|Year : 2020 | Volume
| Issue : 2 | Page : 72-80
Multiple myeloma: an update
Lalit Kumar, Sukesh Nair, Surya Prakash Vadlamani, Priyanshu Chaudhary
Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
|Date of Submission||14-Dec-2020|
|Date of Acceptance||18-Dec-2020|
|Date of Web Publication||31-Dec-2020|
Dr. Lalit Kumar
Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029.
Source of Support: None, Conflict of Interest: None
Survival of patients with multiple myeloma has increased significantly during the past two decades. This has been attributed to a better understanding of biology, the introduction of novel agents (immunomodulators, proteasome inhibitors), autologous stem cell transplantation, and maintenance therapy. Supportive care is an important component of overall care for these patients. Most patients have a high burden of symptoms at initial presentation in form of bone pains, fatigue, anemia, renal impairment, and infections, etc. Almost 10–20% of patients may have serious complications in the first 4–6 weeks. A high index of suspicion and timely intervention is important to reduce morbidity and mortality. Therapy-related complications, e.g., neuropathy, thromboembolism, cytopenias, GI symptoms (constipation/diarrhea), and relapse of disease, pose therapeutic challenges. Protocol-based approach, systematic assessment with respect to the quality of life and functioning and coordination with a palliative care team from the beginning may improve overall functioning and outcome.
Keywords: Anemia, bisphosphonates, multiple myeloma, neuropathy, palliative care
|How to cite this article:|
Kumar L, Nair S, Vadlamani SP, Chaudhary P. Multiple myeloma: an update. J Curr Oncol 2020;3:72-80
| Introduction|| |
Multiple myeloma (MM), a disease of malignant plasma cells, accounts for 1% of all malignant disorders and 10–15% of hematological malignancies. While incidence of myeloma is lower in Asia (1.1 per 100,000) and in India (1.0 per 100,000) compared to the West (4.1/100,000), there is evidence that incidence of MM is gradually rising in metropolitan cities in India. Some of the key differences seen in presentation (compared to western population) include younger age at diagnosis (median 55 years compared to 65 years, 8–10% less than 40 years vs. 2%), lower proportion of asymptomatic patients (1–2% Vs 10–20%), higher proportion of patients with anemia (Hb <10 g/dL), International Staging System (ISS) stage III (30 to 50% vs. <20–30%), renal failure [estimated glomerular filtration rate (eGFR) <40mL/min in 26% vs. 19%], and higher proportion of patients with extramedullary disease (10–20%). Limited data suggest that the proportion of high-risk cytogenetics like 17p del, t,(4,14) t(14,16) is similar (10–15%).
Survival of MM patients has improved significantly during the past 2 decades. This has been attributed to a better understanding of biology, refined diagnostic and response criteria, novel agent-based induction, autologous stem-cell transplantation (ASCT) in eligible patients, and use of maintenance therapy. Prior to the year 2000, initial therapy for myeloma patients included cytotoxic chemotherapy: melphalan and prednisolone or VAD (vincristine, adriamycin, and dexamethasone) as continuous infusion. Treatment was associated with low complete response rates (5–15%), and short progression-free survival (PFS) and overall survival (OS: 3–3.5 years). In the past two decades, introduction of novel agents like immunomodulators (thalidomide, lenalidomide, and pomalidomide), proteasome inhibitors (PSI) (bortezomib, carfilzomib) has led to higher response rates (75–95%), including complete response in 15–20% of patients and improved PFS and OS. Currently, these are the backbone of myeloma treatment. The disease is characterized by initial remission for a variable period of time (generally 1.5 to 3 years) followed by relapses with a short duration of remissions in between. Relapse of disease along with associated complications (disease/therapy-related) poses therapeutic challenges.
| Clinical Presentation|| |
Most patients present with bone pains (70%–80%) (backache being most common), anemia (60%–70%), and renal failure in 20–25% of patients. Less commonly, soft tissue masses, neurological symptoms (<10%), and recurrent bacterial infections (10%) may be the presenting symptoms. Other clinical manifestations include disorders of metabolism (hypercalcemia or hyperuricemia) or amyloidosis, cryoglobulinemia, and hyperviscosity syndrome.
