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تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
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Multiple myeloma: Treatment of first or second relapse

Multiple myeloma: Treatment of first or second relapse
Literature review current through: Jan 2024.
This topic last updated: Oct 17, 2022.

INTRODUCTION — Most patients with multiple myeloma (MM) will have an initial response to treatment. However, conventional therapy is not curative and MM will ultimately relapse. In addition, a minority will have primary refractory disease that does not respond to initial treatment.

The choice of therapy for MM in first or second relapse will be discussed here. Many of the same regimens can be used as later lines of therapy if not utilized previously. Administration considerations for common therapies, the initial treatment of MM, the treatment of third or later relapse, and the use of autologous and allogeneic hematopoietic cell transplantation are discussed separately.

(See "Multiple myeloma: Overview of management".)

(See "Multiple myeloma: Administration considerations for common therapies".)

(See "Multiple myeloma: Initial treatment".)

(See "Multiple myeloma: Treatment of third or later relapse".)

(See "Multiple myeloma: Use of hematopoietic cell transplantation".)

ASSESS DRUG SENSITIVITY — The choice of therapy for relapsed MM must consider prior therapy, response, and likelihood of the disease being sensitive or refractory to prior agents (algorithm 1). In general, refractory disease is defined as progressing on or within 60 days of receiving standard doses of a specific therapy.

As an example, MM progressing on or within 60 days of receiving standard doses of lenalidomide (eg, 25 mg daily) is refractory to lenalidomide, and such cases have been excluded from studies evaluating lenalidomide-containing regimens. In contrast, disease progression in a patient that previously received lenalidomide but not within the past 60 days or in a patient on a maintenance dose of single-agent lenalidomide (eg, 10 mg daily) is considered lenalidomide sensitive. Lenalidomide-sensitive MM may respond to a regimen that increases the dose of lenalidomide, reintroduces dexamethasone, and/or adds a third agent (eg, a monoclonal antibody or a proteasome inhibitor).

Whether a patient is lenalidomide sensitive or lenalidomide refractory represents an important determinant of second- or third-line therapy, since many of the regimens that have regulatory approval for this indication incorporate lenalidomide. Our approach is therefore structured according to disease status as it relates to sensitivity or refractoriness to lenalidomide (algorithm 1).

LENALIDOMIDE SENSITIVE — For most patients with lenalidomide-sensitive MM in first or second relapse, we suggest a lenalidomide-containing three-drug regimen (algorithm 1). This includes patients who experience disease progression on a maintenance dose of single-agent lenalidomide (eg, 10 mg daily).

This recommendation is based on evidence derived from phase 3 clinical trials described below evaluating regimens incorporating lenalidomide in patients with relapsed MM who received one to three prior lines of therapy. While most of these trials excluded patients progressing on any dose of lenalidomide, we consider a lenalidomide-containing regimen as an option for patients progressing on a low dose of lenalidomide (≤10 mg). If a response to a lenalidomide-based regimen is not seen, a different regimen can then be pursued. This approach ensures that under appropriate clinical circumstances patients with lenalidomide-sensitive disease derive maximum benefit from lenalidomide and lenalidomide-based regimens before receiving other agents in subsequent lines of treatment.

We consider four-drug regimens for patients with highly aggressive disease. (See 'Aggressive disease' below.)

Daratumumab, lenalidomide, dexamethasone (DRd)

Clinical useDaratumumab, lenalidomide, and dexamethasone (DRd) is one of our preferred regimens for patients with lenalidomide-sensitive MM (algorithm 1). DRd is approved in the United States, Europe, and many parts of Asia for patients with MM who have received at least one prior therapy. Details of the DRd regimen are provided in the table (table 1).

Although direct comparisons between DRd and other three-drug combinations have not been conducted, network meta-analyses that incorporated both direct and indirect comparisons identified DRd as among the most active regimens in relapsed MM among patients who had received one to three prior lines of therapy [1-3].

