Version July 2025
INTRODUCTION —
Multiple myeloma (MM) is a plasma cell neoplasm characterized by clonal plasma cells that produce a monoclonal immunoglobulin. These plasma cells proliferate in the bone marrow and can result in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures. Additional disease-related complications include hypercalcemia, kidney impairment, anemia, and infections. Treatment directed at the underlying plasma cell clone is required to prevent complications and improve overall survival.
MM must be distinguished from the premalignant stages of myeloma, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) (table 1 and algorithm 1). In contrast to MM, active treatment is not routinely indicated for patients with MGUS or SMM. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
The initial chemotherapy for patients with MM treated in resource-rich settings is discussed here. Other aspects of care are discussed separately, including chemotherapy options for patients in resource-poor settings, a general management overview, details regarding the use and timing of autologous hematopoietic cell transplantation, and response assessment.
●(See "Multiple myeloma: Overview of management".)
●(See "Multiple myeloma: Management in resource-limited settings".)
●(See "Multiple myeloma: Use of hematopoietic cell transplantation".)
Separate discussions are also available regarding the administration of common therapies, the use of osteoclast inhibitors, thromboprophylaxis for patients receiving immunomodulatory agents, and the treatment of relapsed or resistant MM.
●(See "Multiple myeloma: Administration considerations for common therapies".)
●(See "Multiple myeloma: The use of osteoclast inhibitors".)
●(See "Multiple myeloma: Prevention of venous thromboembolism".)
●(See "Multiple myeloma: Treatment of first relapse".)
●(See "Multiple myeloma: Treatment of second or later relapse".)
GOALS OF THERAPY —
Patients with MM are not cured with conventional therapy. Treatment alleviates symptoms, reverses cytopenias, and decreases end-organ damage, and is given with the overall goals of achieving and maintaining a response, improving quality of life, and prolonging overall survival.
CHOICE OF THERAPY
Risk-stratified treatment
Risk stratification and other factors impacting choice — Patients with MM can be categorized as having standard-risk or high-risk disease based on the results of fluorescence in situ hybridization (FISH) for specific translocations and/or deletions and certain other tests (table 2). This risk stratification has considerable prognostic value and helps guide the selection of initial therapy (algorithm 2). In addition, three prognostic risk groups (standard risk, intermediate risk, and high risk) can be determined using the Revised International Staging System (R-ISS) (table 3), which uses serum beta-2 microglobulin, albumin, lactate dehydrogenase, and bone marrow FISH results. Risk stratification is discussed in detail separately. (See "Multiple myeloma: Overview of management", section on 'Risk stratification' and "Multiple myeloma: Staging and prognostic studies", section on 'Revised International Staging System (R-ISS)'.)
The choice among treatment regimens should also take into consideration the patient's:
●Age
●Performance status
●Comorbid conditions
●Preferences regarding the type of treatment they receive
●Potential for chemotherapy-related side effects
All patients should be evaluated for supportive care and use of prophylaxis to minimize complications. (See 'Prevention and management of complications' below.)
Although historically the regimens used as induction therapy for transplant-eligible patients differed significantly from those used for patients who are not eligible for transplant, that is no longer the case, particularly as melphalan-based regimens are rarely used for transplant-ineligible patients whereas they were widely used in the past.
Many of the preferred treatment options have not been compared directly with each other in a randomized trial in these patient populations. As such, there is no standard of care and different experts use different regimens. Data supporting their use come largely from single-arm trials or randomized trials comparing these regimens with other regimens. Three-drug regimens are preferred over two-drug regimens whenever possible because they appear to provide an overall survival (OS) benefit. Four-drug regimens may offer additional benefits.
Our approach is generally consistent with that proposed by the International Myeloma Working Group [1-7]. Links to guidelines are provided separately. (See 'Society guideline links' below.)
Standard-risk myeloma — For patients with standard-risk MM (table 2), three-drug regimens are preferred over two-drug regimens because randomized trials have shown that they improve OS (algorithm 2). When compared with three-drug regimens, initial trial results also suggest that four-drug regimens deepen response and improve progression-free survival (PFS), albeit with an increase in toxicity and cost. As such, a choice between three-drug and four-drug regimens is largely driven by patient values, preferences, and access. Those who prioritize PFS may reasonably select a four-drug regimen. Three-drug regimens remain an acceptable option for patients with standard-risk MM who prioritize avoiding the costs and toxicity of adding a fourth drug.
Our preferred regimens for standard-risk MM include:
●Daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) is a reasonable option for patients who prioritize PFS and are willing to accept the increased toxicity and cost. When compared with bortezomib, lenalidomide, and dexamethasone (VRd), DVRd deepens responses and improves PFS [8-10]. (See 'Daratumumab, bortezomib, lenalidomide, dexamethasone' below.)
●Isatuximab, bortezomib, lenalidomide, and dexamethasone (IsaVRd) is a reasonable option for patients who prioritize PFS and are willing to accept the increased toxicity and cost. When compared with bortezomib, lenalidomide, and dexamethasone (VRd), IsaVRd deepens responses and improves PFS [11,12]. (See 'Isatuximab-based four-drug regimens' below.)
●Bortezomib, lenalidomide, and dexamethasone (VRd) (table 4) is a reasonable option for those who prioritize avoiding the costs and toxicity of adding a fourth drug. A randomized phase 3 trial demonstrated superior OS with VRd when compared with lenalidomide plus dexamethasone (Rd) (table 5) [13]. (See 'Bortezomib, lenalidomide, dexamethasone' below.)
●Daratumumab, lenalidomide, and dexamethasone (DRd) (table 6) is an alternative, especially for patients who may not tolerate bortezomib (eg, those with pre-existing neuropathy). DRd has shown improved OS when compared with Rd and is associated with minimal peripheral neuropathy [14]. (See 'Daratumumab, lenalidomide, dexamethasone' below.)
●Bortezomib, cyclophosphamide, and dexamethasone (VCd; also called CyBorD) (table 7) is effective for patients with significant kidney impairment related to myeloma or other factors, and there is minimal thromboembolic risk associated with this combination. It is an important option in countries where lenalidomide is not approved for initial therapy [15]. (See 'Bortezomib, cyclophosphamide, dexamethasone' below and 'Acute kidney injury' below.)
Patients who are eligible for autologous hematopoietic cell transplantation (HCT) are typically treated with three to six cycles of induction therapy followed by autologous stem cell collection. Then a decision is made regarding whether to proceed with autologous HCT (early HCT strategy) or continue the same chemotherapy regimen, reserving HCT for first relapse (delayed HCT strategy). (See 'Incorporating HCT in eligible patients' below.)
The total number of cycles used for an individual patient depends on whether the patient plans to proceed immediately with HCT, how well they tolerate the regimen, and the response to treatment. Those not proceeding to early HCT are typically treated with 8 to 12 cycles, as tolerated, followed by maintenance until progression. Choice of maintenance regimen is discussed in more detail separately. (See 'Maintenance for patients who are ineligible for or defer HCT' below.)
High-risk myeloma — Patients with high-risk MM (table 2) should be encouraged to participate in clinical trials and should be considered for novel therapeutic strategies since they tend to do less well with conventional treatment options. Outside of a clinical trial, we suggest initial treatment with a proteasome inhibitor-containing regimen and/or a CD38-targeting monoclonal antibody-containing regimen. This preference is based on limited data that suggest use of these agents may abrogate the prognostic impact of at least some of these high-risk genetic markers [16-21].
Our preferred regimen depends on whether the patient is a candidate for autologous HCT and comorbidities (algorithm 2):
●HCT ineligible – For patients with high-risk MM who are ineligible for HCT, we administer 8 to 12 cycles of a regimen that includes a proteasome inhibitor, an anti-CD38 monoclonal antibody, or both, followed by maintenance until progression, as described below (algorithm 2).
