turgor should be evaluated for signs of dehydration or fluid overload. Fluid overload is a particular concern if the patient is rigorously rehydrated. Oral fluid intake should be encouraged when nausea is controlled and the patient is no longer at risk for aspiration. Administration of antiemetics may be indicated. Amino glycosides should be held for 48 hours after the patient has received contrast for CT scans [27,28,72,90]. The oncologist may write an order requesting the pharmacy to adjust medication doses according to renal function.