As an example, a network meta-analysis that used single-agent dexamethasone as a reference point identified DRd as the most effective three-drug regimen as illustrated by the hazard ratio (HR) for progression-free survival (PFS) [2]:

DRd (HR 0.13; 95% CI 0.09-0.19)

KRd (HR 0.24; 95% CI 0.18-0.32)

ERd (HR 0.25; 95% CI 0.19-0.33)

DVd (HR 0.27; 95% CI 0.18-0.38)

IRd (HR 0.26; 95% CI 0.19-0.35)

Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

If available, we suggest the use of fixed-dose, subcutaneously administered daratumumab in combination with hyaluronidase (daratumumab-hyaluronidase) rather than intravenous daratumumab. While most of the initial trials evaluating the efficacy of daratumumab used the intravenous formulation, the subcutaneous formulation has comparable efficacy with lower rates of infusion-related reactions, rapid administration time, similar drug cost, and lower total administration cost [4,5]. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Anti-CD38 monoclonal antibodies'.)

Efficacy – When compared with lenalidomide plus dexamethasone alone (Rd), DRd improves PFS and overall survival (OS) without major increases in toxicity [6-8].

In a multicenter, open-label phase 3 trial (POLLUX), 569 patients with relapsed/refractory MM were randomly assigned to receive DRd versus Rd, each administered until disease progression or unacceptable toxicity [6-8]. The trial excluded MM progressing on any dose of lenalidomide. After a median follow-up of 80 months, DRd resulted in:

Higher overall response rates (ORR; 93 versus 76 percent), very good partial response (VGPR) or better (78 versus 48 percent), and complete response (CR) or better (51 versus 21 percent) with higher rates of minimal residual disease negativity (33.2 versus 6.7 percent with a 10-5 sensitivity threshold).

Superior PFS (83 versus 60 percent at 12 months; 68 versus 41 percent at 24 months; HR 0.41, 95% CI 0.31-0.53). On subgroup analysis, the PFS benefit did not differ by prior therapy.

Superior OS (median OS 68 versus 52 months; HR 0.73; 95% CI 0.58-0.91). Prespecified subgroup analyses illustrated this OS benefit regardless of age, disease stage, and cytogenetic risk. The analysis also showed an OS benefit in patients with one prior line of therapy (median OS 78 versus 58 months).

Toxicity – In patients treated with DRd on the POLLUX trial, approximately 12 percent discontinued therapy due to an adverse event [6].

When compared with Rd, DRd resulted in higher rates of neutropenia (59 versus 43 percent), diarrhea (43 versus 25 percent), upper respiratory tract infection (32 versus 21 percent), and cough (29 versus 13 percent).

Other common nonhematologic toxicities of any grade were fatigue (35 percent), constipation (29 percent), and muscle spasms (26 percent). Infusion reactions (mostly mild) were reported in 48 percent of patients; of these, the vast majority (92 percent) occurred during the first infusion.  

The most common grade 3 or 4 nonhematologic toxicities were fatigue (6 percent) and diarrhea (5 percent).

Carfilzomib, lenalidomide, dexamethasone (KRd)

Clinical useCarfilzomib, lenalidomide, and dexamethasone (KRd) is one of our preferred regimens for patients with lenalidomide-sensitive MM (algorithm 1). KRd is approved in the United States and Europe for the treatment of relapsed MM. While carfilzomib results in less neurotoxicity than bortezomib, there is a higher incidence of cardiac toxicity. We typically obtain pretreatment echocardiogram and electrocardiogram (EKG) to assess baseline cardiovascular status. Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – When compared with Rd alone, KRd improves PFS and OS without a major increase in toxicity.

In a multicenter phase 3 trial (ASPIRE), 792 patients with relapsed MM were randomly assigned to receive KRd versus Rd [9-12]. Approximately 67 and 20 percent of patients had received prior bortezomib and lenalidomide, respectively. The trial excluded patients progressing on any dose of lenalidomide or bortezomib. When compared with Rd alone, KRd resulted in the following:

An improved ORR (87 versus 67 percent) along with deeper responses (CR 32 versus 9 percent, and stringent CR 14 versus 4 percent).