•For most patients, we suggest a four-drug regimen (IsaVRd or DVRd) rather than a three-drug regimen. IsaVRd has demonstrated a PFS benefit over VRd alone in the HCT-ineligible population [11,12]. We are comfortable substituting daratumumab for isatuximab based on extrapolation of data from the HCT-eligible population and the expectation that the two anti-CD38 monoclonal antibodies are likely to have similar efficacy. (See 'Isatuximab-based four-drug regimens' below and 'Daratumumab, bortezomib, lenalidomide, dexamethasone' below.)
•For frail patients, we prefer VRd (table 4) or DRd (table 6) as these combinations have demonstrated an OS benefit over Rd alone [13,14]. (See 'Bortezomib, lenalidomide, dexamethasone' below and 'Daratumumab, lenalidomide, dexamethasone' below.)
•VCd (table 7) is an acceptable alternative for patients at higher risk of complications with lenalidomide (eg, acute kidney injury, increased thromboembolic risk) and for those in countries in which lenalidomide is not approved for initial therapy [15]. (See 'Bortezomib, cyclophosphamide, dexamethasone' below.)
●HCT eligible – For patients with high-risk MM who are candidates for autologous HCT, we administer three to six cycles of a four-drug regimen that contains a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, typically DVRd or IsaVRd. (See 'Daratumumab, bortezomib, lenalidomide, dexamethasone' below and 'Isatuximab-based four-drug regimens' below.)
We then collect stem cells and proceed with HCT, followed by two-agent maintenance until progression (algorithm 2). This preference for early HCT and the choice between single or double HCT is discussed separately. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Early versus late HCT' and "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Tandem HCT and/or consolidation'.)
As described in more detail below, the addition of daratumumab or isatuximab to VRd deepens responses and improves PFS. (See 'Daratumumab, bortezomib, lenalidomide, dexamethasone' below and 'Isatuximab-based four-drug regimens' below.)
In addition, limited data suggest that the prognostic impact of at least some of these high-risk genetic markers may be abrogated by the use of a proteasome inhibitor and/or an anti-CD38 monoclonal antibody. As an example, several trials of proteasome inhibitor-containing regimens suggested that outcomes in patients with high-risk MM, while expected to be worse, were similar to those of standard-risk MM, although the number of patients with high-risk MM was small [16,21,22]. In addition, a meta-analysis of patients with high-risk MM included in six phase 3 trials reported a PFS benefit when daratumumab was added to initial therapy (hazard ratio [HR] 0.67, 95% CI 0.47-0.95) or subsequent therapy (HR 0.45, 95% CI 0.30-0.67) [17].
Special populations — The general treatment principles described above apply to most treatment settings and patient populations. However, patients with kidney injury, frail adults, and patients being treated in resource-poor settings require special consideration.
Acute kidney injury — In patients with acute kidney injury due to cast nephropathy, regimens that act rapidly and can be used safely without major dose adjustment are preferred. Lenalidomide is typically avoided. Our approach to patients with this presentation is discussed separately. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis", section on 'Overview of approach'.)
Frail adults — Frail adults are often older patients with comorbidities and limited ability to perform instrumental and standard activities of daily living who experience higher rates of treatment discontinuation due to toxicity, and inferior PFS and OS [23-28]. Older adults may benefit from a more formal comprehensive geriatric assessment to assess frailty. (See "Comprehensive geriatric assessment for patients with cancer".)
Dose modifications are needed in this population. For all of the regimens discussed below, we advise that the dose of lenalidomide be decreased to 15 mg (instead of 25 mg), and in some cases to 10 mg (eg, in the setting of kidney dysfunction), and the dose of dexamethasone to 20 mg once a week (instead of 40 mg once a week). For patients who attain a good response after 9 to 12 months of a regimen that includes lenalidomide plus dexamethasone, we discontinue dexamethasone and continue lenalidomide alone rather than both drugs as maintenance. Support for this transition is discussed separately. (See 'Lenalidomide plus dexamethasone' below.)
The choice of initial regimen should take into account tolerability and convenience (algorithm 2):
●Rd (table 5) is an effective oral regimen and is our preferred option for frail patients with standard-risk MM unable to tolerate a three-drug regimen. (See 'Lenalidomide plus dexamethasone' below.)
●VRd (table 4) is a three-drug option, especially for patients with high-risk MM, that can be given at a modified dose and schedule to enhance tolerability in this population [29]. If tolerated, VRd improves OS over that seen with Rd alone [13]. (See 'Bortezomib, lenalidomide, dexamethasone' below and 'High-risk myeloma' above.)
●DRd (table 6) is another important three-drug option, which was associated with an OS advantage over that seen with Rd alone [14]. (See 'Daratumumab, lenalidomide, dexamethasone' below.)
While response rates mirror those in other populations, the main challenge is treatment discontinuation and/or early mortality due to toxicity. In a phase 2 trial (HOVON 143) of ixazomib, daratumumab, plus dexamethasone in frail patients with newly diagnosed MM, one-half were unable to complete the planned induction therapy [30].
Resource-limited settings — Newer agents for the treatment of MM are not routinely available in many countries due to the lack of regulatory approval or due to high cost. In these settings, the choice of initial therapy should consider alternative regimens. These include several melphalan-based regimens and thalidomide-based regimens. These are discussed in more detail separately. (See "Multiple myeloma: Management in resource-limited settings".)
COORDINATING CARE
Incorporating HCT in eligible patients — High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT; rescue) is a standard of care for eligible patients with newly diagnosed MM. As such, all patients with MM should be assessed at the time of diagnosis to determine whether they are eligible for autologous HCT, and the initial chemotherapy given to patients who are candidates for HCT should avoid agents that may damage stem cells (eg, melphalan). (See "Multiple myeloma: Overview of management", section on 'Determine transplant eligibility'.)
Patients who are eligible for HCT are typically treated with three to six cycles of induction therapy followed by autologous stem cell collection (algorithm 2). Then a decision is made regarding whether to proceed with autologous HCT (early HCT strategy) or continue the same chemotherapy regimen reserving HCT for first relapse (delayed HCT strategy). Both approaches so far have produced similar overall survival (OS) rates, with the incorporation of HCT associated with longer duration of progression-free survival (PFS).
Whether to pursue an early versus delayed HCT strategy depends on clinical features and risk stratification, response to induction therapy, and patient preferences regarding the timing of transplant. This is discussed in more detail separately. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Early versus late HCT'.)
Maintenance for patients who are ineligible for or defer HCT — There is ongoing debate regarding the role of maintenance therapy in patients with MM who are ineligible for or defer autologous HCT and experts differ in their approach. We suggest maintenance therapy for most patients; this preference places a high value on delaying progression and the potential for an as-yet-unproven OS benefit and places a lower value on the risks associated with continued therapy.
Our preferred maintenance depends on risk stratification and comorbidities (algorithm 2). The risk of second cancers must be discussed with all patients who are treated with lenalidomide maintenance [31]. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Immunomodulatory drugs'.)
●High-risk MM – Following 8 to 12 cycles of triplet or quadruplet induction therapy, we offer patients with high-risk MM two-agent maintenance until time of disease progression.
For those initially treated with daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd), isatuximab, bortezomib, lenalidomide, and dexamethasone (IsaVRd), or bortezomib, lenalidomide, and dexamethasone (VRd), we offer maintenance with both lenalidomide and bortezomib. Maintenance with lenalidomide plus carfilzomib is an acceptable alternative for patients unable to tolerate standard-dose bortezomib due to neuropathy. Maintenance with lenalidomide plus daratumumab is an acceptable alternative for patients unable to tolerate bortezomib or carfilzomib and for those initially treated with VRd.
For those initially treated with daratumumab, lenalidomide, and dexamethasone (DRd), we offer maintenance with both lenalidomide and daratumumab.
●Standard-risk MM – Following 8 to 12 cycles of quadruplet therapy (DVRd or IsaVRd), we offer patients with standard-risk MM maintenance with single-agent lenalidomide until progression. For patients with standard-risk MM who receive initial therapy with the triplet VRd, maintenance with lenalidomide plus daratumumab is a reasonable alternative for those who are willing to accept a modest increase in toxicity (cytopenias, infections) with the goal of delaying progression, and for patients who remain minimal residual disease (MRD) positive after the initial 8 to 12 cycles of therapy. For those initially treated with DRd, we offer maintenance with both lenalidomide and daratumumab.
