Multiple myeloma


In 2023, it is estimated that more than 35700 people will be diagnosed with multiple myeloma, and more than 12,590 people will die from the disease in the U.S.

A cancer of antibody producing cells.

More than 170,000 patients are living with the disease in the US.

Estimated 175,000 cases annually diagnosed worldwide.

Incidence about 5.6 cases per 100,000 people, and mortality rate 3.6 cases per 100,000 persons (SEER).

The incidence increases with age, with a median age at diagnosis of 69 years.

Men are more likely to develop myeloma than women.

With new therapies survival increased by 50% longer than patients treated with older treatments.

5-year survival nearly 50%.

Strongest risk factor is advancing age, and other risk factors include environmental or occupational exposure to herbicides, insecticides, petroleum products, heavy metals, plastics, dust particles, and asbestos.

If a parent or sibling has myeloma the risk for other immediate family members increases by 4.

Patients with Gaucher’s diseae 30 fold increased risk.

Obesity associated with a 2-3 times the normal risk.

Some studies have shown associations between multiple myeloma and excess body weight, particularly central obesity in adult women.

Obesity, older age, and racial-ethnic disparities can all contribute to the increasing incidence of plasmacytomas and multiple myeloma.

Five-year survival rate reported by SEER results increase from 24% in 1975 to 34% in 2003 because of newer and more effective treatment options.

Poor prognosis associated with decreased serum albumin, increased beta 2 microglobulin, the presence of abnormal cytogenetics, increased interleukin 6, increased C reactive protein, high lactate dehydrogenase, extra medullary disease, insufficiency, high serum free light chains, abnormal kappa/lambda ratio, increased plasma cell labeling index, cytogenetic changes and the presence of circulating plasma cells.

Poor prognosis and survival associated with short telomeres.

Almost all patients have abnormal chromosomes by fluorescence in situ hybridization including translocations, deletions, and aneuploidy but with standard metaphase analysis only 18-30% have abnormal karyotypes and is explained by low proliferative rate on multiple myeloma cells needed for conventional cytogenetics.

Cytogenetic abnormalities on conventional studies indicates the presence of a high proliferative rate malignancy with poor prognosis.

Smoldering myeloma defined as an asymptomatic process with an M protein in serum of greater than 3 g per liter or greater than 10% clonal plasma cells without organ or tissue impairment or symptoms.

Patients with smoldering multiple myeloma developed symptomatic myeloma at a rate of 10% per year for the first 5 years of followup, 3-4% per year for the next 5 years, and then after 10 years the risk is 1-2% per year.

In smoldering myeloma the M protein must be IgG or IgA subtype and the plasma cells must be clonal.

Smoldering myeloma evaluation requires followup every 3-6 months.

Smoldering multiple myeloma risk factors for progression of disease include plasma cell mass, M protein size, percentage of bone marrow clonal plasma cells, abnormal free light chain ratio, evolutionary pattern and pattern of magnetic resonance imaging abnormalities (Blade J).

Smoldering multiple myeloma must be distinguished from monoclonal gammopathy of unknown significance, symptomatic myeloma, and primary systemic amyloidosis.

Smoldering myeloma is now known as asymptomatic multiple myeloma and represents a progression of MGUS with a greater burden of plasma cells in the bone marrow, that is greater than 10%, and a higher annual risk of transformation to multiple myeloma, 10% for the first five years with subsequent reduction.

Patiens with a free lightc chain ratio of <0.125 or >8 have an increased progression to symptomatic myeloma.

Smoldering will evolve into symptomatic disease in a range between 2 and 3 years.

In smoldering the risk of progression is increased in the presence of light chain proteinuria of greater than 50 mg per 24 hours and findings of IgA monoclonal heavy chains.

The presence of asymptomatic lytic lesions implies a poor prognosis with the median time to progression for smoldering myeloma of less than one year, that explains why these lesions are excluded from patients with this diagnosis.

At the time of diagnosis two thirds of patients have bone pain, and are likely to subsequently sustain pathological fractures, particularly of the skull, spine and ribs.

70-80% of patients will have bone involvement, with risk for skeletal related events.

Uncoupling of normal bone remodeling results in cancer-inducing bone destruction.

Extended survival associated with increased risk of skilled related events.

A prior malignancy associated with a 40% increased risk of developing a subsequent malignancy (Jonsdottir).

Multiple myeloma bone lesions usually do not heal, and fractures can result in permanent disability and may require surgery or joint replacement.

In patients with MM untreated for osteolytic lesions the median time to first skeletal related event is approximately 9 months (Berenson JR).

The risk of fracture is higher than for cancer of the breast, prostate, or lung.

Pathologic fractures associated with 20-44% increased risk for death..

Time to progressive disease for a low risk group with smoldering myeloma is 3-8 years while for high risk patients they will evolve into symptomatic disease within one to 2 years after diagnosis.

Treatment for smoldering myeloma is observation.

Majory of patients with high risk smoldering myeloma patients evolve into myeloma that requires treatment.

Active and symptomatic disease requires one or more of the following: calcium elevation of greater than 11.5 g per deciliter, renal insufficiency with creatinine of 2 mg per deciliter or greater, anemia with hemoglobin of less than 10 g, and lytic or osteopenia bone disease.

Anemia occurs in 75% of patients.

A heterogeneous disorder with variable outcomes, as some patients may live for only several months, while others can survive a decade or more.

At diagnosis 5% have localized tumors, designated plasmacytomas, and 95% have systemic diseasewith bone marrow involvement.

80% of patients have osteolytic lesions.

