Multiple Myeloma

Multiple myeloma is a type of blood cancer that develops from plasma cells, a specialized white blood cell involved in antibody production. In multiple myeloma, malignant plasma cells proliferate uncontrollably in the bone marrow and often produce abnormal antibodies that have no function. These cancerous cells and antibodies can cause a number of problems.

Patients with multiple myeloma may experience bone pain or fractures, fatigue, frequent infections, kidney failure, high blood calcium, and anemia. While currently incurable, multiple myeloma is treatable. Treatment options range from chemotherapy and corticosteroids to newer targeted therapies, immunotherapies, and stem cell transplants aimed at achieving remission. Median 5-year survival is around 50%, but outlook depends greatly on individual factors. With advancing modern treatments, survivals extending 10 years or more are becoming more common.Ongoing research strives to unlock new drug combinations, immunotherapies, and personalized medicine approaches to make durable remissions possible for all patients. The ultimate goal is transforming myeloma into a manageable chronic condition rather than a lethal disease.

Executive Summary

  • Multiple myeloma (MM) is a blood cancer arising from malignant plasma cells in the bone marrow. These cancerous cells crowd out healthy cells, leading to impaired immune function and abnormal protein production.

  • MM is the second most common hematologic malignancy, with a higher prevalence in individuals over 60, Black people, and those with a family history of the disease. Exposure to radiation or certain chemicals, as well as conditions like MGUS and a weakened immune system, can also increase risk.

  • MM progresses through stages, starting with a pre-malignant phase known as MGUS. Genetic alterations and further cellular changes drive the progression to symptomatic MM, characterized by organ damage and diverse clinical presentations.

  • Diagnosis involves a combination of blood tests, imaging studies, and bone marrow examination. Treatment strategies have evolved significantly, with improved survival rates attributed to novel therapies targeting malignant cells and addressing complications.

  • Current treatment approaches include chemotherapy, immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and targeted therapies. The choice of treatment depends on disease stage, individual risk factors, and the presence of complications.

  • While MM remains incurable, advancements in treatment have led to improved survival rates and enhanced quality of life for patients. Ongoing research focuses on novel therapies and combination approaches to further extend survival and potentially achieve long-term remission.

Multiple Myeloma in Depth

Definition and Overview

Multiple myeloma is a blood cancer that affects plasma cells in the bone marrow. Healthy bone marrow produces antibodies to defend against infection.

In multiple myeloma, cancerous plasma cells grow uncontrollably and crowd out normal infection-fighting cells. Malignant plasma cells produce abnormal M protein, a hallmark of multiple myeloma.

Incidence and Prevalence

MM accounts for 1% of all cancers and is the second most common hematologic malignancy after lymphoma. In 2016, there were estimated to be 24,2802 to 30,330 new cases and 12,650 deaths. The global 5-year prevalence is around 230,000 patients. In the Western world, the incidence rate is about 5 cases per 100,000 people. The median age at diagnosis is around 66-70 years, with 37% of patients under 65. MM is rare in people under 30, with a reported frequency of 0.02% to 0.3%, and slightly more common in men.

Risk Factors

The following factors can raise a person's risk of developing myeloma:

Age

Myeloma is most common in people over 60. The average diagnosis age is 70 years with 2% of cases occurring in people under 40.

Race

Myeloma is more common in Black people than in White people with prevalence noted in the Middle East, North Africa, and the Mediterranean region.

Medical conditions

Pernicious anemia may increase the risk of myeloma and MGUS.

Family history

Individuals with a family history of myeloma or MGUS have a 2 to 3 times higher risk of developing these conditions compared to those without a family history. The reason for the increased risk is unclear. More research is needed to understand how family history affects myeloma risk.

Weakened immune system

Organ transplant patients on immunosuppressive medications have a higher risk of myeloma; however, this risk is low with <1% of organ transplant recipients developing myeloma. Furthermore, HIV increases myeloma risk.

Gender

Myeloma is more common in men. The reasons for this are unclear and could involve various factors such as genetics and lifestyle.