| Diagnosis|| |
The spectrum of plasma cell dyscrasias includes a range of conditions [Table 1]; clinical features of many of these may overlap.
|Table 1: Percentage distribution of various plasma cell dyscrasias cases registered in myeloma clinic at IRCH-AIIMS (2011–18), n = 1552|
Click here to view
Bone marrow (BM) examination, serum and urine electrophoresis for the presence of paraprotein (myeloma or M protein) and immunofixation, and skeletal survey are essential components of the initial workup for myeloma. A skeletal survey including X-rays of the skull, pelvis, ribs, vertebrae, shoulder girdle, and long bones is required. Radiologically, typical myeloma lesions are multiple, osteolytic and have sharp punched-out margins. These lesions are well seen on X-rays of the skull, ribs, and pelvic bones. In the vertebrae, there may be partial or complete compression and the pedicles are often spared. Vertebral destruction may be associated with a paraspinal soft tissue mass. SCC may occur secondary to extra-dural involvement or vertebral collapse. Pathological fractures of the humerus or neck of the femur may be seen. Osteoporosis is a frequent finding in myeloma; it is multifactorial in etiology and includes diffuse marrow involvement. It may occur with or without bone lesions. Osteoporosis alone is not considered a sign of bone disease unless it causes bony deformity such as vertebral collapse.
Magnetic resonance imaging (MRI) is useful in patients with a negative bone survey, and to delineate areas requiring radiation therapy or surgical intervention. One-third of patients considered to have a solitary plasmacytoma have BM abnormalities consistent with MM. In recent years, whole-body positron emission tomography (FDG PET-CT scan) is being used; a PET-CT scan is superior, identifying both extra-medullary and medullary lesions in patients with negative X-rays. The routine use of a bone scan is not helpful.
Serum free light chain (FLC) ratio (kappa/lambda ratio) is useful in monitoring the course of the disease and response to therapy particularly in patients with light-chain myeloma who do not have measurable disease on serum and urine electrophoresis. On electrophoresis, paraprotein (M protein) is either immunoglobulin G (IgG) (60%–70%) or IgA type (15%–20%), and 15–18% of patients have only light chains.
The International Myeloma Working Group (IMWG) has established criteria (based on end-organ damage, acronym CRAB (hypercalcemia, renal impairment, anemia and bone mesons) to distinguish asymptomatic myeloma from active disease. These are given in [Table 2].
The presence of at least one of the these markers is considered sufficient for a diagnosis of MM, regardless of the presence or absence of symptoms or CRAB features.
Monoclonal gammopathy of uncertain significance (MGUS) is a premalignant condition that may progress to myeloma. It is defined by the presence of M protein <3 g/dL, absence of lytic bone lesions, anemia, hypercalcemia or renal insufficiency, and a BM with <10% plasma cells. Patients with MGUS are asymptomatic, have no evidence of end-organ damage but do have a 1% annual risk of progression to myeloma. The risk of conversion to myeloma may depend on the amount of M protein and immunoglobulin isotype and the ratio of serum FLC. For patients with serum M protein <1.5 g/dL and IgG subtype and normal serum FLC ratio (0.26–1.65), the risk of conversion to myeloma is low (5% at 20 years). Such patients can be followed up once in a year. Patients with serum M protein >1.5 g/dL, and IgA subtype and abnormal FLC ratio have a higher risk for conversion to myeloma (58% at 20 years) and should be followed up at 3- to 6-month intervals.