Survival correlates with stage of the disease with the 5 year survival is 67.6% for localized disease and substantially higher than patients with generalized and more advanced disease at about 42%.

The disease course varies from indolent to aggressive.

Renal impairment occurs in 20 to 40% of newly diagnosed patients.

Acute renal injury in myeloma is a medical emergency and antimyeloma therapy needs to be initiated immediately.

Kidney injury complicated 50% of patients with multiple myeloma and is associated with increased morbidity and mortality.

Renal insufficiency limits treatment options as it disqualifies patients with stem cell transplantation.

Multiple myeloma disqualifies patients for kidney transplants for renal failure.

Patients with multiple myeloma who do not recover renal function have a higher risk of death.

All patients with myeloma at diagnosis should have serum creatinine, estimated GFR, electrolyte measurements as well as free light chain and urine electrophoresis of a sample from a 24-hour urine collection.

Malignant plasma cells produce abnormal antibody proteins including intact immunoglobulins, light chains, and even fragments of light chains

When these abnormal proteins are caried into the kidney they can block urine flow or form deposits that damage the kidney tissue.

The damage that forms prevents toxins other on wanted multiple on passing into the urine and must accumulate in the blood.

To diagnosed kidney disease or myeloma requires definitively a biopsy, but this has been used sparingly.

The presence of renal impairment is associated with shorter overall survival and increased early death rates compared to patients with normal kidney function.

The median survival of patients with renal involvement is less than two years.

Renal impairment in patients with myeloma is caused mainly by the toxic effects of the monoclonal light chain on basement membranes of the glomeruli and or the renal tubule.

The presence of renal impairment with a creatinine of 2 mg per deciliter or greater is defined as having substage B for stages, I,II, and III Durie-Salmon multiple myeloma staging system.

Patients with creatinine of 2 mg per deciliter or greater are categorized as stage III in ISS staging system, as 82% of such patients have a Beta2-microglobulin value of greater than 5.5 mg per liter.

Patients with hyperdiploid karyotypes have good prognosis with chemotherapy induction and high dose chemotherapy with bone marrow transplantation.

Patients with the (4:14) or 17p gene deletion have poor prognosis with most conventional therapy.

Chromosome 13 abnormalities associated with unfavorable outcomes after conventional and stem cell transplant treatments.

Aneuploidy occurs frequently with monosomies including chromosomes 13, 14, 16 and 22 more frequent than trisomies of 3, 5, 7, 9, 11, 15, 19 and 21.

Abnormalities involving chromosome 1q such as gain or amplification is associated with unfavorable outcomes and is observed in his many is 40% of newly diagnosed MM patients.

Hyperdiploid changes are associated with multiple trisomies and a low incidence of IgH translocations.

Nonhyperdiploid lesions have a high prevalence of IgH translocations.

In IgH translocations associated with 5 recurrent chromosomal partners including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (fibroblast growth factor receptor 3), 16q23 and 20q11.

CD138 immunostains utilized for quantification of myeloma.

Cross talk of myeloma cells with osteoblasts, osteoclasts, stromal cells, and T cells occur through cell to cell contact, or by chemokine, of cytokine adhesion molecule and metalloprotease over production.

MM is characterized by a reduction in diversity and function of T cells and natural killer cells as well as increased regulatory T cells and myeloid derived suppressor cells, leading to immune dysfunction which can contribute to disease progression and treatment resistance and more susceptibility to infections.

Most common symptoms on presentation are fatigue, bone pain and recurrent infections.

Cortical bone and medullary compartments are linked anatomically, but are functionally distinct.

Bone findings result of either inhibition of osteoblastic activity and or activation of osteoclast activity.

Cortical involvement results in endosteal scalloping, with invasion of the periosteum and at times extra osseous extension.

Bone lesions most commonly involve the vertebra, ribs, skull, pelvic bones and femur in descending order.

The presence of three or more focal bone lesions is indicative of an unfavorable prognosis.

Distal bone involvement is less common than proximal bone involvement.

Diffuse osteopenia without focal bone lesions and sclerotic bone lesions may occur, uncommonly.

Plasmacytomas mostly arise as direct extension from skeletal tumors when they disrupt cortical bone.

Susceptibility to infection is due in part to a decreases in the production of normal immunoglobulins, defects in the complement system and other processes that occur with myeloma.

Predisposition to infection with encapsulated bacteria, such as Streptococcus pneumoniae, and Haemophilus influenzae.

Increased susceptibility to infection also related to immunosuppressive agents utilized to treat the disease.

Cumulative immunosuppression of the disease and its treatments result in emergence of infections, such as cytomegalovirus, varicella zoster, Aspergillus spp. and Fusarium spp.

In recent ears changes in the spectrum of infections, with an increased risk of fungal infections, such as aspergillosis and fusariosis.

Probable change of infections related to progressively aggressive treatments.

Invasive aspergillosis after hematopoietic stem cell transplant (HSCT) increasingly common and the risk is 4.5 times higher than patients with chronic myelogenous leukemia in chronic phase (Marr KA).

Anemia present in about 70% of patients at the time of diagnosis.

Serum creatinine is elevated in almost half of patients.

About 15% have hypercalcemia.

Approximately 1-2% of patients have extramedullary disease at the time of initial diagnosis and 8% develop extramedullary disease later in the course.

Conventional x-ray studies reveal skeletal abnormalities in approximately 80% of patients and include fractures, lytic lesions and osteoporosis.

Bone scans and serum alkaline phosphatase levels are normal due to the absence of osteoblast activity.

The presence and extent of bone marrow and extramedullary involvement are important factors influencing prognosis and clinical management.