Radiation or chemical exposure

Exposure to radiation, asbestos, benzene, pesticides, and chemicals used in rubber manufacturing may increase the risk of developing myeloma. Carpenters, furniture makers, and paper makers are at higher risk due to exposure to wood products. Myeloma is also common among firefighters and those exposed to herbicides like Agent Orange.

MGUS

A small amount of M protein in the blood increases the risk of developing myeloma, lymphoma, or Waldenstrom macroglobulinemia by 1% to 2% per year. 

Monoclonal gammopathy of undetermined significance (MGUS) involves an excess of large protein molecules called immunoglobulins in the blood. MGUS is commonly detected incidentally during routine blood tests. It typically doesn't cause symptoms or require treatment. However, few MGUS patients develop myeloma. MGUS patients see a specialist regularly for check-ups.

Pathophysiology of Multiple Myeloma

Chemistry

MM is a stage in monoclonal gammopathy. It is believed to come from a pre-malignant phase of MGUS. MGUS involves the detection of monoclonal immunoglobulins in the blood or urine without organ damage. It is common and detectable in over 3% of people over 50. The cell of origin is a post-germinal center plasma cell. MGUS is usually harmless, but there is a 1% risk of it developing into MM each year.

The causes of MGUS development and progression to MM are unknown. Genetic alterations can increase promoter gene expression and resistance to apoptosis, leading to higher plasma cell proliferation and population. As per the "second hit" hypothesis, progression may occur due to additional cytogenetic lesions acquired by the original plasma cell clone, due to genetic instability or abnormalities in the hematopoietic microenvironment.

Excess monoclonal immunoglobulins can cause hyperviscosity, platelet dysfunction, and renal tubular damage, leading to neurologic derangements, bleeding, and renal failure. Marrow occupation by plasma cell clones causes anemia, thrombocytopenia, and leukopenia. The interaction between myeloma cells and the bone microenvironment leads to osteoclast activation and osteoblast suppression, causing bone loss. Many signaling cascades, chemokines, and interleukins are involved in this process.

MM clonal plasma cells (PCs) are found in multiple skeletal sites at the time of diagnosis. Malignant clonal plasma cells establish themselves in bone marrow niches during initial disease development. Clonal PCs migrate and populate the bone marrow, leading to the development of pre-myeloma disease stages like MGUS, smoldering MM, and MM. Multiple tumor lesions in the bone marrow are a defining feature of MM. Elevated numbers of MRI-detectable lesions are a predictor of poor prognosis in asymptomatic or symptomatic myeloma. 

Poor outcomes and elevated clonal PCs in peripheral blood are independent of bone marrow (BM) tumor burden, indicating a role for circulating PCs in MM disease progression and relapse after therapy. MM PCs are important in aggressive forms of MM, such as extramedullary disease and plasma cell leukemia (PCL). 

MM PCs disseminate like solid tumor metastasis, losing adherence to BM microenvironment cells that normally keep them in the niche. Tumor cells migrate through blood vessels to secondary sites. Tumor cells must stop on the BM endothelium and move out of the blood into tissues by following chemotactic factors produced by BM cells to reach new BM sites. The last stage of MM PC dissemination involves colonizing new BM sites to support tumor cell growth.

Clinical Presentation and Symptoms

MM's presentation varies from patient to patient. The disease can have a gradual onset but also cause severe symptoms. In older adults, constitutional symptoms or CRAB (hypercalcemia, renal dysfunction, anemia, and/or bone pain with lytic lesions) are commonly observed. In a single-institution study on newly diagnosed MM, the most common symptoms were anemia (73%), bone pain (58%), elevated creatinine (48%), fatigue (32%), hypercalcemia (28%), and weight loss (24%).

Hypercalcemia from bone demineralization can cause increased thirst, urination, bone pain, abdominal pain, nausea/vomiting, and altered mental status. Renal failure from light chain case nephropathy and/or hypercalcemia can cause edema, acidosis, and electrolyte disturbances. Anemia can develop due to bone marrow replacement or decreased erythropoietin levels. Symptoms may include fatigue, pallor, palpitation, and worsening of previous heart failure or angina. Bone pain from osteolytic lesions can cause fractures, vertebral collapse, reduced height, spinal cord compression, radicular pain, or kyphosis.