About 15% of patients have a smoldering (SM) or asymptomatic myeloma, characterized by the presence of a serum monoclonal protein (IgG or IgA >3 g/dL), >10% (up to 60%) of atypical plasma cells in the BM or both, in the absence of target organ damage. The probability of progression to symptomatic or active myeloma is 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% for the next 10 years. The current approach is to keep such patients under close observation and to start therapy only in the presence of target organ damage. Selected patients with osteopenia may be considered for bisphosphonate therapy. Patients with high-risk SM may be considered for clinical trials or very close observation.
| Staging|| |
The Durie and Salmon staging system, which was described in 1975, was based upon the levels of hemoglobin, serum calcium, serum creatinine, serum, and urine paraprotein (M protein), and the number and size of bone lesions. One of the major limitations of this staging system was that the numbers of lytic bone lesions on plain X-ray were observer-dependent. This staging has now been replaced by the ISS which has been validated in several clinical studies. ISS [Table 3] uses a combination of serum β2 microglobulin and serum albumin, and correlates well with long-term outcome. However, ISS cannot distinguish MGUS or SM myeloma from active or symptomatic myeloma.
Also, stage III ISS is a composite group, where serum β2 microglobulin can be elevated because of myeloma burden as well as renal failure (may be present in 20%–25% of patients at diagnosis). Recently, ISS has been revised based on serum LDH and the presence or absence of high-risk cytogenetics [Table 4].
| Cytogenetics|| |
A number of cytogenetic abnormalities have been identified in myeloma [Table 5]. Hyperdiploidy (characterized by multiple trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21) is identified in 50%–60% of patients with myeloma and is associated with longer survival. Structural abnormalities such as del 13 are detected in about 50% of patients, del (16q) in 20%, del (17p) in 10%, and gain of 1q21in 30%–43% of patients. Translocation involving immunoglobulin heavy chain gene locus t(4,14) (p16.3;q32) occurs in 14%–20% of patients and t(14,16) (q32;q23) in 2%–10% of patients. These are associated with a poor prognosis. Hyperdiploidy and cyclin D translocations (t[11;14] and t[6;14]) are associated with a good prognosis. Secondary genetic events such as deletion p53, and del 13 or hypodiploidy have a poor outcome. Interphase fluorescence in situ hybridization detects Del 13 in more patients than conventional cytogenetic markers. Currently, there are no specific treatment guidelines for patients diagnosed to have Del 13 at baseline. Patients with good cytogenetic markers do well with high dose chemotherapy (HDCT) and ASCT. Proliferation as measured by the plasma cell labeling index, β2 microglobulin, or gene expression profiling (GEP) is another poor risk feature. GEP has been utilized (i) to identify high-risk patients and (ii) to differentiate between normal plasma cells and those in MGUS, MM, AL amyloidosis, and extra-medullary plasmacytomas.
| Pathogenesis|| |
MGUS is considered to be the initial event in the pathogenesis of myeloma. A multistep development model suggests that MGUS might progress to SM myeloma, and ultimately to myeloma. Being a plasma cell, the MM cell precursor is considerably a terminally differentiated B-lymphocyte that appears to have passed the normal steps; with its immunoglobulin genes having undergone the crucial stages of antigen selection, isotype switching, and somatic hypermutation in the germinal center. The first genetic “event” of a multistep neoplastic process could take place by the random acquisition of translocations to the IgH locus on chromosome 14q32 or less frequently to the IgL locus (λ light chain on chromosome 22q11; κ light chain on chromosome 2p12).
BM microenvironment in MM
Interaction of malignant plasma cells with BM microenvironment has been reported to play key role in the pathogenesis and progression of MM. The key components of the BM microenvironment include hematopoietic progenitor and stem cells, immune cells, BM stroma cells, BM endothelial cells, osteoclasts and osteoblasts, constituting the cellular, and noncellular components composing a complex niche where plasma cells expand. Direct interaction of plasma cells with these components and growth factors/cytokines secreted by either MM cells or stromal cells or both supports growth, survival, and migration and possibly confers drug resistance to malignant MM cells. The noncellular compartment of the BM provides adhesion for MM plasma cells and has been reported to trigger cell survival and drug resistance and production/secretion of urokinase-type plasminogen activator, metalloproteinase-2, and metalloproteinase-9. The liquid milieu/fluid in the BM niche has been suggested to primarily comprise of cytokines and growth factors such as interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), members of the tumor necrosis factor (TNF) superfamily, transforming growth factor-β1 (TGFβ1), chemokine ligand 3 (CCL3), stroma-derived factor-1 (SDF-1), hepatocyte growth factor (HGF), and interleukin-10 (IL-10), these cytokines have been reported to be regulated by autocrine and paracrine loops. Furthermore, adhesion of myeloma cells to fibronectin confers protection from apoptosis, while binding of myeloma cells to BM stromal cells induces transcription and secretion of cytokines, including IL-6, IGF-1, and TNF, VEGF, and stroma-derived factor-1. In the cellular BM compartment, MM cells interact with hematopoietic and nonhematopoietic cells; these interactions translate into causing immune suppression and lytic bone lesions. BM stromal cells have been shown to signal MM cell growth, survival, migration, and drug resistance (directly through cell–cell contact or indirectly through secretion of soluble factors). Interleukin-6 secreted by BM cells enhances the production and secretion of VEGF by MM cells and vice versa. The abnormal structure of MM tumor vessels has been observed due to induction of pro-angiogenic molecules (e.g., VEGF), enhancer of microvascular density in the BM.