Radiographs are usually obtained for staging purposes, but are limited for evaluating early disease:whole body radiography has  been replaced by more sensitive imaging techniques.

MRI is more sensitive than radiographs in detecting bone marrow involvement however, such studies limited to the spine and pelvis would cause understaging in 10% of patients and will be normal in up to 20% of patients with stage I disease with only bone marrow involvement.

Whole body MRI outperforms radiographs, PET/CT in identification of small lesions and diffuse marrow involvement, and is probably the gold standard for imaging in myeloma.

PET/CT testing can distinguish between active and dormant lesions.

PET/CT-based approaches have high levels of sensitivity and specificity and are crucial for determining the prognosis in multiple myeloma.

Bone end-organ damage is detected and 70% of patients with myeloma at diagnosis.

MRI can identify up to 30% of patients with bone lesions not seem on metastatic bone survey, and is a recommended test in symptomatic patients with normal bone x-rays.

FDG PET is able to detect bone marrow involvement in patients with multiple myeloma, and is helpful in monitoring response to therapy as changes in metabolic activity of myelomatous lesions predict for clinical outcome.

Complete FDG suppression after treatment is associated with improved progression free and overall survival.

In multiple myeloma flow cytometry and gene sequencing can determine the presence of minimal residual disease, detecting as few as 1 myeloma cell among millions of normal cells.

Minimal residual disease-negative status after treatment with newly diagnosed disease is associated with long-term survival-meta-analysis (Munshi, NC).

Patients who are negative for MRD have a very good prognosis.

Patients with high risk cytogenetics who are negative for MRD also has nearly the same risk.

Skeletal complications cause pain, disability, decreased mobility and impaired quality of life which can be improved with treatment.

Front line treatment currently consists of induction therapy followed by transplant-free consolidation or in eligible patients to autologous stem cell transplant with subsequent maintenance to deepen and sustain disease response.

Autologous hematopoietic stem cell transplant improves survival in patients with multiple myeloma and upfront autologous HSCT in transplant eligible patients is the current standard of care.

Studies show upfront autologous, HSCT leads to better progression free survival compared to delaying autologous HSCT until telapse, but there is no significance in overall survival.

In high risk relapsed patients the estimated survival for refractory disease is only 13 months.

Transplantation  can be done immediately after achieving complete remission, but can also be reasonably delayed to a time of relapse.

Approximately 12% of patients are at risk of becoming transplantation ineligible when delaying autologous stem cell transplant.

Stem cells should be collected within 4 to 6 months of diagnoses in all transplantation eligible patients to insure this option is available in the future.

Surgery/radiation therapy are used to treat pathological fractures and the use of bisphosphosphonates is the standard of care for preventing and reducing the rate of skeletal related events in patients with bone metastases or osteolytic lesions.

Bisphosphonates are activate in myeloma as they work by interrupting the recruitment, maturation, and attachment of osteoclasts.

Bisphosphonates induce apoptosis inosteoclasts and in plasma cells.

Imbalance between osteoclast activation and osteoblast suppression with suppression of bone formation leading to purely lytic lesions.

Diagnostic criteria require the presence of at least 10% plasma cells on bone marrow examination, monoclonal protein in serum or urine and evidence of end-organ damage.

Urinary NTX (amino-terminal cross-linked telopeptide of type I collagen), serum CTX (carboxylate-terminal cross- linked telopeptide of type I collagen) and ICTP (CTX generated by matrix metalloproteinases) reflect severity of bone destruction and efficacy of treatment to bisphosphonates, and predict an increase of skeleton related events, disease progression, and overall survival (Terpos E et al).

Rarely involves extramedullary tissues, consisting of soft tissue masses of plasma cells with the aerodigestive tract the most commonly involved.

Soft tissue involvement reported in the orbits, ear canal, liver, spleen, kidneys and rectum.

Symptomatic disease characterized by end organ damage caused by plasma cell infiltration and proliferation and defined as CRAB with hypercalcemia, renal failure, anemia, bone disease.

Symptomatic disease is treated immediately, whereas asymptomatic disease requires clinical observation because early treatment does not show benefit.

The process involves both normal and malignant-cell biology, and treatment is targeted to both types of biology.

Worse outcomes associated with high beta2-microglobulin levels, high LDH levels, gene expression profile, and recurrent cytogenetic abnormalities.

Any chromosomal abnormality is associated with worse prognosis.

The presence of a T(4; 14), T(14; 16), or del(17p)  is uniformly excepted as a marker of worst prognosis.

Some studies identify genetic abnormalities in as many is 89% of patients with newly diagnosed multiple myeloma and 97% of patients with relapsed or refractory myeloma.

Recurrent mutations in KRAS, NRAS, and BRAF have been identified in myeloma with worse overall survival as does a TP53 mutation.

Mutations in the KRAS and NRAS genes can activate the MAPK/ERK pathway promoting cell proliferation and survival.

Depletion of the TP 53 tumor suppressor gene and/or mutations in TP 53 is associated with the poor, prognosis and treatment resistance.

Neuropathy present in 3-13% at the time of diagnosis and prior to the initiation of therapy, and in 37-83% of previously treated individuals.

Peripheral neuropathy is predominately sensory sensorimotor and the present is numbness, burning pain or sensory loss.

Approximately 20% of patients with myeloma have peripheral neuropathy symptoms at diagnosis.

Mechanisms of myeloma perpheral neuropathy include amyloid deposition in perpheral nerves, antibody production that target myelin associated glycoprotein, cytokine mediated injury, and radiculopathy from direct compression by tumor.

Neuro-physiologic abnormalities may be present in 11-52% of untreated patients and 39-46% of previously treated patients.