Improved PFS (median 26 versus 17 months; HR 0.66, 95% CI 0.55-0.78).

Superior OS (median 48 versus 40 months; HR 0.79, 95% CI 0.67-0.95).

Improved quality of life as measured by the QLQ-C30 Global Health Status and Quality of Life scale (difference 5.6 points).

Toxicity – In patients treated with KRd on the ASPIRE trial, approximately 15 percent discontinued therapy due to an adverse event [9].

When compared with Rd, KRd resulted in higher rates of upper respiratory tract infections (30 versus 21 percent), hypokalemia (30 versus 15 percent), muscle spasms (27 versus 21 percent), and hypertension (17 versus 9 percent), but no increase in drug discontinuation due to toxicity.

Other common nonhematologic toxicities of any grade were diarrhea (42 percent), fatigue (33 percent), cough (29 percent), pyrexia (29 percent), and hypokalemia (28 percent).

Other adverse events of interest of any grade included dyspnea (19 percent), hypertension (14 percent), acute renal failure (8 percent), cardiac failure (6 percent), and ischemic heart disease (6 percent).

The most common grade 3 or 4 nonhematologic toxicities were hypokalemia (9 percent), fatigue (8 percent), and diarrhea (4 percent).

Ixazomib, lenalidomide, dexamethasone (IRd)

Clinical useIxazomib, lenalidomide, and dexamethasone (IRd) (table 3) is an all-oral alternative for patients with lenalidomide-sensitive MM (algorithm 1). The combination is approved in the United States and Europe for the treatment of patients with MM who have received at least one prior therapy. We generally utilize this well tolerated regimen in patients with less aggressive disease and in situations where all-oral therapy is clearly preferred or necessary.

Details of the IRd regimen are provided in the table (table 3). Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – When compared with Rd alone, IRd improves PFS without a major increase in toxicity.

In a multicenter phase 3 trial (Tourmaline-MM1), 722 adults with relapsed MM were randomly assigned to receive IRd versus Rd plus placebo [13-16]. To be included, patients had to have relapsed after one to three prior therapies and could not be refractory to lenalidomide or proteasome inhibitor-based therapy. Therapy was continued until disease progression or unacceptable toxicity. At a median follow-up of 15 months, IRd resulted in:

Improved ORR (78 versus 72 percent) and CR rate (12 versus 7 percent), PFS (median 21 versus 15 months; HR 0.74, 95% CI 0.59-0.94), and duration of response (21 versus 15 months). This benefit was seen in both high- and standard-risk cytogenetic subgroups. There was no clear difference in quality of life measures.

Further follow-up after a median of 85 months showed similar OS despite the addition of ixazomib (median 54 versus 52 months; HR 0.94, 95% CI 0.78-1.13) [16]. At the time of progression, the group assigned to placebo were more likely to receive regimens that contained daratumumab, bortezomib, and/or carfilzomib. This difference in subsequent treatment confounds the interpretation of these data.

A similar trial in previously untreated MM (TOURMALINE-MM2) demonstrated improved PFS but not OS with the addition of ixazomib to lenalidomide and dexamethasone [17]. (See "Multiple myeloma: Initial treatment".)

Toxicity – In patients treated with IRd on the Tourmaline-MM1 trial, approximately 17 percent discontinued therapy due to an adverse event [13].

When compared with Rd, IRd resulted in a higher rate of grade 3 or 4 thrombocytopenia (19 versus 9 percent). Other common toxicities included diarrhea (45 percent), constipation (35 percent), nausea (29 percent), vomiting (23 percent), peripheral neuropathy (27 percent), peripheral edema (28 percent), and rash (36 percent).

Other adverse events of interest of any grade included arrhythmias (16 percent); acute renal failure (9 percent); thromboembolism (8 percent); liver impairment (7 percent); hypertension (6 percent); hypotension (6 percent); heart failure (4 percent); and myocardial infarction, encephalopathy, and interstitial lung disease (≤1 percent each).

The most common grade 3 or 4 nonhematologic toxicities were diarrhea (6 percent), rash (5 percent), and fatigue (4 percent).