| Bone Lesions|| |
The presence of osteolytic bone lesions is the hallmark of myeloma. These lesions are due to increased bone resorption. The central pathway in this process involves the receptor activator of nuclear factor kappa B (NFκB) (RANK); RANKL—the ligand for RANK and osteoprotegerin—a decoy receptor for RANKL. Osteoprotegerin prevents bone resorption by preventing binding of RANKL to RANK, thereby inhibiting the upregulation, proliferation, and fusion of osteoclast precursors to produce mature osteoclasts. The increase in the ratio of RANKL to osteoprotegerin results in the activation of osteoclasts and bone resorption. Overexpression of RANKL is probably mediated in part by the release of macrophage inflammatory protein-1 (MIP-1) by neoplastic plasma cells. The balance of bone resorption and formation is also affected by other systemic and local factors, e.g., glucocorticoids, 1,25-dihydroxyvitamin D3, parathyroid hormone, prostaglandins, cytokines including IL-1, IL-6, IL-11, IL-17, and TNF.
Current management of myeloma is based on the initial assessment for transplant eligibility. Patients who are ≤65–70 years of age, in good ECOG performance status and without significant co-morbidities are considered transplant eligible. Such patients receive four to six cycles of induction therapy followed by autologous stem-cell transplant. This is followed by maintenance therapy for more than two years. The goals of induction therapy are (i) rapid reduction in myeloma load (thereby rapid symptomatic recovery) and reversal of end-organ damage, (ii) to achieve deep responses (complete response, CR or very good partial response, VGPR), (iii) the ability to collect an adequate number of stem cells (>2 × 106 CD34+ cells per kg body weight) in transplant recipients, and (iv) with minimal toxicity.
Patients who are “transplant-ineligible” or elderly are advised induction therapy (9–12 cycles) followed by maintenance therapy. In addition, all patients should receive supportive care in the form of bisphosphonates, initially 3 monthly for 1–2 years then at longer intervals.
Currently, three-drug combination—one immunomodulator (thalidomide or lenalidomide), proteasome inhibitor (bortezomib), and dexamethasone—is being used for induction. The choice of induction therapy has evolved over a period of time—starting with doublet (thalidomide or lenalidomide + dexamethasone or bortezomib plus dexamethasone) to triplet combination in recent years. Commonly used triplet combinations are bortezomib plus thalidomide plus dexamethasone (VTd) bortezomib plus lenalidomide plus dexamethasone (VRd), bortezomib plus cyclophosphamide plus dexamethasone (VCd), or bortezomib plus liposomal doxorubicin plus dexamethasone (PAd). In a randomized trial, VTd was superior to VCd in terms of response rate (reviewed in ref. ).
A recent study from our institute has evaluated the impact of induction therapy on transplant outcome; among 326 patients, 194 (59.5%) patients had received induction with two drugs (doublets) and 132 (40.5%) with three drugs (triplets). The triplet-based induction was superior as regards to response (95.4% vs. 84.02%, P < 0.003), stem-cell mobilization (CD34+ ≥2 × 106/kg, 88.6% vs. 76.8%, P < 0.005) and lower day 100 transplant-related mortality (P < 0.001). Day +100 post- transplant overall response (97.4% vs. 91.7%, P = 0.124) and complete response rates (72.5% vs. 68.0%, P = 0.38) were similar.