Risk factors for peripheral neuropathy include drug therapy, duration and intensity of drug therapy, cumulative dose of treatment, age and cold morbidities such as diabetes and alcohol, and presence of pre-existing neuropathy.

Risk factors include: male sex, occupation as a firefighter, obesity, dioxin/Agent Orange exposure, and 9/111 responders.

Thalidomide neuropathy causes a small and large fire sensory peripheral neuropathy with symmetrical loss of all modalities, in the lower extremities were affected most.

Cardiac comorbidities are present in approximately one third of patients at diagnosis.

More than 70% of patients with multiple myeloma experience a cardiac event during follow-up, including congestive heart failure.

Cardiac disease in myeloma include advanced age, chronic anemia, hemodynamically significant A/V shunts, and hyperviscosity.

Amyloid like chain amyloidosis is present in about 10% of patients with myeloma and can manifest as heart failure.

No cure exists presently, although modern treatments have suggested long-term survival with approximately 1/3 of patients achieving cure.

Treatments include immunomodulatory drugs, proteasome inhibitors , and antibody-based therapies.

Allogeneic BMT achieves long-term disease-free survival of 15%-20% of patients.

Two transplantations with high dose melphalan associated with a seven-year event-free and overall survival rates of 20 and 40%, respectively.

High-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) is still the best option for multiple myeloma even after almost 2 decades with newer and highly effective induction agents according to a recent systematic review and two meta-analyses.

Analysis of five randomized controlled trials conducted since 2000 concluded that HDT/ASCT is still the preferred treatment approach.

Patients typically relapse within three years post auto-HSCT without maintenance therapy.

Maintenance therapy after induction in ASCT improves not only progressive free survival but also overall survival.

Single agent lenalidomide maintenance therapy has been the treatment of choice but the regimens including carfilzomib  plus lenalidomide improved progression free survival in high risk patients.

A combination of carfilozomib, lenalidomide , and dexamthetasone versus lenalidomide alone as maintenance after autologous stem cell transplantation resulted in a median, progression free survival of the three agents of 59.1 months versus 41.4 months in the lenalidomide group alone (Dytfeld D).

Despite a lack of demonstrable overall survival benefit, there is a significant progression-free survival (PFS) benefit, low treatment-related mortality, and potential high minimal residual disease-negative rates conferred by HDT/ASCT in newly-diagnosed multiple myeloma.

In a large series the median overall survival after aHSCT was 72.9 months, compared to 47.6 months among patients who did not undergo aHSCT

The combined odds for complete response were 1.27 with HDT/ASCT, compared with standard-dose therapy.

The combined hazard ratio for PFS was 0.55 and 0.76 for overall survival in favor of HDT.

PFS was best with tandem HDT/ASCT followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation and single HDT/ASCT alone compared with SDT.

None of the HDT/ASCT approaches had a significant impact on overall survival.

Meanwhile, treatment-related mortality with HDT/ASCT was minimal, at less than 1%.

The event-free and overall survival rates for two high-dose transplantations are double over single transplantations.

Patients typically relapse within three years post auto-HSCT without maintenance therapy.

Patients who receive a complete remission after AHSCT may have 100 million residual myeloma cells.

The use of thalidomide in intensive melphalan chemotherapy with stem cell transplantation increases the rate of complete remission and event-free survival in previously untreated patients but does not increase overall survival.

Stem cell transplant most common indication.

Response rates are not valid surrogates for determining survival in myeloma studies.

Complete response rate requires: absence of original monoclonal protein in serum and urine that is maintained for a minimum of six weeks, less than 5% plasma cells in the bone marrow, no increase in size and number of lytic lesions, and disappearance of the soft tissue plasmacytomas.

Partial response requires: 50% or greater reduction in the level of the serum monoclonal protein, maintain for a minimum of six weeks, reduction in 24 hour urinary light chain excretion by 90% or greater to 200 mg, maintain for a minimum of six weeks, for patients with non-secretory disease. 50% or greater reduction in plasma cells in the bone marrow, maintain for a minimum of six weeks, a 50% or greater reduction in the size of soft tissue plasmacytomas, and no increase in the size of a number of lytic bone lesions.

Compared to the rapid reduction in levels of plasma proteins when patients undergo treatment, focal bone lesions take 1-2 year to regress and are often the first sites of relapse.

When patients evolve to myeloma from monoclonal gammopathy of uncertain significance or from a smoldering phase treatment rarely results in a complete remission and when that occurs it does effect the likelihood of survival reflecting the reestablishment of a stable condition.

Candidates for auto-transplantation should not receive induction therapy with stem cell damaging agents, such as melphalan, which can preclude stem cell harvest.

Use of high dose therapy and autologous bone marrow transplant as part of induction therapy associated with an improved response, but not a survival advantage for early vs late transplantation.

The administration of high dose melphalan for transplant patients is 200 mg per meter squared as the standard dose.

ASCT after high dose chemotherapy associated with a median survival of more than 5 years.

ASCT associated with a 3-5% mortality.

Autologous stem cell transplantation (ASCT) can be performed either early in the disease or at the time of first relapse with both strategies being useful.

A short course of induction therapy, 3-6 months, followed by autologous stem cell transplantation (ASCT) without maintenance therapy results in very good partial responses of 50-60% and complete response rates of 25-50% and a median time to progressive disease around 2 years.

Tandem ASCT or maintenance following ASCT improves progression free survival and overall survival, but the benefits appear to be primarily among those patients obtaining less than a (VGPR) very good partial response.

Tandem ASCT may be beneficial for high-risk patients.