Peripheral neuropathy and carpal tunnel syndrome may occur. If identified, further investigation is needed as this is usually associated with an underlying component of amyloidosis. Hyperviscosity symptoms may include bleeding, confusion, neurologic symptoms, vision changes, or heart failure. Identifying these findings is crucial as it is a medical emergency. MM patients are more prone to infections, especially pneumonia and pyelonephritis. Assessing for recurrent illness is important.

Diagnosis

Diagnosis

  • CBC with platelets, peripheral blood smear, and chemistry panel (BUN, creatinine, calcium, uric acid, LDH)

  • Serum and urine protein (24-hour collection) electrophoresis, immunofixation, quantitative immunoglobulins, serum-free light chains, X-rays (skeletal survey), PET-CT scan or whole-body MRI

  • Bone marrow examination, including cytogenetics and FISH studies.

Multiple myeloma is suspected in patients over 40 years old with persistent unexplained bone pain, especially at night or at rest, along with other typical symptoms or unexplained laboratory abnormalities (such as elevated blood protein or urinary protein, hypercalcemia, renal insufficiency, or anemia), or x-rays showing a pathologic fracture or lytic lesions.

Lab evaluation includes routine blood tests, LDH, serum beta-2 microglobulin, urine and serum immune and protein electrophoresis, and serum free light chains. Patients should undergo a skeletal survey, PET-CT scan, or whole-body MRI to detect bone disease. A bone marrow examination is needed along with conventional cytogenetics and FISH studies.

Routine blood tests include CBC and a chemistry panel. 80% of patients have normocytic-normochromic anemia with rouleaux formation, which is the clustering of 3 to 12 red blood cells in stacks. WBC and platelet counts are typically normal. BUN, creatinine, LDH, beta-2 microglobulin, and uric acid levels may be high. Anion gap can be low. 10% of patients have hypercalcemia at diagnosis.

Immune and protein electrophoresis are done on serum and concentrated urine samples to measure urinary M-protein levels. Serum electrophoresis detects M-protein in 80-90% of patients. Around 10 to 20% of the remaining patients have detectable free monoclonal light chains (Bence Jones protein) in their urine protein and immune electrophoresis tests. Patients rarely have IgM, IgD, or IgE disease. Some patients don't have monoclonal protein at diagnosis, but more develop it as the disease progresses.

Immunofixation electrophoresis identifies the immunoglobulin class of the M-protein and can detect light-chain protein if serum immunoelectrophoresis is negative. It is performed when multiple myeloma is strongly suspected, even if the serum test is negative.

Serum free light-chain analysis can confirm the diagnosis, monitor therapy efficacy, and provide prognostic data.

Beta-2 microglobulin level is measured to confirm or likely diagnose, and along with serum albumin, it stages patients in the international staging system. Beta-2 microglobulin is a protein on all cell membranes. Concentration varies with tumor mass and renal dysfunction severity.

X-rays include a skeletal survey. 80% of cases have punched-out lytic lesions or diffuse osteoporosis. Bone scans are usually not helpful. Whole-body MRI is used to provide more detail when there are specific sites of pain or neurologic symptoms. PET-CT scans provide prognostic information and help determine solitary plasmacytoma or multiple myeloma.

Bone marrow aspiration and biopsy reveal ≥ 10% plasma cells, indicating myeloma. Bone marrow involvement in myeloma can be patchy, so some patient samples may have less than 10% plasma cells. Plasma cell percentage in bone marrow is usually abnormal. Plasma cell morphology does not correlate with immunoglobulin class. Chromosomal studies on bone marrow can reveal karyotypic abnormalities in plasma cells that affect treatment choices and survival.

Diagnosis and differentiation from other malignancies and monoclonal gammopathy typically require multiple criteria.

  • Clonal bone marrow plasma cells or plasmacytoma.

  • M-protein in plasma and/or urine.

  • Organ damage (hypercalcemia, renal insufficiency, anemia, bony lesions)

  • Myeloma is indicated by Bence Jones proteinuria > 200 mg/24 hour or abnormal serum-free light chain levels, osteolytic lesions, and sheets or clusters of plasma cells in the bone marrow.