●Frail patients – Following 8 to 12 cycles of treatment with modified triplet therapy or lenalidomide plus dexamethasone (Rd), we offer frail patients with standard-risk MM maintenance with single-agent lenalidomide until progression. (See 'Frail adults' above.)
The rationale for maintenance therapy in MM includes the incurability of MM and recognition that relapse may present acutely with life-threatening complications. Prospective trials suggest that maintenance therapy prolongs PFS, but data are mixed as to whether there is meaningful improvement in OS. Additional support for maintenance comes from extrapolation of data that have shown improved OS with maintenance therapy after HCT. This is discussed in more detail separately. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Maintenance'.)
Lenalidomide maintenance was incorporated into both arms of the randomized trials that demonstrated improved OS with VRd versus Rd (SWOG S0777) and with DRd versus Rd (MAIA) [13,32,33]. However, the impact of maintenance on the outcomes seen in these trials cannot be assessed given the lack of a maintenance-free control arm.
The trials that have evaluated maintenance therapy in patients not undergoing HCT have limitations in terms of their ability to inform decisions regarding maintenance therapy. In some patients, factors other than maintenance differed between the two arms. In others, the regimens used are outdated. As an example, the FIRST trial demonstrated better OS with continuous Rd when compared with 18 months of melphalan, prednisone, and thalidomide (MPT) in transplant-ineligible patients with previously untreated MM [34-36]. However, these two arms differed in both the length of therapy and agents used. The same trial evaluated duration of Rd therapy with a third arm and demonstrated that continuous Rd improved PFS when compared with 18 months of Rd, the primary endpoint of the study. As another example, the experimental arms of the IMROZ study that demonstrated improved PFS with IsaVRd versus VRd and the MAIA study that demonstrated improved OS with DRd versus Rd in HCT-ineligible patients included the assigned anti-CD38 monoclonal antibody in the induction and maintenance phases of treatment, while the control arm received maintenance with lenalidomide and dexamethasone alone [12,14,32]. Nevertheless, given the demonstrated OS benefit in MAIA, for those initially treated with DRd, we offer maintenance with both lenalidomide and daratumumab.
A 2015 meta-analysis compared continuous therapy versus fixed-duration therapy in patients with newly diagnosed MM [37]. This analysis was restricted to the 1218 patients who were progression-free and alive at one year after random assignment (ie, those eligible for continuous therapy). Two trials used lenalidomide maintenance while one used maintenance with bortezomib and thalidomide. After a median follow-up of 52 months, maintenance therapy resulted in improved PFS (median 32 versus 16 months, hazard ratio [HR] 0.47; 95% CI 0.40-0.56), second PFS (median 55 versus 40 months, HR 0.61; 95% CI 0.50-0.75), and OS (69 versus 60 percent alive at four years, HR 0.69; 95% CI 0.54-0.88). The improved second PFS suggests that the administration of maintenance therapy did not adversely impact the ability to respond to subsequent therapy. However, it is not clear whether all patients in the control arms had access to lenalidomide and bortezomib at the time of relapse. Toxicity and impact on quality of life were not examined.
Studies have evaluated single-agent lenalidomide as maintenance in standard-risk MM, as there are known risks to continuous glucocorticoid therapy, and the benefits are unclear. In two randomized trials, there was no clear benefit from the addition of prednisone to lenalidomide maintenance [38,39]. Another trial demonstrated similar efficacy and better tolerability with Rd for nine cycles followed by reduced-dose lenalidomide maintenance without dexamethasone when compared with continuous Rd in intermediate-fit older adults [40]. (See 'Lenalidomide plus dexamethasone' below.)
An open-label, multicenter, randomized, phase III trial (Myeloma XI) compared maintenance with single-agent lenalidomide (10 mg daily on 21 of 28 days per cycle) versus observation in 1917 patients with MM followed for a median of 31 months [41]. In a prespecified subgroup analysis of the 723 patients ineligible for transplant who underwent initial treatment with at least six cycles of induction that included cyclophosphamide, dexamethasone, and either thalidomide or lenalidomide, lenalidomide maintenance improved PFS (median 26 versus 11 months; HR 0.44, 95% CI 0.37-0.53) but not OS (OS at three years 67 versus 70 percent; HR 1.02, 95% CI 0.80-1.29). However, of the patients assigned to lenalidomide, approximately 70 percent had dose modifications, and 15 percent discontinued lenalidomide due to toxicity.
Data regarding carfilzomib maintenance are extrapolated from the transplant setting. The FORTE trial demonstrated improved PFS with two-drug maintenance (carfilzomib plus lenalidomide) when compared with lenalidomide maintenance (three-year PFS from randomization to maintenance 75 versus 65 percent; HR 0.64; 95% CI 0.44-0.94) [42]. As maintenance was investigated as a second randomization, the population studied included patients with standard- and high-risk MM treated with different induction regimens with or without HCT. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'High-risk disease'.)
There are limited data regarding ixazomib maintenance. In a placebo-controlled, randomized trial (TOURMALINE-MM4) of >700 patients with newly diagnosed MM not undergoing autologous transplant, ixazomib maintenance prolonged PFS (median PFS 17 versus 9 months, HR 0.66, 95% CI 0.54-0.80) [43]. Rates of grade 3 or greater treatment-emergent adverse events were increased (37 versus 23 percent). The most common any grade adverse events were nausea (27 percent), vomiting (24 percent), and diarrhea (23 percent).
Prevention and management of complications — In addition to therapy directed at the malignant clone, the management of most patients with MM includes preventive measures to reduce the incidence of skeletal events, kidney damage, infections, neuropathy, and thrombosis.
●Skeletal lesions and bone health – Osteoclast inhibitors (eg, bisphosphonate therapy or denosumab) are administered to prevent skeletal events in patients with one or more lesions on skeletal imaging and those with osteopenia (algorithm 3). (See "Multiple myeloma: The use of osteoclast inhibitors".)
Skeletal lesions can result in bone pain, pathologic fractures, and spinal cord compression.
•Pathologic fractures or impending fractures of long bones require stabilization. Vertebral fractures may benefit from kyphoplasty or vertebroplasty. Most pain related to lytic lesions can be controlled with the combination of analgesics and active myeloma chemotherapy. (See "Management of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma".)
•Spinal cord compression is a clinical emergency and should be suspected in patients with severe back pain, weakness, or paresthesias of the lower extremities, or bladder or bowel dysfunction or incontinence. (See "Treatment and prognosis of neoplastic epidural spinal cord compression".)
●Kidney impairment – All patients with MM should take measures to minimize kidney damage (eg, avoid nephrotoxins such as aminoglycosides and nonsteroidal anti-inflammatory drugs [NSAIDs] and maintain adequate hydration). Many medications used for myeloma require dose adjustment for kidney impairment (eg, lenalidomide, zoledronic acid). Treatment of kidney impairment is directed at the underlying cause. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis".)
●Infection – Prophylactic measures used to minimize infection in patients with MM include yearly influenza vaccines, pneumococcal vaccine at the time of diagnosis, and the use of prophylactic antivirals and antibiotics (including Pneumocystis prophylaxis). (See "Infections in patients with multiple myeloma" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
Patients suspected of having an infection should be treated promptly with empiric antibiotics. (See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)
●Thromboprophylaxis – Patients with MM are at increased risk of having comorbidities known to be risk factors for the development of venous thromboembolism (VTE) in the general population. In addition, treatment with immunomodulatory drugs (eg, lenalidomide, pomalidomide, thalidomide) is associated with high rates of VTE. All patients with MM should have an assessment of their VTE risk so that appropriate prophylaxis may be employed (algorithm 4). (See "Multiple myeloma: Prevention of venous thromboembolism".)
●Neuropathy – Peripheral neuropathy, often painful, can occur in association with various chemotherapeutic agents, including both proteasome inhibitors (especially bortezomib) and immunomodulatory agents. The frequency and severity of peripheral neuropathy with bortezomib can be reduced by adjusting the route (subcutaneous rather than intravenous administration) and frequency (once versus twice weekly) of administration. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Specific recommendations for bortezomib'.)