Elotuzumab, lenalidomide, dexamethasone (ERd)

Clinical useElotuzumab, lenalidomide, and dexamethasone (ERd) is approved in the United States, Europe, and many parts of Asia for patients with MM who have received at least one prior therapy (algorithm 1). We typically utilize ERd in patients with less aggressive disease characteristics.

Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – When compared with Rd alone, ERd improves PFS and OS without a major increase in toxicity in relapsed or refractory MM.

In an open-label, multicenter, phase 3 trial (ELOQUENT-2), 646 patients with MM relapsed after one to three prior lines of therapy were randomly assigned to receive ERd versus Rd [18-20]. The trial excluded patients progressing on any dose of lenalidomide. All patients received thromboembolic prophylaxis and those assigned to elotuzumab received premedication with diphenhydramine, ranitidine, and acetaminophen, or their equivalents. After a median follow-up of 46 months, ERd resulted in:

Improved PFS (median 19 versus 15 months; one-year PFS 68 versus 57 percent; four-year PFS 21 versus 14 percent; HR 0.71, 95% CI 0.59-0.86). Subgroup analysis demonstrated similar efficacy across age groups and disease risk groups, including those with del(17p).

Improved OS (median 48 versus 40 months; four-year OS 50 versus 43 percent; HR 0.78, 95% CI 0.63-0.96).

In contrast, another randomized trial of ERd versus Rd in newly diagnosed, transplant ineligible MM (ELOQUENT-1) did not demonstrate a PFS benefit with the addition of elotuzumab (HR 0.93, 95% CI 0.77-1.12) [21].

Toxicity – In patients treated with ERd on the ELOQUENT-2 trial, approximately 9 percent discontinued therapy due to an adverse event [18]. When compared with Rd, ERd resulted in:

A higher rate of severe (grade 3 or 4) adverse events (78 versus 67 percent). There was an increased incidence of opportunistic infection (22 versus 13 percent), including fungal infection (10 versus 5 percent) and herpes zoster infection (14 versus 7 percent) [22].

A higher rate of invasive second primary malignancies (9 versus 6 percent), including solid tumors (3.5 versus 2.2 percent) and skin cancer (4.4 versus 2.8 percent) [22].

Infusion reactions occurred in 10 percent of patients. The majority (70 percent) occurred with the first infusion and only two patients discontinued treatment due to an infusion reaction.

Other common nonhematologic toxicities of any grade were diarrhea (47 percent), fatigue (47 percent), pyrexia (37 percent), constipation (36 percent), cough (31 percent), muscle spasms (30 percent), back pain (28 percent), peripheral edema (26 percent), nasopharyngitis (25 percent), and insomnia (23 percent).

The most common grade 3 or 4 nonhematologic toxicities were fatigue (8 percent), diarrhea (5 percent), back pain (5 percent), and pyrexia (3 percent).

LENALIDOMIDE REFRACTORY — For patients with lenalidomide-refractory MM, the choice among non-lenalidomide-containing regimens is influenced by whether the disease is refractory to bortezomib and/or daratumumab (algorithm 1).

MM refractory to both lenalidomide and bortezomib may respond to a combination that incorporates a different proteasome inhibitor (eg, carfilzomib) or a different immunomodulatory agent (eg, pomalidomide), in combination with dexamethasone and a monoclonal antibody (eg, daratumumab). In contrast, MM refractory to both lenalidomide and daratumumab is presumed to be resistant to other anti-CD38 monoclonal antibodies and is typically treated with non-antibody-containing regimens.

Refractory to lenalidomide alone — For patients with MM refractory to lenalidomide alone, we offer daratumumab, bortezomib, and dexamethasone (DVd); daratumumab, pomalidomide, and dexamethasone (DPd); isatuximab, pomalidomide, and dexamethasone (IsaPd); or bortezomib, pomalidomide, and dexamethasone (VPd) (algorithm 1).