Patients treated with autologous stem cell transplant and with progressive disease are at increased risk of early death from infection.

The 4-year overall survival (OS) rate is 82.3% among patients diagnosed with multiple myeloma at age 65 years or younger, who are eligible for autologous stem cell transplantation (ASCT), according to a retrospective study.

In phase II trials of lenalinomide and dexamethasone in previously untreated patients yielded a VGPR in 67% after a median of 19 cycles of treatment (Lacy MQ).

Bortezomib given subcutaneously on a weekly basis has the same efficacy as standard intravenous dosing twice a week with significantly less neurotoxicity.

Regimens containing bortezomib with thalidomide or lenalidomide led to 100% overall response rates and VGPR rates of more than 60% comparing favorably with ASCT.

These high response rates with the above new agents can be increased when they receive ASCT, suggesting ASCT still is a vital treatment.

VAD treatment generally preferred induction therapy for patients under the age of 70 years who are candidates for stem cell transplant.

Initial chemotherapy provides a response rate of 40-60% with a median duration of remission of 18 months and median survival duration of 30-60 months.

Standard chemotherapy has a complete response rate of <10%.

Conventional salvage chemotherapy results in responses of 20-40% with a median survival of 3-12 months.

Melphalan plus prednisone produces response rates, defined as greater than 50% reduction in monoclonal proteins, in 50-60% of patients.

Intergroupe Franocphone du Myelome randomized 488 patients 65-75 years of age to melphalan/prednisone, melphalan/dexamethasone, dexamethasone alone or dexamethasone and interferon alfa: none of the regimens had a significant number of complete responses and melphalan/dexamethasone has a significantly higher overall response rate at 70%, with increased incidence of infections and no significant improvement in median time to progression or median overall survival.

Combination chemotherapy with vincristine, BCNU, melphalan, cyclophosphamide and dexamethasone have response rates and survival times similar to melphalan and prednisone.

Overall results of allogeneic BMT complete remission rate of 22%-50% with treatment related toxicity 25%-56% primarily related to GVHD, infection and disease relapse.

Patients with lytic lesions or osteopenia should receive bisphosphonates indefinitely.

Up to 80% of patients at diagnosis present with osteolytic lesions, often with pain, bone fractures and hypercalcemia.

Malignant plasma cells stimulate bone resorption by osteoclasts and inhibit bone producing cells, the osteoblasts with an unbalanced bone destruction leading to bone lysis.

The number and function of osteoblasts are decreased with osteolytic lesions.

Multiple studies have demonstrated positive results for chimeric antigen receptor (CAR) T-cells in treating relapsed and refractory multiple myeloma.

The CAR T-cells that have shown the most therapeutic promise are those targeting the CD19 protein, and the BCMA protein in multiple myeloma.

B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B-cells.

BCMA is a cell surface receptor that is expressed primarily by plasma cells, including malignant plasma cells.

BCMA refers to B-cell maturation antigen.

BCMA is expressed in almost every patient with myeloma but is not expressed in normal tissues in the body.

BCMA and its ligands result in activation and proliferation of plasma cells and BCMA signaling, is responsible for harmful effects of malignant plasma cells.

In refractory or relapsed MM patients CAR-T-cell therapy directed at BCMA has objective response rate 50-90%.

As multiple myeloma progresses it involves BCMA over expression on multiple myeloma cells, leading to increase up regulation of survival, growth, and immunosuppressive genes.

Activin A is a stromally derived osteoblast inhibitor induced by myeloma cells and is implicated in the pathogenesis of bone disease (Vallet S et al).

Activin-A serum levels are elevated in newly diagnsed and relapsed patients with myeloma.

Activin a levels correlate with advanced disease and high bone resorption.

Dickkopf-1 (Dkk1 and sclerosin inhibit Wingless type and integrase 1 (Wnt) signaling and are implicated in myeloma bone disease by inhibitinh osteoblast formation.

Dkk1 serum levels are elevated with active myeloma and sclerosin levels are elevated in the plateau phase of disease.

Osteoblastic activity is inhibited by DKK1 and activin A, molecules known to be elevated in the serum of patients with myeloma.

Myeloma lesions and osteoporosis result from increased osteoclast activity probably mediated by increased levels of macrophage inflammatory protein 1alpha and receptor activator of nuclear factor-kappaB ligand (RANKL) and decreased levels of decoy receptors of RANKL (osteoprotegerin).

Plasma cells express RANKL on their surface and promote the availability of RANKL within the bone marrow microenvironment inducing stromal cell expression by a cell to cell contact.

To stem overproduction and activation of osteoclasts, osteoblasts secrete osteoprotegerin, which binds and sequesters RANKL, but myeloma cells reduce the availability of osteoprotegerin in the bone marrow microenvironment.

The bone microenvironment, myeloma cells, osteocytes, and stromal cells secrete factors such as RANKL, MIP-1-alpha, interleukin 3 and interleukin 6, which increase osteoclast activity, and additional factors such as DKK-1, SFRP2, and sclerostin, which inhibit osteoblast function.

The imbalance in bone homeostasis due to increaed bone resorption, rates and decreased bone formation activity, resulting in the development of clinically relevant lytic bone lesions and hypercalcemia.

In a phase 3 study of multiple myeloma, randomization to zoledronic acid or not: disease progression in the control was associated with skeletal related events in 78.35 of cases vs. 55.5% in zoledronic acid group (Musto P).

Zoledronic acid is the only bisphosphonate confers survival advantage in myeloma.

Denosumab in newly diagnosed myeloma patients is noninferior to zoledronic acid for time to slekeltal-related events.