At a median follow-up of 62.5 months, median OS was 97.5 months vs. 100.0 months, p = 0.606 and PFS was 54.5 months vs. 57 months, p = not significant, respectively. Currently, VRd combination is considered the standard induction in transplant-eligible patients. Most recently, Kumar et al. reported the results of a randomized (ENDURANCE) trial comparing VRd and carfilzomib, lenalidomide, and dexamethasone (KRd) among 1087 newly diagnosed MM patients lacking p53 mutation. PFS (primary endpoint) was similar for both regimens, 34.6 (KRD) and 34.4 months, respectively. Estimated 3-year OS was 86% and 84% (P = ns). Cardiac, pulmonary, and renal toxicities were more common with KRD while peripheral neuropathy was more common with VRD. These results suggest that as of now VRD remains standard induction therapy for standard or intermediate-risk MM.
Autologous stem-cell transplantation
Post induction therapy, transplant eligible patients undergo ASCT. Prior to transplant, all patients are evaluated for their fitness for transplant: organ function, performance status, and disease status. For peripheral blood stem cell mobilization, patients receive inj G-CSF 10 µg/day in two divided doses for 5 days followed by aphaeresis. Target is to collect 2 to 2.5 × 106 CD34+ cells. About 10–20% of patients may have poor mobilization. These can be identified by doing peripheral blood CD34 counts on day 4 of G-CSF. Patients with CD34+ cells <20/mm3 are likely to have poor mobilization. Options for such patients include chemo-mobilization using cyclophosphamide 2–4 g/m2 or Plerixafor, a CXCR4 –chemokine inhibitor. Patients with prior melphalan or radiation are poor mobilizers and therefore these should be avoided during induction in transplant eligible patients. Once adequate number of stem cells are harvested, they can be cryopreserved at −80°C or in liquid nitrogen for long-term storage. At our center, we keep stem cells at 4°C. This is followed by HDCT with melphalan 200 mg/m2 IV followed by stem cell infusion 24h later. This practice of keeping stem cells at 4°C is cost-effective and stem cells are viable (>90%) for up to 96h. 24 hours post stem cell infusion patients receive inj G-CSF 5 mcg /kg daily until engraftment. Once stable, patients are then discharged and followed up in the outpatients department with reassessment for the response on day 100. During the post-transplant period, patients are kept in an isolation room, reverse barrier nursing is practiced, and patients receive prophylactic antibiotics, antifungals, antivirals, and packed cells and platelets support.,
Initial studies have used thalidomide 100–200 mg/ day; among the six randomized studies, three had shown improved PFS and OS. Neuropathy was the main toxicity. Subsequent studies have used lenalidomide 5–10 mg daily 15–21 days every 28 days. These studies have shown improved PFS. Second malignancy has been reported in 4–6% of patients. Inj Bortezomib 2 mg every 2 weeks has been used in studies from Europe. Currently, Lenalidomide 10 mg daily for 21 days out of 28 days for 2 years is recommended. Recent studies have suggested that prolonged maintenance beyond 2 years may be even better.
Induction therapy for transplant-ineligible or elderly patients
Patients aged 65–70 years receive 9–12 cycles of three-drug combination as mentioned above followed by maintenance. For patients who are frail or have significant co-morbidities, two-drug combinations (lenalidomide–dexamethasone, bortezomib–dexamethasone) are a reasonable choice. Dose modifications have been suggested for patients who are elderly or have organ dysfunction to reduce toxicity [Table 6].