Daratumumab, bortezomib, dexamethasone (DVd)

Clinical useDaratumumab, bortezomib, and dexamethasone (DVd) is one of our preferred regimens for patients with relapsed MM refractory to lenalidomide (algorithm 1). DVd is approved in the United States, Europe, and many parts of Asia for patients with MM who have received at least one prior therapy.

Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Although direct comparisons between DVd and other three-drug combinations have not been conducted, two network meta-analyses that incorporated both direct and indirect comparisons identified monoclonal antibody-containing three-drug combinations such as DVd as the most active regimens in relapsed MM [1,2].

If available, we suggest the use of fixed-dose, subcutaneously administered daratumumab in combination with hyaluronidase (daratumumab-hyaluronidase) rather than intravenous daratumumab. While most of the initial trials evaluating the efficacy of daratumumab used the intravenous formulation, the subcutaneous formulation appears to have similar efficacy with lower rates of infusion-related reactions, a faster administration time, similar drug cost, and lower total administration cost [4,5]. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Anti-CD38 monoclonal antibodies'.)

Efficacy – When compared with bortezomib plus dexamethasone alone (Vd), DVd improves progression-free survival (PFS) and overall survival (OS) without major increases in toxicity.

In a multicenter, open-label phase 3 trial (CASTOR), 498 patients with relapsed/refractory MM were randomly assigned to receive up to eight cycles of DVd versus Vd [23-26]. The trial excluded patients refractory to bortezomib or another proteasome inhibitor. After a prespecified interim analysis at a median follow-up of 7.4 months found that DVd was associated with improved PFS, the trial was stopped early and patients assigned to Vd were offered daratumumab at the time of progression. After a median follow-up of 73 months, DVd was associated with the following:

Higher overall response rate (ORR; 84 versus 63 percent), very good partial response (VGPR) or better (62 versus 29 percent), and complete response (CR) or better (29 versus 10 percent) with higher rates of minimal residual disease negativity (15.1 versus 1.6 percent with a 10-5 sensitivity threshold).

Improved PFS (median 16.7 versus 7.1 months; HR 0.31, 95% CI 0.25-0.40).

Improved OS (median 49.6 versus 38.5 months; HR 0.74, 95% CI 0.59-0.92). Prespecified subgroup analyses illustrated this OS benefit regardless of age, disease stage, and cytogenetic risk.  

Another randomized phase 3 trial (LEPUS) of DVd versus Vd in 211 Chinese patients reported a similar PFS benefit (HR 0.28, 95% CI 0.17-0.47) and safety profile [27].

Toxicity – In patients treated with DVd on the CASTOR trial, approximately 7 percent discontinued therapy due to an adverse event [23].

When compared with Vd, DVd resulted in higher rates of thrombocytopenia (60 versus 44 percent), neutropenia (20 versus 10 percent), lymphopenia (13 versus 4 percent), peripheral sensory neuropathy (50 versus 38 percent), and second primary cancers (4.1 versus 0.4 percent).

Infusion reactions (mostly mild) were reported in 45 percent of patients; of these, the vast majority (98 percent) occurred during the first infusion.

Other common nonhematologic toxicities of any grade were diarrhea (32 percent), upper respiratory tract infection (25 percent), fatigue (21 percent), cough (24 percent), constipation (20 percent), dyspnea (19 percent), insomnia (17 percent), and peripheral edema (17 percent).

The most common grade 3 or 4 nonhematologic toxicities were pneumonia (8 percent), hypertension (7 percent), peripheral sensory neuropathy (5 percent), fatigue (5 percent), diarrhea (4 percent), and dyspnea (4 percent).

Bortezomib, pomalidomide, dexamethasone (VPd)

Clinical useBortezomib, pomalidomide, and dexamethasone (VPd) is an off-label combination for the treatment of MM. We consider it to be an acceptable alternative for patients refractory to lenalidomide alone or to lenalidomide and daratumumab (algorithm 1).

Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – When compared with Vd alone, VPd improves PFS.

In an international phase 3 trial (OPTIMISMM), 559 patients with MM progressing after prior lenalidomide were randomly assigned to receive VPd versus Vd [28-30]. Approximately 75 percent had received a prior proteasome inhibitor and 70 percent were refractory to lenalidomide. After a median follow-up of 16 months, VPd resulted in the following:

An improved ORR (82 versus 50 percent) with deeper responses (CR 12 versus 3 percent, and stringent CR 3 versus <1 percent).