Treatment Approaches

Myeloma treatment has improved in the past 20 years, and long-term survival is now a realistic goal. Therapy treats malignant cells in symptomatic patients or those with myeloma-related organ dysfunction.

Conventional chemotherapy for symptomatic patients

  • Thalidomide, lenalidomide, or pomalidomide, and/or bortezomib, carfilzomib, or ixazomib, with corticosteroids and/or chemotherapy.

  • Monoclonal antibodies: elotuzumab, isatuximab, daratumumab.

  • For relapsed or refractory myeloma, SINE selinexor and histone deacetylase inhibitor panobinostat are used.

  • For relapsed or refractory myeloma, immune-based treatments target BCMA, highly expressed on myeloma cells.

  • Venetoclax is an inhibitor for patients with the t(11;14) genetic marker.

  • Maintenance therapy options include corticosteroids, thalidomide, lenalidomide, and oral ixazomib.

Autologous stem cell transplantation possible.

Consider radiation therapy for specific symptomatic areas resistant to systemic therapy.

Treatment of complications such as anemia, hypercalcemia, renal insufficiency, infections, and skeletal lesions (particularly those at high risk of fracture).

Treatment response- Defining response to cancer treatment is indicated by.

  • Decreases in M-protein levels in serum and urine.

  • Decreased levels of serum free light chain.

  • Increased red blood cell count.

  • Renal function improvement in patients with renal failure.

  • Normalizing calcium levels in individuals with high levels.

  • Reduced bone pain.

  • Fatigue decrease.

Autologous peripheral blood stem cell transplantation may be considered for patients with stable or responsive disease after initial therapy, and who have adequate cardiac, hepatic, pulmonary, and renal function. Newer treatments are effective and may reduce or eliminate the need for transplantation. Recent clinical trials found that stem cell transplantation as part of initial therapy resulted in longer progression-free survival, but did not improve overall survival.

Allogeneic stem cell transplantation after nonmyeloablative chemotherapy or low-dose radiation therapy can result in 5 to 10 years of myeloma-free survival in certain patients. Allogeneic stem cell transplantation with chemotherapy is still experimental due to the high risk of graft versus host disease.

Maintenance therapy

Maintenance therapy with nonchemotherapeutic drugs, like interferon alfa, has been attempted. It extends remission but does not enhance survival and has notable adverse effects. Corticosteroids alone are effective for maintenance treatment after a positive response to corticosteroid-based regimens.

Thalidomide and lenalidomide are effective maintenance treatments. There are concerns about secondary malignancies in patients on long-term lenalidomide therapy, particularly after autologous stem cell transplantation. Consider the risk of secondary cancers versus improved survival.

Ixazomib is effective as a single agent for maintenance therapy but it is unknown if ixazomib combined with lenalidomide is more effective.

The role of antibodies in maintenance therapy is unclear.

Risk factors for rapidly treating myeloma in patients with organ dysfunction include:

Patients with these risk factors have active myeloma and need immediate treatment, despite no improvement in overall survival shown in most early treatment trials. Immediate treatment is typically not given to patients without risk factors or end-organ dysfunction unless symptoms or complications arise.

Treatment of malignant cells

In the past, conventional chemotherapy for multiple myeloma involved using oral melphalan and prednisone in cycles of 4 to 6 weeks for 8 to 12 cycles, with monthly response evaluations. Superior outcomes have been achieved with proteasome inhibitors (bortezomib, carfilzomib, or ixazomib) or immunomodulatory agents (lenalidomide or thalidomide).

Chemotherapeutic agents like cyclophosphamide, bendamustine, doxorubicin, and liposomal pegylated doxorubicin are more effective when combined with an immunomodulatory drug (thalidomide, lenalidomide, or bortezomib). 

Initial treatment with bortezomib, lenalidomide, and corticosteroids improves survival. Adding daratumumab to bortezomib and dexamethasone improves outcomes.