|Table 6: Suggested dose reduction according to age (adapted from ref.)|
Click here to view
| Radiation Therapy|| |
Almost 40% of myeloma patients may require radiation therapy for pain relief some time during the course of their disease. Patients with compression fractures or impending fractures of weight-bearing bones should be first considered for surgical stabilization prior to radiotherapy (RT). For pain due to vertebral body collapse in the absence of spinal cord compression (SCC) and soft tissue disease, vertebroplasty may be potentially beneficial. In cases of rapidly evolving symptomatic SCC, a surgical evaluation is recommended because an expeditious intervention may enhance the chance of immediate and sustained neurologic recovery. RT alone also provides very effective palliative treatment for such patients. In addition, RT has shown to provide pain relief with reduction of analgesic drugs, ameliorate neurologic symptoms, promote recalcification of bone, and improve both motor function and quality of life (QoL) in patients with MM. The use of bisphosphonates (e.g., pamidronate and zoledronate) has been shown to reduce skeletal-related events and pain, with a reduction in the use of RT.
Consensus opinion of the International Lymphoma Radiation Oncology Group (ILROG) panel is that for bony sites, where the goal is limited to symptom relief, a hypofractionated regimen with a total dose of 8–30 Gy (e.g., 8 Gy in one fraction, 20 Gy in five daily fractions, or 30 Gy in 10 daily fractions, delivered as five fractions per week) is acceptable. For an epidural disease with SCC, or a bulky mass, when durable local control is intended, 30 Gy in 10–15 daily fractions, at five fractions per week, should be considered. For cases with a nerve root or SCC, coverage with glucocorticoids is recommended (e.g., dexamethasone 4 mg qid, prednisone 50–75 mg bid, or equivalent) and can also be considered to prevent pain flare (e.g., dexamethasone 4 mg bid).
| Supportive Care|| |
As soon as diagnosis of myeloma is suspected, adequate hydration (3L/m2, approximately 10–12 glass) must be ensured to prevent renal dysfunction. It is our practice to give allopurinol 5–10 mg/kg/day for the first one week (reduce dose to 100 mg daily in patients with serum creatinine >2 mg %). For pain, the use of NSAIDS should be avoided. Paracetamol or tramadol is safer. Similarly, avoid IVP or use of contrast for CT scan until essential and ensure adequate renal function. Any underlying infection must be treated adequately, with care to avoid nephrotoxic antibiotics. Palliative RT can be used for impending cord compression or to ease severe bone pain.
Packed red cells can be transfused to keep Hb above 8–8.5 g %. Erythropoiesis-stimulating agents are recommended in anemic patients with myeloma-associated renal failure. In addition, patients with adequate eGFR (≥60mL/min) also receive injection zoledronic acid (4 mg in 100mL saline over 20–30min) once in 3 months for the first 2 years then once in 6 months indefinitely along with calcium and vitamin D supplement to reduce bone pains and strengthen bones. For patients with renal impairment, the zoledronic acid dose is reduced to 50% (if serum creatinine is 2–3 mg %), and avoid if serum creatinine is >3 mg %. Pamidronate is relatively safer for patients with renal failure. Denosumab, a RANK ligand inhibitor, is another option for such patients.
Vertebroplasty or kyphoplasty may be considered for symptomatic vertebral compression fractures.
Peripheral neuropathy is an important complication, mostly thalidomide and bortezomib related. Potential mechanisms are degeneration of dorsal root ganglion, related to angiogenesis inhibition and cytokine modulation (thalidomide related), and inhibition of the ubiquitin-proteasome system for bortezomib-induced neuropathy. Sensory neuropathy and neuropathic pain are common; motor neuropathy and autonomic damage are less frequent. Prompt recognition of predisposing factors (such as diabetes mellitus, vitamin deficiencies) and appearance of signs and symptoms, through a periodic neurological assessment with appropriate scales, are extremely important. In patients developing neuropathy symptoms/signs, bortezomib dose adjustment is recommended [Table 7]. Once a week administration of bortezomib by subcutaneous route has reduced bortezomib-induced peripheral neuropathy (from 37 to 40% with the intravenous route on days 1, 4, 8, 11 and <10% with weekly schedule and subcutaneous route) without affecting response rates. Studies suggest an inflammatory etiology for bortezomib-induced neuropathy and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce its incidence and/or severity. Moreover, gabapentin or pregabalin, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, carbamazepine, and opioid-type analgesics have been used according to the pain severity.