A baseline dental exam is now strongly recommended for patients receiving bisphosphonates or denosumab.

Osteoclasts accumulate at bone resorbing surfaces adjacent to myeloma cells, but are not increased in areas uninvolved with malignancy.

Malignant plasma cells localize in the bone marrow through the interaction of adhesion receptors with their ligands on bone marrow stromal cells and extracellular matrix proteins.

Adhesion of myeloma cells in the bone marrow microenvironment is mediated by plasma cell membrane receptors.

The bone marrow micro environment plays a crucial role in the biology of the disease, where myeloma cells interact with various cells in the bone marrow, including stromal cells, osteoclast, and immune cells, through cell adhesion molecules, and cytokines.

These interactions promote the growth and survival of myeloma cells, and lead to bone destruction, and immune dysfunction.

The dysregulation of the Wnt signaling pathway, and up regulation of DKK1 promote osteoclastic activity, resulting in lytic bone lesions.

Hypo and hyper methylation occur in epigenetic of certain genes contributing to the disease pathogenesis and bone marrow micro environment contributes to treatment resistance by protecting myeloma cells.

Hypercalcemia occurs in 15% of patients at diagnosis.

Approximately 20% of patients with myeloma have a creatinine of 2.0 mg/dl at diagnosis.

Patients should receive influenza and Pneumococcal vaccinations.

Angiogenesis is increased in myeloma.

New definition for relapsed/recurrent patients include those who show disease progression within 60 days of discontinuing therapy.

Prognosis with relapsed MM is poor with median overall survival of less than 1 year among patients who have received 2 or more line of therapy (Kumar SK et al).

Despite improved therapy and overall survival, patients with international staging system II or III disease with more than one adverse lesio, still have a median overall survival of less than 2 years.

Response rate to VAD (vincristine, adriamycin and dexamethasone) approximately 55-65%.

In newly diagnosed patients response rate to pegylated liposomal doxorubicin, vincristine and dexamethasone (DVd) 88% with 12% complete remissions.

DVd regimen decreases angiogenic activity in myelomatous bone marrows.

Bortezomib therapy in patients with 13q deletion can produce durable responses indicating this drug can overcome the adverse affects of 13q del abnormalities.

APEX study (Assessment of Proteasome Inhibition of Extending Remissions), a phase III trial comparing high dose dexamethasone to single gent bortezomib in patients with relapsed disease: overall response rate of 38% for bortezomib and 18% for high dose dexamethasone.

SUMMIT (Study of Uncontrolled Multiple Myeloma managed with proteasome Inhibition Therapy) 27% response rate to bortezomib, complete remission and partial response, was 27% among 202 relapsed or refractory myeloma patients with a median of 6 prior therapies.

CREST trial out of 27 patients refractory myeloma patients treated with 1.0 mg/m2 30% achieved a complete or partial remission and 38% of patients receiving 1.3 mg/m2 obtained a complete or partial remission.

In the CREST trial the addition of dexamethasone to bortezomib increased response rates to 37% in the 1.0 mg/m2 group and to 50% in the 1.3 mg/m2 patients.

Response rate of bortezomib, melphalan, prednisone and thalidomide (VMPT) overall response rate of 67%, with 43% achieving a very good or better partial response (Palumbo).

Bortezomib plus doxorubicin results in 72% response rate with 36% achieving a complete or near complete remission, and bortezomib plus pegylated liposome doxorubicin has a response rate of 48% (Orlowski)

EVOLUTION trial of bortezomib, dexamethasone, cyclophosphamide and lenalidomide (VDCR) in patients who were previously untreated and with a Karnofsky score of 50% or higher-bortezomib 1.3 mg/m2 I.V. days 1,4,8, and 11, dexamethasone orally 40 mg on days 1,8, and 15, lenalidomide 15 mg days 1-14 and cyclophosphamide 100-5000 mg/m2 orally days 1 an 8: overall response rate 100%, 20% with a stringent complete remission, 36% complete remission or better, and 69% a very good partial response.

Carfilzomib when combined with lenalidomide, and dexamethasone (CRd) in myeloma has a response rate of 100% in newly diagnosed patients, and a complete or near complete response rate of 61%.

The ASPIRE study compared lenalidomide and dexamethasone with or without carfilozomib in relapsed or refractory myeloma: clear advantage for the carfilozomib arm-26.3 month progression free survival vs. 17.6 months.

Carfilozomib and dexamethasone reduce chance of death compared to bortezomib and dexamethasone in patients with relapsed or refractory myeloma: reduced chance of death 21%, and an overall survival benefit of 7.6 months (ENDEAVOR).

It is suggested the triple drug combination of carfilzomib, lenalidomide and dexamethasone should be the standard ofcare for relapsed or refractory myeloma.

RVD-lenalidomide, bortezomib, dexamethasone trial of 66 newly diagnosed patients as initial therapy followed by autologous stem cell transplant or maintenance therapy: 100% of patients achieved a partial response or better, with high rates of complete response, or near complete response and had a median follow-up of 21 months, the estimated 18 month progression free survival and overall viable rates were 75% and 97% with or without autologous stem cell transplant, respectively- indicating RVD is equally effective with or without autologous stem cell transplant (Anderson KC et al).

In the DETERMINATION clinical trial: among adults with multiple myeloma RVD plus ASCT was associated with longer progression free survival then RVD alone, but no overall survival benefit was observed; five year survival was 79 to 80%.