Peripheral neuropathy is more frequent and severe in those who have previously received neurotoxic therapy and those with pre-existing neuropathy [44]. Regimens that do not include bortezomib (eg, daratumumab, lenalidomide, and dexamethasone) may be preferred as initial therapy in such patients. (See 'Daratumumab, lenalidomide, dexamethasone' below.)
When neuropathy occurs, it can impair quality of life and ability to perform activities of daily living. Management is discussed separately, including dose modification and/or treatment discontinuation. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Bortezomib' and "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Thalidomide and related agents'.)
●Hypercalcemia – Patients with hypercalcemia may be asymptomatic or present with anorexia, nausea, vomiting, polyuria, polydipsia, constipation, weakness, confusion, or stupor. The treatment of hypercalcemia depends on the calcium level, the rapidity with which it developed, and the patient's symptoms. Emergency treatment with hydration, glucocorticoids, bisphosphonate or denosumab, and/or hemodialysis/calcitonin is indicated for symptomatic patients. (See "Treatment of hypercalcemia".)
REVIEW OF CHEMOTHERAPY REGIMENS —
Several regimens are available for the treatment of newly diagnosed MM. The most common are discussed in the following sections. A choice among them is presented in more detail above (algorithm 2). (See 'Choice of therapy' above.)
Additional options for patients treated in resource-poor settings are presented separately. (See "Multiple myeloma: Management in resource-limited settings".)
Four-drug regimens — Three-drug regimens are preferred over two-drug regimens whenever possible because they appear to provide an overall survival (OS) benefit. When compared with three-drug regimens, four-drug regimens deepen response and improve progression-free survival (PFS) and may improve OS, albeit with an increase in toxicity and cost. As such, a choice between three- and four-drug regimens is largely driven by disease characteristics along with patient values and preferences. We prefer four-drug regimens for patients with high-risk MM and consider both three-drug and four-drug regimens to be acceptable options for patients with standard-risk MM. (See 'Standard-risk myeloma' above and 'High-risk myeloma' above.)
Support for four-drug regimens comes from a 2024 meta-analysis of seven randomized trials that evaluated the addition of an anti-CD38 monoclonal antibody to a backbone regimen that included a proteasome inhibitor and an immunomodulatory drug in >3700 patients with newly diagnosed MM [45]. Four-drug regimens resulted in higher response rates, deeper responses, and improved PFS (hazard ratio [HR] 0.55, 95% CI 0.46-0.66). While they also resulted in a statistically significant improvement in OS (HR 0.65, 95% CI 0.53-0.79), the confidence in the OS benefit is limited by a small number of events and relatively short follow-up. Four-drug regimens increased grade 3 or greater neutropenia (relative risk [RR] 1.81), infection (RR 1.22), and thrombocytopenia (RR 1.3), and made stem cell mobilization more challenging. There was little to no difference in serious adverse effects and secondary malignancy.
The four-drug regimens described below incorporate an anti-CD38 monoclonal antibody (daratumumab or isatuximab) and have demonstrated a benefit over three-drug regimens in this setting. In contrast, a randomized trial (GMMG-HD6) failed to show a clinical benefit from adding the anti-SLAMF7 monoclonal antibody elotuzumab as a fourth drug to bortezomib, lenalidomide, and dexamethasone in this setting [46]. In addition, daratumumab, carfilzomib, lenalidomide, and dexamethasone (DKRd) is an investigational four-drug regimen that has demonstrated deep responses in single-arm trials [47,48]. However, it has not been directly compared with other regimens and suggests in other populations that carfilzomib-based regimens have similar efficacy but greater toxicity than bortezomib-based regimens. (See 'Carfilzomib, lenalidomide, dexamethasone' below.)
Daratumumab, bortezomib, lenalidomide, dexamethasone
●Clinical use – Daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) is one of our preferred options for the initial treatment of MM, and daratumumab-hyaluronidase has regulatory approval for use in this combination in the United States. (See 'Standard-risk myeloma' above and 'High-risk myeloma' above.)
While the trials that have evaluated DVRd incorporated daratumumab into the induction, consolidation, and maintenance phases of treatment, data from the CASSIOPEIA trial suggest that those who receive a total of six cycles of daratumumab with induction have a limited benefit from an additional two years of daratumumab maintenance [49-52]. Given the uncertainty of benefits, we do not routinely offer post-hematopoietic cell transplantation (HCT) maintenance daratumumab following six cycles of daratumumab-based quadruplet induction therapy. (See 'Daratumumab, bortezomib, thalidomide, dexamethasone' below.)
●Efficacy and toxicity – DVRd has been compared with bortezomib, lenalidomide, and dexamethasone (VRd) in two randomized trials. The addition of daratumumab to VRd deepens responses and improves PFS, albeit with a modest increased toxicity and cost. The impact on OS is unclear as follow-up is short.
In a phase 2 trial (GRIFFIN), 207 patients with newly diagnosed MM eligible for HCT were randomly assigned to receive induction with four cycles of VRd with or without daratumumab (DVRd versus VRd), followed by autologous HCT plus two cycles of consolidation with the assigned regimen, then up to two years of maintenance with either lenalidomide alone or with lenalidomide plus daratumumab [8,9]. After a median follow-up of 50 months, DVRd improved stringent complete response rates (67 versus 48 percent) and PFS (four-year PFS 87 versus 70 percent; hazard ratio [HR] 0.45, 95% CI 0.21-0.95). Median OS was not reached for either group (HR 0.90, 95% CI 0.31-2.56). Toxicity was greater with DVRd, with higher rates of neutropenia and upper respiratory tract infections.
A subsequent phase 3 trial (PERSEUS) compared DVRd versus VRd in 709 patients with newly diagnosed MM eligible for HCT [10]. The trial design was similar to GRIFFIN except that maintenance was continued until progression for most patients. Those treated with DVRd who had sustained measurable residual disease (MRD) negativity were eligible to discontinue daratumumab and continue lenalidomide maintenance until progression. After a median follow-up of 48 months, DVRd improved MRD negativity rates (75 versus 48 percent) and PFS (48-month PFS 84 versus 68 percent; HR 0.42, 95% CI 0.30-0.59). OS data are immature with a small percentage of deaths in both arms (9.6 versus 12.4 percent). The addition of daratumumab increased the rates of neutropenia, thrombocytopenia, and infections. Stem cell mobilization and collection were feasible with DVRd, although a higher percentage of patients received plerixafor for mobilization (40 versus 23 percent).
Isatuximab-based four-drug regimens — Isatuximab, bortezomib, lenalidomide, and dexamethasone (IsaVRd) is one of our preferred options for the initial treatment of MM. Initial reports from randomized trials have reported deeper responses with the addition of isatuximab to bortezomib, lenalidomide, and dexamethasone [11,12] and to carfilzomib, lenalidomide, and dexamethasone (IsaKRd) [53]. We are comfortable using IsaVRd instead of DVRd based on the expectation that the two anti-CD38 monoclonal antibodies likely have similar efficacy, although they have not been directly compared. In contrast, further follow-up is needed regarding the use of IsaKRd given the toxicity of the carfilzomib, lenalidomide, and dexamethasone (KRd) backbone, as discussed separately. (See 'Carfilzomib, lenalidomide, dexamethasone' below.)
●IsaVRd – IsaVRd has not been directly compared with other four-drug regimens, and follow-up comparing it to VRd and isatuximab, lenalidomide, and dexamethasone (IsaRd) is short.
In transplant-eligible patients, the addition of isatuximab to VRd deepens responses with a modest increase in toxicity. The impact on PFS and OS is unclear as follow-up is short. In transplant-ineligible patients, the addition of isatuximab to VRd also improved PFS without an increase in serious adverse events (AE).