Improved PFS (median 11 versus 7 months; HR 0.61, 95% CI 0.49-0.77). A PFS benefit was seen in high- and standard-risk MM, MM refractory to lenalidomide, and MM with prior bortezomib exposure. OS data are not mature.

Similar scores on assessment of health-related quality of life.

Toxicity – In the patients treated with VPd on the OPTIMISMM trial, adverse events resulted in treatment discontinuation in 11 percent [28]. There were six deaths attributed to toxicity (pneumonia, cardiac arrest, and unknown cause). When compared with Vd, VPd resulted in:

Higher rates of neutropenia (42 versus 9 percent), infection (31 versus 18 percent), and febrile neutropenia (3 percent versus none). Use of antiviral, antibiotic, and antifungal agents were at the discretion of the investigator.

More grade 3 or 4 thromboembolic events (13 versus 2 cases, none fatal) despite mandatory prophylactic antithrombotic therapy for those assigned to VPd.

Other common toxicities of any grade were peripheral neuropathy (48 percent), constipation (37 percent), peripheral edema (37 percent), fatigue (37 percent), diarrhea (34 percent), pyrexia (23 percent), cough (21 percent), upper respiratory tract infection (21 percent), and back pain (19 percent).

The most common grade 3 or 4 toxicities were pneumonia (11 percent), hyperglycemia (9 percent), peripheral neuropathy (8 percent), fatigue (8 percent), and diarrhea (7 percent).

Refractory to lenalidomide and bortezomib — Patients who have experienced disease progression on or within 60 days of receiving standard doses of bortezomib and lenalidomide are considered to be refractory to both agents. Such patients may respond to a combination that incorporates a different proteasome inhibitor (eg, carfilzomib) or a different immunomodulatory agent (eg, pomalidomide), in combination with a monoclonal antibody (eg, daratumumab).

For patients with MM refractory to both lenalidomide and bortezomib, we offer either daratumumab, carfilzomib, and dexamethasone (DKd) or isatuximab, carfilzomib, and dexamethasone (IsaKd) (algorithm 1). Other options in this context are daratumumab, pomalidomide, and dexamethasone (DPd); isatuximab, pomalidomide, and dexamethasone; and elotuzumab, pomalidomide, and dexamethasone (EPd).

Daratumumab, carfilzomib, dexamethasone (DKd)

Clinical useDaratumumab, carfilzomib, and dexamethasone (DKd) is one of our preferred treatments for patients with relapsed MM refractory to lenalidomide and bortezomib (algorithm 1). DKd is approved in the United States for patients with MM who have received one to three prior lines of therapy.

Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – When compared with carfilzomib plus dexamethasone alone (Kd), DKd improves PFS without major increases in toxicity. [1,2].

In a multicenter, open-label phase 3 trial (CANDOR), 466 patients with relapsed/refractory MM were randomly assigned 2:1 to receive DKd versus Kd, each administered until disease progression or unacceptable toxicity [31,32]. After a median follow-up of 28 months, DKd improved ORR (84 versus 73 percent) and PFS (median 28.6 versus 15.2 months; HR 0.59, 95% CI 0.46-0.78). OS data are not yet mature.

When compared with the general MM population, enrolled patients were younger (median age 64 years) and more fit (95 percent with Eastern Cooperative Oncology Group performance status [ECOG PS] 0 or 1). Older patients and those with intermediate fitness had higher rates of treatment-related fatal adverse events with DKd.

While twice-weekly carfilzomib was used in the CANDOR trial described below, DKd can be given using once-weekly carfilzomib (20/70 mg/m2). Support for this alternative dosing comes from a nonrandomized phase 1b study (EQUULEUS, NCT01998971) that used DKd with once-weekly carfilzomib in 85 patients with relapsed or refractory MM [33]. A cross-trial comparison versus CANDOR suggested comparable efficacy and safety to twice-weekly dosing with an ORR of 81 percent and an estimated median duration of response of 28 months [34].