|Table 7: Dose modification guideline for bortezomib related neuropathic pain and/or peripheral sensory or motor neuropathy (https://www.google.com/url?q=https://www.velcade.com/files/pdfs/VELCADE_PRESCRIBING_INFORMATION) (adapted from ref.)|
Click here to view
Many patients with myeloma develop bacterial infections. This increased susceptibility is due to hypo-γ-globulinemia, neutropenia, and low cell-mediated immunity. Gram-positive organisms (e.g., Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae) are the common pathogens. Patients receiving dexamethasone should receive trimethoprim–sulphamethoxazole prophylaxis. Patients on bortezomib should receive prophylactic acyclovir against herpes zoster.
Patients of myeloma receiving thalidomide/lenalidomide are at high risk to develop venous thrombosis, particularly when receiving in combination with dexamethasone. All such patients receive prophylaxis with low-dose aspirin (75–100 mg), low-molecular-weight heparin or warfarin.,
| Rehabilitation|| |
While there has been significant improvement in survival of MM patients, many patients continue to have symptoms related to bone damage [pain, deformity, limited range of motion (ROM), upper and lower extremity dysfunction, or persistent neurological deficits], therapy-related side effects (fatigue, anorexia, constipation, dysphagia, neuropathy, gait disturbance, myopathy, osteoporosis, etc.), sleep disturbance, anxiety, depression, along with co-morbidities of old age. These factors prevent a return to normal functioning and better QoL. A systematic assessment with respect to the QoL and functioning should be performed for all patients diagnosed with MM, with incorporation of a well-targeted rehabilitation where required. This may improve the overall functioning of such patients suffering from a debilitating disease, helping to provide them with a good QoL.
| Conclusions|| |
Survival of patients with myeloma has improved significantly in the past two decades. Compared to a median survival of 3 to 3.5 years prior to the year 2000, presently median survival is 5.5 to 6 years. For patients undergoing ASCT median survival is 8.5 to 9.5 years. Recently, a number of newer agents have been added with significant activity and have been approved for the treatment of relapse. These include carfilzomib, ixazomib, pomalidomide, and Selinexor. Selinexor, an oral, selective inhibitor of XPO1-mediated nuclear export, leads to the reactivation of tumor suppressor proteins. The efficacy of Selinexor with low-dose dexamethasone in triple-class refractory relapse/refractory myeloma led to its approval by the FDA for this indication. In addition, two monoclonal antibodies such as daratumumab (anti-CD38) and elotuzumab (anti-SLAM F7) have been moved to the front line. A combination of VTD (bortezomib, thalidomide, and dexamethasone) and daratumumab was superior to VTD in terms of response rate, MRD (minimal residual disease) negativity, and PFS in a recent study. Other strategies currently being explored include vaccination against MM antigens, along with immunomodulatory agents such as IMiDs or the anti-PD-1 antibody and CAR-T cell therapy. It is hoped that these strategies would lead to further improvement in response and long-term control of the disease in near future.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
India State-Level Disease Burden Initiative Cancer Collaborators. The burden of cancers and their variations across the states of India: The Global Burden of Disease Study 1990–2016. Lancet Oncol 2018;19:1289-06.
Kumar L, Verma R, Radhakrishnan VR Recent advances in the management of multiple myeloma. Natl Med J India 2010;23:210-8. Review.
Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al
. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111:2516-20.
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al
. International myeloma working group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538-48.
Kyle RA, Larson DR, Therneau TM, Dispenzieri A, Kumar S, Cerhan JR, et al
. Long-term follow-up of monoclonal gammopathy of undetermined significance. N Engl J Med 2018;378:241-9.
Lakshman A, Rajkumar SV, Buadi FK, Binder M, Gertz MA, Lacy MQ, et al
. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J 2018;8:59.
Durie BG, Salmon SE A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975;36:842-54.
Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, et al
. International staging system for multiple myeloma. J Clin Oncol 2005;23:3412-20.
Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al
. Revised international staging system for multiple myeloma: A report from international myeloma working group. J Clin Oncol 2015;33:2863-9.