Phase III study of 460 patients with newly diagnosed disease who were to undergo autologous stem cell transplant were randomized to receive induction therapy with 3 cycles bortezomib, with dexamethasone plus thalidomide or dexamethasone plus thalidomide alone-following double stem cell transplantation the randomization was continued with two consolidation cycles and then dexamethasone maintenance: bortezomib containing regimens associated with superior results-complete remission rates with induction of 32% vs. 12%, higher very good response rates, 4.7% of patients without bortezomib had progressive disease and not patient with bortezomib had progressive disease.

In a phase 3 trial evaluating more than 600 patients assigned to receive maintenance lenalidomide or placebo following high-dose therapy and autologous stem cell transplantation, followed by two months of lenalidomide treatment after achieving complete remission:Lenalidomide maintenance therapy almost doubled three-year progression free survival at 68% versus 35% for placebo (Attal M et al).

Maintenance therapy of lenalidomide in patients who have a a remission after autologus stem cell transplanation results in slowing of disease progression by 54% (Attal M et al).

In a phase III Intergroup Study of Lenalidomide maintenance therapy of 10 mg a day following ASCT resulted in a 60% reduction in the risk of disease progression, with significant fewer patients experiencing an event compared with placebo, 19.9% versus 41.5%, median time to disease progression for lenalidomide compared to placebo was 42.3 months versus 21.8 months (McCarthy PL).

Lenalidomide alone is the best therapy for maintenance therapy for myeloma according to a meta analysis.

The survival of patients with MM after they become refractory to bortezomib and one of the immune mediated inflammatory disease drugs is about 9 months (International Myeloma Working Group).

Up to 10-20% of patients with newly diagnosed myeloma develop deep vein thrombophlebitis in the first 6 months of therapy: VTE prophylaxis is recommended.

As compared to a single stem-cell transplantation a double transplantation with high dose chemotherapy improves overall survival.

Stem-cell transplantation is recommended for young patients as part of the initial treatment or at the time of disease progression.

The median duration of remission in patients treated with stem-cell transplantation does not exceed three years and almost all patients relapse.

The complete remission rate after high-dose chemotherapy and stem-cell transplant is the most important prognostic factor for survival.

Maintenance therapy after stem cell transplantation with thalidomide in the Intergroupe Francophone du Myelome 99-02 showed at a median 29 month follow-up that 52% of patients had improvement in event free survival compared with 36% and 37% with observation and palidronate, only arms, respectively.

Thalidomide inhibits multiple myeloma cell growth and survival, decreases the adhesion of myeloma cell and bone marrow stroma, alters secretion of cytokines such as IL-6, sensitizes myeloma cells to chemotherapy, and has antiangiogenic effects.

Response rates to thalidomide in newly diagnosed patients around 30% and in combination with steroids up to 60%.

Phase III trials MM-009 and MM-010 revealed response time and progression improved with lenalidomide plus dexamethasone compared with dexamethasone alone.

Response rate in recurrent or refractory disease with dexamethasone and lenalidomide is about 50%.

Lenalidomide, cyclophosphamide and dexamethasone in relapsed myeloma has an overall response rate of 65%, complete response rate of 5%, and the rate of very good partial response or better was 15% (Schey SA et al).

A combination of lenalidomide, infusional adriamycin and dexamethasone (RAD) in patients with relapsed disease had and overall response rate of 73% with 15%complete remissions and 45% very good partial responses, with a median time to progression of 45 weeks, and the median progression free survival of 40 weeks (Knop S).

In the combination study of lenalidomide, infusional adriamycin and dexamethasone (RAD) there was no difference in time to progression among patients who achieved a complete remission compared to those with a very good partial response, and the presence of a deletion 17p13 was associated with a lower response and shorter time to progression (Knop S).

Relapsed patients that are naive to an agent are generally treated with a new regimen incorporating such an agent.

Response rates decrease with every successive relapse: 58% at first relapse to 15% at fourth relapse.

Prognosis is poor for relapsed and refractory disease, with an expected survival of <1 year compared to an expected usrvival of around 3 years with relapsed myeloma.

In a phase 2 trial Carfilzomib had an overall response rate in heavily pretreated patients of 24% and an additional 13% had a minor response with an overall clinical benefit of 37%.

Relapsed patients are considered for ASCT with high dose chemotherapy, and long term survivors of ASCT are considered for retreatment with such therapy.

Efficacy in relapsed patients with thalidomide: 32% response rate and 2 year event free and overall survival 20% and 48%, respectively.

Combination of dexamethasone, thalidomide,, cisplatin, doxorubicin, cyclophosphamide and etoposide in relapsed and refractory myeloma resulted in a 32% partial response and a complete response rate of 16% (LeeCK et al).

Adding thalidomide to pegylated liposomal doxorubicin , vincristine and dexamethasone have relatively high complete or nearly complete remission rates of 46% in newly diagnosed and refractory myeloma patients.

In patients with refractory or relapsed disease combination of bortezomib and low dose melphalan induce near complete remission and partial remissions in 9% and 32%, respectively in phase I/II trials.

Near complete remission rate of 12% and partial remission rate of 41% reported in a study of refractory/ relapsed patients treated with thalidomide plus low dose melphalan.

High-dose chemotherapy with autologous stem cell support improves remission rates, progression free survival, and overall survival and is the standard of care for younger patients.

Autologous transplantation is not curative.

Optimal time for induction therapy prior to autologous stem cell transplant is not known., although most studies suggest a pretransplant induction period of 4-6 months.

Free light chain assay is useful to monitor many patients with oligosecretory and nonsecretory myeloma.

Serum light chain measurement is highly sensitive and is a better alternative than 24 hour urine collections for determination of para protein levels.

Serum free light chains enable early monitoring of patient’s response and residual disease.

Serum free light chains has a half-life of 2.6 hours.