In a phase 3 trial (GMMG-HD7), 660 patients with newly diagnosed MM eligible for HCT were randomly assigned to receive induction with three cycles of VRd with or without isatuximab (IsaVRd versus VRd) [11]. An initial analysis reported that IsaVRd resulted in deeper responses with improved MRD negativity rates after induction (50 versus 36 percent; overall response [OR] 1.82, 95% CI 1.33-2.48). IsaVRd resulted in higher rates of grade 3 or 4 neutropenia (23 versus 7 percent) and grade 3 or 4 infections (12 versus 10 percent). Treatment-related deaths included one in the IsaVRd arm (septic shock) and four in the VRd arm. The protocol included autologous HCT and a second randomization that investigates the addition of isatuximab to maintenance lenalidomide. Data regarding longer-term outcomes are pending.
In another phase 3 trial (IMROZ), 446 patients with newly diagnosed MM ineligible for HCT were randomly assigned to receive treatment with isatuximab plus VRd or VRd alone [12]. After induction, patients in each arm received maintenance with isatuximab plus Rd or Rd alone, respectively; the addition of isatuximab was allowed for those with biochemical or clinical progression on Rd. After a median follow-up of 60 months, IsaVRd improved PFS (5-year PFS 63 versus 45 percent; HR 0.60, 95% CI 0.41-0.88). IsaVRd also demonstrated numerical improvements in OS that did not reach statistical significance, although the ability to assess OS is limited by the crossover allowed in the trial (5-year OS 72 versus 66 percent; HR 0.78, 99% CI 0.41-1.48). The two treatment arms had similar rates of serious AEs during treatment and AEs leading to discontinuation.
In another phase 3 trial (BENEFIT) in patients ineligible for HCT, adding bortezomib to IsaRd deepened responses, although with an increase in peripheral neuropathy and cardiac disorders [54]. After a median follow-up of 24 months, PFS and OS estimates are immature (IsaRd 24-month PFS 80 percent, OS 92 percent; IsaVRd 24-month PFS 85 percent, OS 91 percent).
●IsaKRd – IsaKRd is an experimental regimen in patients with newly diagnosed MM, and we do not use it, regardless of risk stratification (algorithm 2). While initial studies suggest that IsaKRd has activity in this setting [53,55-57], it has not been directly compared with other four-drug regimens, and follow-up comparing it to KRd is short. In addition, extrapolation of other data suggests that the backbone of KRd is not more effective than VRd and has increased toxicity and costs.
The addition of isatuximab to KRd deepens responses, albeit with a moderate increase in toxicity. The impact on PFS and OS is unclear as follow-up is short.
In a phase 3 trial (IsKia EMN24) presented in abstract form, 302 patients with newly diagnosed MM eligible for HCT were randomly assigned to receive induction with four cycles of KRd with or without isatuximab (IsaKRd versus KRd), followed by autologous HCT plus four cycles of consolidation with the assigned regimen at full dose, then 12 cycles of consolidation with reduced doses of the assigned regimen [53]. After a median follow-up of 21 months, IsaKRd improved MRD negativity rates (67 versus 48 percent with a threshold of 10-6 measured by next-generation sequencing). There was a moderate increase in toxicity with IsaKRd, demonstrating a higher percentage of grade ≥3 neutropenia (36 versus 22 percent), although a difference in grade ≥3 infection rates did not reach statistical significance (15 versus 11 percent). PFS and OS data are immature. There were four deaths in the IsaKRd arm (one progressive disease, three infections) and one death in the KRd arm (infection).
Daratumumab, bortezomib, thalidomide, dexamethasone
●Clinical use – Daratumumab, bortezomib, thalidomide, and dexamethasone (DVTd) is approved by the US Food and Drug Administration (FDA) for the treatment of patients with newly diagnosed MM who are eligible for autologous HCT. However, this and other thalidomide-containing regimens are not commonly used in the United States as initial therapy. DVTd is used more frequently in other countries.
●Efficacy and toxicity – When compared with VTd, DVTd improves PFS and OS without a major increase in toxicity.
In a phase 3 trial (CASSIOPEIA), 1085 patients with newly diagnosed MM eligible for HCT were randomly assigned to receive induction with four cycles of bortezomib, thalidomide, and dexamethasone with or without daratumumab (DVTd versus VTd), followed by autologous HCT plus two cycles of consolidation with the assigned regimen [49-52]. The 886 patients achieving a partial response or better were then randomly assigned to observation versus daratumumab maintenance with daratumumab every eight weeks for a maximum of two years. After a median follow-up of 80 months, the addition of daratumumab to induction resulted in:
•Improved PFS (median PFS 84 versus 53 months; HR 0.61, 95% CI 0.52-0.72).
•Improved OS (estimated 72-month OS 87 versus 78 percent; HR 0.55, 95% CI 0.42-0.73).
•While collection of CD34+ cells was more difficult in the DVTd arm, approximately 90 percent of patients in both arms proceeded with HCT and achieved hematopoietic reconstitution.
•When compared with VTd, DVTd increased neutropenia, lymphopenia, and pneumonia. Infusion reactions to daratumumab (mostly mild) were reported in 35 percent.
After a median follow-up of 71 months from second randomization, daratumumab maintenance improved PFS among patients who underwent VTd induction (72-month PFS 54 versus 21 percent; HR 0.34, 95% CI 0.26-0.44) and to a lesser degree among those who underwent DVTd induction (72-month PFS 60 versus 51 percent; HR 0.76, 95% CI 0.58-1.00). OS data from second randomization are immature. Infusion-related reactions were reported in 55 percent of patients receiving daratumumab maintenance (mostly grade 1 or 2), and 3 percent discontinued daratumumab due to an adverse event.
The results of the second randomization question the value of continued daratumumab maintenance after induction with a daratumumab-containing regimen. Those who received a total of six cycles of daratumumab with induction had a relatively small PFS benefit from an additional two years of daratumumab maintenance. It is not clear whether this PFS benefit will translate into an OS benefit. In addition, the patients in this trial did not receive lenalidomide maintenance, and it is not known how the incorporation of standard lenalidomide maintenance may impact the value of daratumumab in this setting. Given the uncertainty of benefit, we do not routinely offer maintenance daratumumab following six cycles of daratumumab-based quadruplet induction therapy and HCT.
Daratumumab, bortezomib, melphalan, prednisone
●Clinical use – Daratumumab, bortezomib, melphalan, and prednisone (DVMP) is an alternative four-drug regimen for the treatment of patients with newly diagnosed MM who are ineligible for autologous HCT. Oral melphalan is not available in the United States, but it is widely available elsewhere.
Importantly, DVMP is not an appropriate regimen for patients who are candidates for HCT. Melphalan-containing regimens should be avoided prior to the collection of stem cells since their use has been associated with damage to the hematopoietic stem cell compartment. Melphalan-containing regimens have a larger role in the management of myeloma in resource-poor settings. (See "Multiple myeloma: Management in resource-limited settings".)
●Efficacy and toxicity – When compared with VMP, DVMP improves both PFS and OS without a major increase in toxicity.
In a phase 3 trial (ALCYONE), 706 patients with newly diagnosed MM ineligible for HCT were randomly assigned to receive nine cycles of bortezomib, melphalan, and prednisone with or without daratumumab until disease progression (DVMP versus VMP) [58,59]. The addition of daratumumab resulted in:
•Higher rates of OR (91 versus 74 percent) and minimal residual disease negativity (22 versus 6 percent).
•Superior PFS (51 versus 19 percent at three years, median 36 versus 19 months; HR 0.42, 95% CI 0.34-0.51).
•Superior OS (78 versus 68 percent at three years; HR 0.60, 95% CI 0.46-0.80).
•More grade 3 or 4 infections (22 versus 15 percent during induction and 11 percent during maintenance). Daratumumab-related infusion reactions occurred in 28 percent.
While these results suggest that the addition of daratumumab during induction and maintenance can deepen responses and delay progression, it is not known whether PFS was improved due to the addition of daratumumab, the use of maintenance, or both. An OS benefit was seen, but only 10 percent of patients in the control arm received daratumumab at the time of progression, and all of these patients were alive at three years. As such, it is not known whether this OS benefit is due to the incorporation of daratumumab into initial therapy, or the use of suboptimal second and subsequent therapies in the majority of patients.