Toxicity – In patients treated with DKd on the CANDOR trial, approximately 26 percent discontinued therapy due to an adverse event [31,32]. Fatal adverse events occurred in 9 percent, including respiratory tract infections and cardiac failure.

When compared with Kd, DKd resulted in more treatment-emergent fatal adverse events (9 versus 5 percent), more grade 3 or greater adverse events (87 versus 76 percent), and higher all grade rates of diarrhea (36 versus 17 percent), upper respiratory tract infection (33 versus 23 percent), and fatigue (25 versus 19 percent).

Other common nonhematologic toxicities of any grade were hypertension (35 percent), dyspnea (23 percent), and pneumonia (24 percent).

The most common grade 3 or 4 nonhematologic toxicities were hypertension (21 percent), pneumonia (17 percent), fatigue (8 percent), dyspnea (5 percent), diarrhea (5 percent), and upper respiratory tract infection (4 percent).

Other adverse events of interest of any grade included respiratory tract infections (78 percent), viral infections (24 percent), peripheral neuropathy (20 percent), infusion reaction (45 percent), cardiac failure (9 percent), and acute renal failure (7 percent).

Isatuximab, carfilzomib, dexamethasone (IsaKd)

Clinical useIsatuximab, carfilzomib, and dexamethasone (IsaKd) is one of our preferred treatments for patients with relapsed MM refractory to lenalidomide and bortezomib (algorithm 1). IsaKd is approved in the United States for patients with relapsed or refractory MM who have received one to three prior lines of therapy. IsaKd is approved in Europe for patients who have received at least one prior therapy. IsaKd is approved in parts of Asia for certain adults with relapsed MM.

Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – When compared with Kd alone, IsaKd improves PFS without major increases in toxicity.

In an open-label, multicenter, phase 3 trial (IKEMA), 302 patients with relapsed MM who had received one to three prior lines of therapy were randomly assigned in a 3:2 ratio to receive IsaKd versus Kd until disease progression or unacceptable toxicity [35,36]. After a median follow-up of 21 months, IsaKd resulted in:

A similar ORR (87 versus 83 percent), with deeper responses (VGPR or better 73 versus 56 percent).

Improved PFS (median not reached versus 19 months, HR 0.53, 95% CI 0.32-0.89). OS data are immature.

Toxicity – In patients treated with IsaKd on the IKEMA trial, adverse reactions resulted in dose interruptions in 33 percent and treatment discontinuation in 8 percent [36]. Fatal adverse reactions occurred in 3 percent, including pneumonia and cardiac failure.

The most common adverse reactions of any grade were infusion-related reactions (46 percent), fatigue (28 percent), hypertension (37 percent), diarrhea (36 percent), upper respiratory tract infection (36 percent), pneumonia (29 percent), dyspnea (28 percent), and bronchitis (23 percent). Over 90 percent of patients developed anemia and thrombocytopenia. Neutropenia developed in 55 percent and was grade 3 or greater in 19 percent.

The most common grade 3 or greater nonhematologic toxicities were pneumonia (21 percent) and hypertension (20 percent).

Daratumumab, pomalidomide, dexamethasone (DPd)

Clinical useDaratumumab, pomalidomide, and dexamethasone (DPd) is a widely used regimen for patients with MM refractory to both lenalidomide and bortezomib (algorithm 1). DPd is approved in the United States for patients with MM who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor.

Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – In a multicenter, open-label phase 3 trial (APOLLO), 304 patients with relapsed/refractory MM were randomly assigned to receive pomalidomide and dexamethasone (Pd) with or without subcutaneous daratumumab, each administered until disease progression or unacceptable toxicity [37]. The addition of daratumumab improved PFS (median PFS 12.4 versus 6.9 months, HR 0.63, 95% CI 0.47-0.85). OS data are immature.  

These results were consistent with those seen in two open-label, nonrandomized trials of DPd, which reported estimated one-year PFS of 66 and 75 percent among patients who had received at least two (MMY1001) or one to two (MM-014) prior regimens, respectively [38,39].