Adverse markers include increased plasma cell labeling index, increased beta 2 microglobulin, low levels of serum albumin, circulating plasma cells and bone marrow plasmablastic features.

Vascular endothelial growth factor and fibroblast growth factor stimulate angiogenesis, inhibit multiple myeloma cell migration and reduce dendritic cell formation.

Defects in immunological functions of dendritic function in myeloma, with lack of CD80 and CD86 molecules, defective antigen presentation, and accumulation of immature and inactivated dendritic cells.

Patients with smoldering myeloma do not require treatment, as they could be in that phase for 1-3 years.

Median time to progression to myeloma from smoldering myeloma in some series is 5-7 years, reflecting considerable heterogeneity of the biology of the disease.

Patients younger than 70 years of age and in good general health that are candidates for auto-transplantation should not receive stem cell damaging chemotherapy (melphalan) agents as induction.

No evidence exists to suggest that a good partial response before autologous stem cell transplant is inferior to a complete response with regard to overall survival.

For non-transplant candidates a number of regimens can be considered as appropriate regimens.

International Staging System incorporates reproducible parameters of albumin and beta microglobulin resulting in low, intermediate and high risk groups with median survival of 62, 45 and 19 months, respectively.

Efficacy of retreatment is approximately proportional to the depth and duration of the initial remission, that is, the better the response and a longer remission, the higher the predicted efficacy pretreatment.

Retreatment of multiple myeloma is associated with 60% response rate, in patients who had an initial partial response only (Wolf J et al).

Treatment may result in eventual regrowth of neoplastic tissue, osteo-lysis, anemia, and immune dysfunction.

Approved as a single agent for multiple myeloma in patients who previously received at least 3 lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or in patients who are double-refractory to a PI and an immunomodulatory agent.

Approved in combination with pomalidomide and dexamethasone for the third line treatment of patients with myeloma who receive prior therapy with lenalidomide and proteosome inhibitors.

With relapsed/refractory multiple myeloma previously exposed to lenalidomide, the combination of pomalidomide plus bortezomib and low?dose dexamethasone (PVd) improved response and progression-free survival, results of the phase 3 OPTIMISMM trial.

The addition to bortezomib, melphalan and prednisone (VMP) reduced the risk of progression or death compared to VMP alone for newly diagnosided myeloma patients (ALCYONE Trial).

CoMMpass study Carfilzomib, Revlimid, and dexamethasone was associated with a better response rate than bortezomib lenalidomide and dexamethasone: 18 month event free survival rate was 87% with K or D versus 72% with RVD.

Antibody therapies approved by the FDA include elotuzumab and daratumumab- monoclonal antibodies to be approved for multiple myeloma therapy.

A human IgG1 antibody that targets the CD-38 transmembrane protein expressed abundantly on malignant plasma cells.

CD 38 is ubiquitous on the surface of multiple myeloma cells and normal plasma cells.

Daratumumab is a human immunoglobulin Gk monoclonsl antibody that targets CD 38.

The addition of subcutaneous Daratumumab to bortezomib, lenalidomide, and dexamethasone (VRd) , and lenalidomide maintenance therapy had a significant benefit effect on progression free survival among transplantation eligible patients with newly diagnosed myeloma.

Combinations of monoclonal antibodies plus immunomodulatory Imide drugs or proteasome inhibitors have shown substantial activity in myeloma.

Venetoclax is efficacious in the 11; 14 translocation or high BCL-2-expressing myeloma subset.

Recently approved agents include Pomalidomide(Pomalyst), panobinostat (Farydak), daratumumab(Darzalex), ixazomib (Ninlaro) and elotuzumab(Empliciti).

Elotuzumab for combination treatment with lenalidomide and dexamethasone for treatment of patients with multiple myeloma who have failed 1-3 prior regimens.

Panobinostat is a deacetylase inhibitor.

Data from almost 5,000 U.S. veterans, statins may improve survival for multiple myeloma patients: patients who used a statin had a 21% reduced risk of death from any cause and a 24% reduced risk of death from myeloma, and overall survival of statin users was 39.5 months compared to 27 months among nonusers.

Pembrolizumab when added to dexamethasone in combination with lenalidomide or pomalidomide associated with an increased relative risk of death in myeloma

((Idecabtagene Vicleucel))induced responses in a majority of healthy pre-treated patients with refractory and relapse myeloma: MRD negative status was achieved in 26% of patients: BCMA CAR T-cell therapy have shown deep responses in patients with advanced disease, with a median progression free survival of 8.8 months.

Ciltracabtagene in multiple myeloma had a 98% response rate at the median follow-up of 27.7 months.

High rates of durable complete responses are reported with ((ciltacabtagene autoleucel)) in patients with relapsed or refractory multiple myeloma: phase 2 CARTITUDE-2 study.

A single Cilta-cel infusion resulted in the lower risk of disease progression or death than standard care in lenalidomide refractory patients with multiple myeloma, who had received 1 to 3 previous therapies (CARTRITUDE-4 trial),

BCMA directed CAR-T cell therapies have not generated survival curves with the plateau in patients with multiple myeloma, and most patients are likely to have eventual relapse.

Levels of monoclonal immunoglobulins in the serum and 24 hour. Urine specimens remain gold standard for monitoring a patient’s response to therapy.

For many patients with myeloma, it is  difficult to monitor individuals have who have oligosecretary or non-secretary disease.

A limitation of using serum and proteins to monitor patients with myeloma as it has a long half-life of approximately 21 day,  so levels change slowly.

Bispecific antibodies elranatamab, teclistamab and talquetemab have been improved for the management of refractory multiple myeloma.


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