Three-drug regimens — Three-drug regimens discussed below are a mainstay of initial therapy for most patients with MM based on numerous phase 3 trials summarized below. A choice among these regimens is presented in more detail separately (algorithm 2). (See 'Choice of therapy' above.)
Bortezomib, lenalidomide, dexamethasone
●Clinical use – The combination of bortezomib, lenalidomide, and dexamethasone (VRd) (table 4) is one of our preferred treatment options for standard-risk MM (algorithm 2). Specific administration considerations are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies".)
●Efficacy – When compared with lenalidomide plus dexamethasone (Rd) alone, VRd improves OS.
In a multicenter, open-label phase 3 trial (SWOG S0777), 525 patients with previously untreated MM were randomly assigned to receive six months of induction therapy with either VRd or Rd, each followed by Rd maintenance until progression or unacceptable toxicity [13,60]. Approximately one-third of patients had high-risk disease. At a median follow-up of 84 months, VRd resulted in the following:
•Higher rates of OR (82 versus 72 percent) and complete response (CR; 16 versus 8 percent)
•Superior PFS (median 41 versus 29 months; HR 0.74, 95% CI 0.59-0.93)
•Superior OS (median not reached versus 69 months; HR 0.71, 95% CI 0.54-0.93)
In a subset analysis, the benefit with VRd was also seen in patients with high-risk disease with median PFS numerically higher with VRd (38 versus 16 months), although these differences were not statistically significant likely due to small numbers. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Specific recommendations for bortezomib'.)
●Toxicity – In SWOG S0777, VRd was associated with greater toxicity and a greater number of patients discontinuing therapy due to toxicity (55 versus 22 patients) [13].
Major toxicities of VRd include peripheral neuropathy, transient cytopenias, fatigue, and gastrointestinal distress. Thromboprophylaxis and antiviral prophylaxis are required. Of note, the SWOG S0777 trial VRd protocol used twice-weekly intravenous bortezomib. Neurotoxicity rates are lower with once-weekly subcutaneous bortezomib.
Toxicities, dose adjustments for organ impairment, and options for thromboembolism prophylaxis are discussed separately. (See "Multiple myeloma: Prevention of venous thromboembolism" and "Multiple myeloma: Administration considerations for common therapies".)
Daratumumab, lenalidomide, dexamethasone
●Clinical use – The combination of daratumumab, lenalidomide, and dexamethasone (DRd) (table 6) has demonstrated tolerability and efficacy in the management of patients with newly diagnosed MM. It is an option for the initial treatment of MM, especially for patients who cannot receive or tolerate bortezomib (eg, those with pre-existing neuropathy). DRd is approved by the US FDA for the treatment of patients with newly diagnosed MM who are ineligible for autologous HCT. Although it does not have regulatory approval in this setting, we are comfortable substituting isatuximab for daratumumab in this combination given the expectation that the two anti-CD38 monoclonal antibodies likely have similar efficacy. Although they have not been directly compared, IsaRd has demonstrated similar tolerability and response rates to those seen with DRd [54].
●Efficacy – When compared with lenalidomide plus dexamethasone (Rd) alone, DRd improves OS without a major increase in toxicity.
In a multicenter, open-label phase 3 trial (MAIA), 737 patients with newly diagnosed MM ineligible for HCT were randomly assigned to receive Rd with or without daratumumab (Rd versus DRd) [32]. Treatment was continued until disease progression or unacceptable side effects. After a median follow-up of 56 months, the addition of daratumumab resulted in [14]:
•Deeper responses (CR or better 51 versus 30 percent).
•Improved PFS (five-year PFS 53 versus 29 percent; median not reached versus 34 months; HR 0.53, 95% CI 0.43-0.66).
•Improved OS (five-year OS 66 versus 53 percent; HR 0.68, 95% CI 0.53-0.86).
•Improved measures of healthcare-related quality of life, including quicker, sustained improvements in patient-reported outcomes, including pain [33].
Use of DRd in the relapsed setting is discussed separately. (See "Multiple myeloma: Treatment of first relapse", section on 'Daratumumab, lenalidomide, dexamethasone (DRd)'.)
●Toxicity – In MAIA, DRd increased rates of grade 3 or 4 neutropenia (54 versus 37 percent) and pneumonia (19 versus 11 percent) [32]. More patients receiving daratumumab had dose adjustments or discontinuation of lenalidomide (74 versus 56 percent). Infusion reactions were reported in 41 percent of patients receiving daratumumab. Most reactions were mild and associated with the first infusion.
Major toxicities of DRd include cytopenias, infections, and gastrointestinal distress. Thromboprophylaxis and antiviral prophylaxis are required.
Daratumumab was administered intravenously (IV) in the MAIA trial, but the subcutaneous formulation is now more widely used as it is equally effective as IV, the rate of infusion reactions is lower, and the formulation is more convenient for patients given the brief period of administration.
Toxicities, dose adjustments for organ impairment, and options for thromboembolism prophylaxis are discussed separately. (See "Multiple myeloma: Prevention of venous thromboembolism" and "Multiple myeloma: Administration considerations for common therapies".)
Bortezomib, cyclophosphamide, dexamethasone
●Clinical use – The combination of bortezomib, cyclophosphamide, and dexamethasone (VCd, also called CyBorD) (table 7) has demonstrated tolerability and efficacy in the management of patients with newly diagnosed MM. In general, we prefer VRd or DRd given the OS benefit for these regimens when compared with Rd (algorithm 2). VCd is a reasonable alternative for patients at higher risk of complications with lenalidomide (eg, acute kidney injury, increased thromboembolic risk) and for those in countries in which lenalidomide is not approved for initial therapy. (See 'Acute kidney injury' above.)
The dosing schedule for VCd typically used in practice, with weekly rather than twice-weekly dosing of bortezomib and dexamethasone, is a modification of that used in clinical trials to reduce neurotoxicity and dexamethasone-related toxicity. (See "Multiple myeloma: Administration considerations for common therapies".)
●Efficacy and toxicity – In a phase 2 trial (EVOLUTION), 140 patients with newly diagnosed MM were randomly assigned to receive initial treatment with bortezomib and dexamethasone in combination with lenalidomide (VRd), cyclophosphamide (VCd), or both (VDCR) [15]. After an interim analysis, the protocol was amended to change the VCd regimen to include an additional dose of cyclophosphamide (VCd-mod). Following four cycles of therapy, OR rates were 73, 63, 82, and 80 percent in patients who received VRd, VCd, VCd-mod, and VDCR, respectively. Corresponding rates of very good partial response (VGPR) or better were 32, 13, 41, and 33 percent. Approximately 88 percent of patients receiving VCd-mod experienced at least one severe (grade 3/4) toxicity with the most common being neutropenia (24 percent), neuropathy (18 percent), and anemia (12 percent).
Further details on toxicities and dose adjustments for organ impairment are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies".)
Bortezomib, thalidomide, dexamethasone
●Clinical use – The combination of bortezomib, thalidomide, and dexamethasone (VTd) (table 8) is a reasonable alternative if it is not possible to administer VRd or DRd because of lack of availability of lenalidomide as induction therapy, and in patients presenting with acute kidney injury. In these circumstances, VTd and VCd are two primary options, and the choice between the two is based on experience with the regimen and drug availability; in the United States, VCd is more widely used than VTd.
●Efficacy and toxicity – Randomized trials have compared VTd (table 8) versus VCd, thalidomide and dexamethasone (Td), and bortezomib plus dexamethasone (VD). When compared with VCd, VTd results in higher response rates, although PFS and OS data are not mature. The addition of bortezomib to Td improves response rates and PFS; longer follow-up is required to evaluate OS. In contrast, the addition of thalidomide to VD has yet to demonstrate an improvement in PFS or OS.
•VTD versus VCD – In a multicenter phase 3 trial (IFM2013-04), 340 patients with newly diagnosed MM were randomly assigned to receive initial treatment with four cycles of VTD or VCD, each followed by HCT [61]. VTD resulted in a higher OR rate (92 versus 83 percent) and VGPR rate (66 versus 56 percent). VTD resulted in more neurologic toxicity and less hematologic toxicity. There were five deaths during induction, two in the VTD arm (infection, pulmonary embolism) and three in the VCD arm (infections and disease progression). Survival data are not mature.