Treating relapsed or refractory myeloma

Combining proteasome inhibitors with immunomodulatory agents and other treatments may be used for patients with relapsed or refractory myeloma. These drugs are often combined with other effective drugs that the patient hasn't tried yet. However, patients who have had long remissions may respond well to the same treatment that initially put them in remission. Patients who don't respond to one drug combination may respond to a different drug in the same class.

Monoclonal antibodies can be effective in relapsed or refractory myeloma and include daratumumab, isatuximab, elotuzumab. Combining these antibodies with thalidomide, lenalidomide, pomalidomide, and dexamethasone enhances their effectiveness. Daratumumab is more effective when combined with bortezomib and dexamethasone. Additionally, both daratumumab and isatuximab show improved efficacy when added to carfilzomib and dexamethasone. Treatment with monoclonal antibodies and dexamethasone alone is effective in many patients without additional costs or adverse effects.

Selinexor and panobinostat are effective when combined with other myeloma medications.

Three B-cell maturation antigen (BCMA)- targeting immune treatments are available. Treatments for myeloma include cellular therapies like CAR-T cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) and a bispecific antibody called teclistamab that targets CD3 on T cells. Effective treatments can cause acute adverse effects (cytokine release syndrome, neurologic problems) and a high risk of severe infections.

Venetoclax is effective for treating myeloma patients with the genetic marker t(11;14).

Treatment of Complications

Besides treating malignant cells, therapy should also address complications.

Anemia

Recombinant erythropoietin can treat anemia in patients who do not respond well to chemotherapy. Transfuse packed red blood cells if anemia causes cardiovascular or significant systemic symptoms. Plasma exchange is rarely needed for myeloma patients with hyperviscosity. Patients with myeloma may need intravenous iron for reasons unrelated to their iron deficiency. Anemia patients should regularly measure serum iron, transferrin, ferritin, and vitamin B12 levels to monitor iron stores.

Hyperuricemia

Hyperuricemia can occur in patients with high tumor burden and metabolic issues. Most patients don't need allopurinol. Allopurinol or rasburicase is used for patients with high serum uric acid or tumor burden and a high risk of tumor lysis syndrome.

Renal Compromise

Adequate hydration can improve renal compromise. Patients with high levels of Bence Jones proteinuria (≥ 10 to 30 g/day) can still have normal kidney function if they have a urine output > 2000 mL/day. Dehydration and high-osmolar IV contrast can cause acute oliguric renal failure in patients with Bence Jones proteinuria. Plasma exchange can be effective in certain cases. Avoid nephrotoxic drugs. Prompt treatment of myeloma is crucial to reduce nephrotoxic monoclonal immunoglobulin levels and reverse the condition.

Hypercalcemia

Hypercalcemia is treated with saluresis, IV bisphosphonates (preferably zoledronic acid), and sometimes calcitonin or prednisone. Denosumab treats hypercalcemia in patients with severe renal failure. Avoid calcium-rich foods, calcium supplements, and vitamin D.

Infection

Infection risk increases during chemotherapy-induced neutropenia. Herpes zoster virus infections are common in patients treated with specific antimyeloma drugs, including proteasome inhibitors (bortezomib, carfilzomib, ixazomib) and monoclonal antibodies (daratumumab, isatuximab, elotuzumab). Newer BCMA treatments have a high risk of severe infection.

Treat documented bacterial infections with antibiotics. Routine antibiotic prophylaxis is not recommended.

Antiviral drugs are used preventively for patients on proteasome inhibitors or monoclonal antibodies.

Prophylactic IV immune globulin is typically used for patients with low immunoglobulin levels and frequent infections to reduce infection risk.

Pneumococcal and influenza vaccines are not effective in most patients with immune deficiency. Live vaccines not recommended for immunocompromised patients. The nonviable recombinant zoster vaccine is less effective than the live-attenuated zoster vaccine for preventing herpes zoster.

Skeletal lesions

Skeletal lesions need multiple supportive measures. Maintaining mobility and taking calcium and vitamin D supplements can help protect bone density. Measure vitamin D levels at diagnosis and periodically, adjusting dosing accordingly. Analgesics and low-dose radiation therapy (18 to 24 gray) can relieve bone pain. Radiation therapy can cause toxicity and may affect the patient's ability to receive chemotherapy.