Landgren O Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: Biological insights and early treatment strategies. Hematology Am Soc Hematol Educ Program 2013;2013:478-87.
Fairfield H, Falank C, Avery L, Reagan MR Multiple myeloma in the marrow: Pathogenesis and treatments. Ann N Y Acad Sci 2016;1364:32-51.
Terpos E, Ntanasis-Stathopoulos I, Gavriatopoulou M, Dimopoulos MA Pathogenesis of bone disease in multiple myeloma: From bench to bedside. Blood Cancer J 2018;8:7.
Paul B, Lipe B, Ocio EM, Usmani SZ Induction therapy for newly diagnosed myeloma. Am Soc Clin Oncol Educ Book 2019;39:e176-86.
Kumar L, Gundu N, Kancharia H, Sahoo RK, Malik PS, Sharma A, et al
. Multiple myeloma-effect of induction therapy on transplant outcomes. Clin Lymphoma Myeloma Leuk2020. doi: 10.1016/j.clml.2020.08.021. Epub ahead of print.
Kumar S, Jacobus SJ, Cohen AD, Weiss M, Callander NS, Singh AA, et al
. Carfilzomib, lenalidomide and dexamethasone (KRD) versus bortezomib, lenalidomide and dexamethasone (VRD) for initial therapy of newly diagnosed multiple myeloma (NDMM): Results of ENDURANCE (E1A11) phase III trial. J Clin Oncol2020;38(suppl):LBA3-LBA3.
Kumar L, Ramavath D, Kataria B, Tiwari A, Raj A, Chellapuram SK, et al
; for AIIMS Myeloma Group. High-dose chemotherapy followed by autologous stem cell transplant for multiple myeloma: Predictors of long-term outcome. Indian J Med Res 2019;149:730-9.
] [Full text]
Kagoya Y, Nannya Y, Kurokawa M Thalidomide maintenance therapy for patients with multiple myeloma: Meta-analysis. Leuk Res 2012;36:1016-21.
McCarthy PL, Holstein SA, Petrucci MT, Richardson PG, Hulin C, Tosi P, et al
. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: A meta-analysis. J Clin Oncol 2017;35:3279-89.
Parameswaran H, Pasquini CM, Stadtmauer AE, Fraser R, Fei M, Devine MS, et al
. Long-term follow-up of BMT CTN 0702 (STaMINA) of post autologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM). J Clin Oncol 2020;38:8506.
Palumbo A, Anderson K Multiple myeloma. N Engl J Med 2011;364:1046-60.
Terpos E, Morgan G, Dimopoulos MA, Drake MT, Lentzsch S, Raje N, et al
. International myeloma working group recommendations for the treatment of multiple myeloma-related bone disease. J Clin Oncol 2013;31:2347-57.
Berenson JR, Hillner BE, Kyle RA, Anderson K, Lipton A, Yee GC, et al
; American Society of Clinical Oncology Bisphosphonates Expert Panel. American society of clinical oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma. J Clin Oncol 2002;20:3719-36.
Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, et al
. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: An international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol 2018;19:370-81.
Grammatico S, Cesini L, Petrucci MT Managing treatment-related peripheral neuropathy in patients with multiple myeloma. Blood Lymphat Cancer 2016;6:37-47.
Richardson PG, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, et al
. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: Impact of a dose-modification guideline. Br J Haematol 2009;144:895-903.
Leebeek FW Update of thrombosis in multiple myeloma. Thromb Res 2016;140(Suppl 1):S76-80.
Devarakonda S, Cottini F, Bumma N, Khan A, Sharma N, Chaudhry M, et al
. Multiple myeloma: Clinical updates from the American Society of Clinical Oncology Annual Scientific Symposium 2020. J Clin Med2020;9:3626.
Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, et al
. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase 3 study. Lancet 2019;394:29-38.
Shah N, Aiello J, Avigan DE JG, Borrello IM, Chari A, et al
. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma. J Immunother Cancer 2020;8:e000734. doi: 10.1136/jitc-2020-000734.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]