•VTD versus TD – Two randomized trials comparing VTD versus TD included a total of 860 patients with previously untreated MM undergoing single or double autologous HCT [62-64]. The addition of bortezomib did not impact stem cell mobilization and resulted in higher response rates and improved PFS. Patients receiving VTD had higher rates of peripheral neuropathy, thromboembolism, infection, and skin rash, but lower rates of gastrointestinal distress.
•VTD versus VD – Two randomized trials have compared VTD versus VD. One trial in HCT-eligible patients compared lower than usual doses of bortezomib and thalidomide (vtD) versus standard doses of VD and demonstrated deeper responses and less peripheral neuropathy in those assigned to vtD [65]. vtD therapy was associated with a significantly higher percentage of patients requiring the addition of cyclophosphamide to collect an adequate number of stem cells. In another trial, 502 patients with previously untreated myeloma who were not candidates for HCT were randomly assigned to receive VTD, VD, or bortezomib, melphalan, and prednisone (VMP) [66]. At a median follow-up of 43 months, there was no significant difference in median PFS (15, 15, and 17 months) or OS (52, 50, and 53 months).
Further details on toxicities, dose adjustments for organ impairment, and options for thromboembolism prophylaxis are discussed separately. (See "Multiple myeloma: Prevention of venous thromboembolism" and "Multiple myeloma: Administration considerations for common therapies".)
Nonstandard regimens — The regimens described below have not been approved by regulatory agencies for the initial treatment of MM and there have been concerns raised about use in this population. They are approved for use in the relapsed setting, and there may be specific scenarios where their use for initial treatment may be reasonable.
Ixazomib, lenalidomide, dexamethasone
●Clinical use – Ixazomib, lenalidomide, and dexamethasone (IRd) is an all oral three-drug regimen that is a treatment option for relapsed MM (table 9). Use in previously untreated patients is not approved by regulatory agencies and thus should be limited at this time [67].
●Efficacy – A placebo-controlled, randomized trial (TOURMALINE-MM2) evaluated the addition of ixazomib to lenalidomide and dexamethasone in 705 transplant-ineligible patients with newly diagnosed MM [68]. Patients received 18 cycles of IRd or placebo-RD, followed by a lower dose of lenalidomide with lower-dose ixazomib or placebo until progression or toxicity.
IRd resulted in a numerically higher median PFS, which did not reach statistical significance but would be clinically meaningful if true (median PFS 35 versus 22 months, HR 0.83, 95% CI 0.68-1.02). This benefit was seen in all prespecified subgroups, including the 280 patients with high-risk cytogenetics (median PFS 24 versus 18 months, HR 0.69, 95% CI 0.51-0.94). An OS difference has not been demonstrated (HR 0.998, 95% CI 0.79-1.26).
Although IRd was not directly compared with VRd or DRd in this trial and cross-trial comparisons have limitations, the PFS benefit seen with IRd appears to be less substantial than that seen with VRd in the SWOG S0777 trial and with DRd in the MAIA trial [13,32]. (See 'Bortezomib, lenalidomide, dexamethasone' above and 'Daratumumab, lenalidomide, dexamethasone' above.)
Use of IRd in relapsed/refractory MM is discussed separately. (See "Multiple myeloma: Treatment of first relapse", section on 'Ixazomib, lenalidomide, dexamethasone (IRd)'.)
●Toxicity – Among patients treated with IRd on TOURMALINE-MM2, there was a small increase in grade 3 or 4 treatment-emergent adverse events (88 versus 81 percent), with lower rates of neutropenia and increased rates of diarrhea, rash, thrombocytopenia, arrhythmia, pneumonia, and heart failure.
Further details on toxicities, dose adjustments for organ impairment, and options for thromboembolism prophylaxis are discussed separately. (See "Multiple myeloma: Prevention of venous thromboembolism" and "Multiple myeloma: Administration considerations for common therapies".)
Carfilzomib, lenalidomide, dexamethasone — We generally do not use carfilzomib, lenalidomide, and dexamethasone (KRd) in patients with newly diagnosed MM, regardless of risk stratification (algorithm 2).
While prospective studies have shown deep responses following KRd plus autologous HCT in newly diagnosed MM [42,69,70], randomized trials have not compared this approach to VRd plus HCT, and extrapolation from studies in the non-transplant setting suggests similar efficacy, but greater toxicity.
In a multicenter phase 3 trial (ENDURANCE E1A11), over 1000 patients with previously untreated MM with no intent for early HCT were randomly assigned to nine months of induction with either KRd or VRd, each followed by a second randomization to lenalidomide maintenance given for either two years or until disease progression or unacceptable toxicity [71]. The vast majority of patients had standard-risk MM; the trial excluded patients with del17p, t(14;16), t(14;20), plasma cell leukemia, or lactate dehydrogenase (LDH) >2 times upper limit of normal. VRd and KRd resulted in similar PFS (median PFS 34 versus 35 months, HR 1.04, 95% CI 0.83-1.31) and OS (3-year OS 84 versus 86 percent, HR 0.98, 95% CI 0.71-1.36). VRd was associated with more peripheral neuropathy, while KRd was associated with more dyspnea, hypertension, heart failure, and acute kidney injury.
Two-drug regimens — Three-drug regimens are preferred over two-drug regimens whenever possible because they appear to provide an OS benefit. The two-drug regimens discussed below are not used frequently, but they are of importance in frail patients who may not be able to tolerate standard three-drug regimens.
Lenalidomide plus dexamethasone
●Clinical use – Lenalidomide plus low-dose dexamethasone (Rd) (table 5) is an effective oral regimen for the initial treatment of MM and is our preferred regimen for frail patients with standard-risk MM unable to tolerate a three-drug regimen (algorithm 2). While the FIRST trial continued Rd until progression, a subsequent trial supports switching to a reduced-dose lenalidomide maintenance without dexamethasone after completing 8 to 12 cycles of Rd. (See 'Frail adults' above and 'Risk-stratified treatment' above.)
●Efficacy – Prospective trials have demonstrated the efficacy of Rd in the initial treatment of MM when compared with dexamethasone alone and with the combination of melphalan, plus prednisone and thalidomide (MPT) [34-36,72-74].
In the FIRST trial, 1623 patients with previously untreated MM who were not candidates for HCT (median age 73 years) were randomly assigned to one of three initial treatment options: Rd until progression; Rd for 18 months; or MPT for 18 months [34-36]. At a median follow-up of 67 months, continuous Rd resulted in the following, when compared with MPT:
•Higher rates of VGPR or better (48 versus 30 percent)
•Shorter time to response (2 versus 3 months)
•Longer PFS (median 26 versus 22 months; HR 0.69)
•Superior OS (median 59 versus 49 months; HR 0.78)
•Lower rates of neutropenia, thrombocytopenia, neuropathy, and constipation
•Higher rates of infections, venous thromboembolism, and cataracts
•No increase in second primary malignancies (7 versus 9 percent)
In the same trial, Rd administered until progression resulted in longer PFS and time until second anti-myeloma therapy than when Rd was stopped after 18 months (median PFS 70 versus 40 months). There was no significant difference seen in the rate of VGPR or better or in OS. Cumulative toxicity rates were higher in patients taking Rd until progression. Given the PFS improvement and general tolerability, we prefer to continue treatment until progression unless there is toxicity.
●Reduced-dose lenalidomide for maintenance – Transition to a reduced-dose lenalidomide maintenance without dexamethasone is supported by a phase 3 trial of 199 intermediate-fit older adults with newly diagnosed MM randomly assigned to continuous Rd until progression or to nine cycles of Rd followed by maintenance with a lower dose of lenalidomide (10 mg daily for 21 out of 28 days each cycle) without dexamethasone (Rd-R) [40]. After a median follow-up of 37 months, Rd-R resulted in trends toward improved PFS (median 20 versus 18 months, HR 0.78; 95% CI 0.55-1.10) and OS (three-year OS 74 versus 63 percent; HR 0.62, 95% CI 0.37-1.03), although these have not reached statistical significance and OS data are immature. Rd-R was better tolerated with less grade 3 or greater non-hematologic toxicity (33 versus 43 percent) and fewer lenalidomide dose reductions (45 versus 62 percent).