Patients with lytic lesions and generalized osteoporosis or osteopenia should receive a monthly IV bisphosphonate (pamidronate or zoledronic acid). Bisphosphonates reduce skeletal complications, bone pain, and may have an antitumor effect. Monthly denosumab is an option for patients with reversible renal failure from myeloma, not caused by hypercalcemia or infusion reactions from bisphosphonate infusion. Denosumab is given subcutaneously, is not cleared by the kidneys, and does not cause infusion reactions. Bisphosphonates and denosumab can rarely cause jaw osteonecrosis. Maintaining good dental health and avoiding dental implants can help reduce the risk of complications.

Novel Therapies and Research

Immune therapies in MM include IMiDs, MoAb-based therapies, checkpoint inhibitors, HDAC inhibitors, vaccines, and cellular therapies.

  • IMiDs trigger MM cell apoptosis, inhibit tumor cell adhesion to the BM, modulate cytokines, inhibit angiogenesis, and enhance T cell, NK cell, and NK-T cell function, while reducing T regulatory cells. Cereblon (CRBN) binding is linked to both cytotoxic and immune-related effects of IMiDs. They enhance the effectiveness of monoclonal antibodies and elotuzumab, which targets SLAMF-7, is approved for treating relapsed refractory MM with lenalidomide. 

  • MM cells, MDSCs, and pDCs express PD-L1 and promote MM cell growth while suppressing the immune function. T and NK cells express PD-1. Checkpoint blockade induces MM cell specific CD4 and CD8 cytolytic T cells (CTLs) and NK cell cytotoxicity, inhibiting MM cell growth in the BM milieu. 

  • Lenalidomide shows clinical efficacy with PD-1 blockade. HDAC6 inhibitor enhances MM cytotoxicity and complements MoAb and PD-L1 antibody. Peptide-based vaccines are being studied to target multiple tumor-associated antigens on MM cells and prevent the progression of SMM to active disease. MM cell/DC fusion vaccines are also being studied to treat minimal residual disease after transplantation and improve outcomes. In both cases, vaccination triggers MM-specific T cell immune responses. Lenalidomide can enhance these responses. A randomized trial is currently comparing lenalidomide alone to lenalidomide plus MM cell/DC fusion vaccine after transplantation.

  • Combining vaccination with checkpoint inhibitors and HDAC6 inhibitors enhances T cell function, boosts anti-MM immunity, and stimulates cytokine production and activation molecules. The potential role of epitope spreading in targeting more tumor-associated antigens and boosting anti-tumor cytotoxic activities is being investigated. CAR T cells, immunotoxins, bispecific MoAbs, and CAR-T cells targeting BCMA have shown preclinical activity and early clinical promise. 

In the future, combining immune approaches such as IMiDs, MoAbs, checkpoint inhibitors, HDAC inhibitors, vaccines, and cellular therapies may provide long-lasting anti-MM immunity and durable response.

Prognosis and Survival Rates

Multiple myeloma is incurable but 5-year survival has improved to 58% due to treatment advances. Unfavorable signs at diagnosis include higher stage, lower albumin levels, higher beta-2 microglobulin levels, elevated LDH levels, specific cytogenetic abnormalities, and higher levels of malignant cells in the blood. Patients with renal failure have poor outcomes unless kidney function improves with therapy, which is typically achieved with current treatment options.

Patients with multiple myeloma should have end-of-life care discussions with clinicians, family, and friends due to the fatal nature of the disease. 

Trends in Survival and Treatment Response

Modern therapies, such as immunomodulatory drugs (IMiDs) and proteasome inhibitors, have improved survival rates for patients with MM over time. In a study, 5-year relative survival increased from 34% in 1989–1992 to 56% in 2001–2005. Siegal et al. found that 5-year relative survival rates for MM increased from 25% in 1975-1977 to 49% in 2005-2011, according to SEER data. The 2005-2011 period aligns with the initial approvals of bortezomib (2003) and thalidomide/lenalidomide (2006). In a 2008 Mayo report, patients who received PI or IMiDs had longer survival from relapse (31 vs 15 months). Patients diagnosed in the last decade had almost double the median survival time.