As a result, for frail older adult patients treated with Rd as initial therapy, we suggest discontinuing dexamethasone after 8 to 12 cycles of Rd, and continuing lenalidomide alone as maintenance. This trial has similar implications for other MM regimens used in newly diagnosed disease in the nontransplant setting that incorporate maintenance dexamethasone (eg, VRd). If there is good disease control after at least one year of initial therapy on such regimens, it is reasonable to omit dexamethasone and continue with lenalidomide maintenance alone.
●Toxicity – Further details on toxicities, dose adjustments for organ impairment, and options for thromboembolism prophylaxis are discussed separately. (See "Multiple myeloma: Prevention of venous thromboembolism" and "Multiple myeloma: Administration considerations for common therapies".)
Bortezomib plus dexamethasone
●Clinical use – The combination of bortezomib plus dexamethasone (Vd) is a two-drug regimen that may be offered to older and/or frail adults with significant kidney impairment. Vd requires a twice-weekly bortezomib schedule, which is associated with a higher risk of severe peripheral neuropathy than that seen with three-drug regimens that use once-weekly dosing. When possible, we prefer the three-drug regimen bortezomib, lenalidomide, and dexamethasone (VRd) (algorithm 2). (See 'Bortezomib, lenalidomide, dexamethasone' above.)
●Efficacy and toxicity – A phase 2 trial examined the use of six cycles of Vd followed by autologous HCT in the treatment of 40 newly diagnosed, previously untreated patients with MM [75]. The OR rate before HCT was 65 percent with the majority of responses occurring within the first two cycles of treatment. The OR rate after HCT was 88 percent with 33 percent CR and 22 percent VGPR. Toxicity was mild.
A phase 3 trial randomly assigned therapy with Vd or VAD (vincristine, doxorubicin, dexamethasone) as induction therapy prior to autologous HCT in 482 patients with newly diagnosed MM [76]. Vd resulted in significantly higher response rates and a trend toward longer PFS. No improvement in OS was seen. This study shows that superior VGPR and CR rates may not translate into meaningful improvements in PFS or OS, and it illustrates the limitations of CR and VGPR as surrogate endpoints in myeloma.
Further details on toxicities and dose adjustments for organ impairment are discussed separately. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors'.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple myeloma".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Multiple myeloma symptoms, diagnosis, and staging (Beyond the Basics)" and "Patient education: Multiple myeloma treatment (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Risk stratification – While experts differ in their preferred initial treatment regimen for multiple myeloma (MM), there is general agreement that the choice must incorporate genetic features, risk of neuropathy and thrombosis, kidney function, and treatment burdens. (See 'Risk stratification and other factors impacting choice' above.)
MM can be categorized as standard-risk or high-risk disease based on the results of fluorescence in situ hybridization (FISH) for specific translocations and/or deletions and certain other tests (table 2). This risk stratification has considerable prognostic value and also helps guide treatment (algorithm 2).
●Induction for standard-risk MM – For most patients with standard-risk MM, we suggest induction with either a four-drug regimen or a three-drug regimen rather than a two-drug regimen (Grade 2B). Most trials suggest that the addition of a third drug improves overall survival while the addition of a fourth drug deepens responses and improves progression-free survival (PFS), albeit with an increase in toxicity and cost. (See 'Standard-risk myeloma' above.)
Choice of therapy is largely driven by disease characteristics and comorbidities, along with patient values, preferences, and access. Acceptable regimens include:
•Daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) or isatuximab, bortezomib, lenalidomide, and dexamethasone (IsaVRd) are reasonable options for patients who prioritize PFS. (See 'Daratumumab, bortezomib, lenalidomide, dexamethasone' above and 'Isatuximab-based four-drug regimens' above.)
•Bortezomib, lenalidomide, and dexamethasone (VRd) is an effective option for those who prioritize avoiding the costs and toxicity of adding a fourth drug (table 4). (See 'Bortezomib, lenalidomide, dexamethasone' above.)
•Daratumumab, lenalidomide, and dexamethasone (DRd) (table 6) and isatuximab, lenalidomide, and dexamethasone (IsaRd) are alternatives, especially for patients who may not tolerate bortezomib (eg, those with pre-existing neuropathy). (See 'Daratumumab, lenalidomide, dexamethasone' above.)
•The doses and schedules of VRd, DRd, and IsaRd can be modified for use in frail adults. Lenalidomide plus dexamethasone (Rd) (table 5) is an acceptable alternative for frail adults who cannot tolerate a three-drug regimen. (See 'Frail adults' above and 'Lenalidomide plus dexamethasone' above.)
•Bortezomib, cyclophosphamide, and dexamethasone (VCd) (table 7) is an alternative for patients at higher risk of complications with lenalidomide (eg, acute kidney injury, increased thromboembolic risk). (See 'Bortezomib, cyclophosphamide, dexamethasone' above.)
●Post-induction management for standard-risk MM – Patients who are eligible for autologous hematopoietic cell transplantation (HCT) receive three to six cycles of induction therapy followed by stem cell collection (algorithm 2). Then a decision is made regarding whether to proceed with HCT (early HCT strategy) or continue the same chemotherapy regimen, reserving HCT for first relapse (delayed HCT strategy). (See 'Incorporating HCT in eligible patients' above.)
Those not proceeding to early HCT are typically treated with an additional 5 to 6 cycles of induction therapy (total of 8 to 12 cycles), as tolerated, followed by maintenance. After induction with DVRd or IsaVRd, we suggest maintenance with single-agent lenalidomide rather than other regimens (Grade 2C), continued until progression. In patients who are treated with induction with VRd, maintenance with either lenalidomide alone or lenalidomide plus daratumumab is an appropriate option, depending on patient preference and minimal residual disease status. For those initially treated with DRd, we suggest maintenance with both lenalidomide and daratumumab (Grade 2C). (See 'Maintenance for patients who are ineligible for or defer HCT' above.)
●High-risk MM – Patients with high-risk MM are encouraged to participate in clinical trials of novel strategies, since they tend to do less well with conventional treatment. Outside of a trial, we use a regimen that includes a proteasome inhibitor, an anti-CD38 monoclonal antibody, or both, as outlined below (algorithm 2). (See 'High-risk myeloma' above.)
•Not HCT eligible – For most patients who are not candidates for autologous HCT, we suggest a four-drug regimen rather than a three-drug regimen (Grade 2C). We consider either IsaVRd or DVRd acceptable options in this setting. After 8 to 12 cycles, we suggest maintenance with lenalidomide and bortezomib (Grade 2C), until time of disease progression. Maintenance with lenalidomide plus carfilzomib is an acceptable alternative for patients unable to tolerate standard-dose bortezomib due to neuropathy. Maintenance with lenalidomide plus daratumumab is an acceptable alternative for patients unable to tolerate bortezomib or carfilzomib.
Acceptable alternatives for frail patients are VRd (table 4), DRd (table 6), and IsaRd. VCd (table 7) is an alternative for patients at higher risk of complications with lenalidomide (eg, acute kidney injury, increased thromboembolic risk).
•HCT eligible – For patients who are candidates for HCT, we suggest induction with DVRd or IsaVRd rather than VRd (Grade 2B). We administer three to six cycles of DVRd or IsaVRd. We then collect stem cells and typically proceed with HCT, followed by maintenance that includes a proteasome inhibitor and lenalidomide until progression. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Maintenance'.)
●Prevention and management of complications – In addition to therapy directed at the malignant clone, the management of most patients with MM includes preventive measures to reduce the incidence of skeletal events (algorithm 3), thrombosis (algorithm 4), kidney damage, infections, and neuropathy. (See 'Prevention and management of complications' above.)
Specific administration considerations, including toxicities and dose adjustments for organ impairment, are discussed in more detail separately. (See "Multiple myeloma: Administration considerations for common therapies".)