Toxicity – In patients treated with DPd on the APOLLO trial, approximately 2 percent discontinued therapy due to an adverse event [37].

When compared with Pd, DPd resulted in more neutropenia (71 versus 54 percent), febrile neutropenia (9 versus 4 percent), and infections (65 versus 52 percent).

Other common nonhematologic toxicities of any grade were pyrexia (20 percent); fatigue, asthenia, and diarrhea (17 percent each); hyperglycemia (5 percent); and infusion-related reaction (5 percent, all grade 1 or 2).  

The most common grade 3 or 4 nonhematologic toxicities were infections (24 percent), fatigue (8 percent), asthenia (6 percent), hyperglycemia (6 percent), and diarrhea (5 percent).  

Isatuximab, pomalidomide, dexamethasone (IsaPd)

Clinical useIsatuximab, pomalidomide, and dexamethasone (IsaPd) is an acceptable alternative in patients with relapsed MM refractory to both lenalidomide and bortezomib (algorithm 1). IsaPd is approved in the United States, Europe, and Asia for patients with MM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – When compared with Pd, IsaPd improves PFS without major increases in toxicity.

In an open-label, multicenter, phase 3 trial (ICARIA-MM), 307 patients with MM who had received at least two lines of prior therapy, including lenalidomide and a proteasome inhibitor, were randomly assigned to receive IsaPd versus Pd [40,41]. After a median follow-up of 35 months, IsaPd resulted in:

A higher ORR (63 versus 33 percent).

Improved PFS (median 11 versus 6 months; HR 0.6, 95% CI 0.46-0.78).

An estimated 7 month improvement in median OS (median 25 versus 18 months; HR 0.76; 95% CI 0.57-1.01). While not statistically significant at current follow-up, this OS benefit would be clinically meaningful if confirmed with longer follow-up.

In a prespecified subgroup analysis, the addition of isatuximab improved ORR and PFS in patients with high-risk MM [42], and in patients with renal impairment [43]. Pharmacokinetic studies suggested no need for isatuximab dose adjustment for renal insufficiency.

Toxicity – In patients treated with IsaPd on the ICARIA-MM trial, approximately 12 percent discontinued therapy due to an adverse event [40,41]. When compared with Pd, IsaPd resulted in:

A higher rate of grade 3 or greater adverse events (91 versus 75 percent), and a similar number of fatal adverse events (14 versus 15 patients).

Higher rates of upper respiratory tract infections (33 versus 19 percent), diarrhea (30 versus 22 percent), and second primary malignancies (7 versus 2 percent).

Other common nonhematologic toxicities of any grade were infusion reactions (38 percent, mostly mild), bronchitis (24 percent), pneumonia (23 percent), fatigue (18 percent), back pain (16 percent), constipation (16 percent), asthenia (14 percent), dyspnea (15 percent), and nausea (15 percent).

The most common grade 3 or 4 nonhematologic toxicities were pneumonia (23 percent), lower respiratory tract infection (5 percent), and urinary tract infection (5 percent).

Elotuzumab, pomalidomide, dexamethasone (EPd)

Clinical useElotuzumab, pomalidomide, and dexamethasone (EPd) is approved in the United States and Europe for MM following at least two prior lines of therapy, including lenalidomide and a proteasome inhibitor (algorithm 1). EPd is approved in parts of Asia for certain adults with relapsed MM.

Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – When compared with Pd, EPd improves PFS and OS without a major increase in toxicity.  

In an open-label, multicenter, phase 2 trial (ELOQUENT-3), 117 patients with MM refractory to or relapsed and refractory to lenalidomide and a proteasome inhibitor were randomly assigned to receive EPd versus Pd [44,45]. After a minimum follow-up of 45 months, EPd resulted in:

A higher ORR (53 versus 26 percent) with a median time to response of two months.

Improved PFS (median 10.3 versus 4.7 months; HR 0.54, 95% CI 0.34-0.86).

Improved OS (median 30 versus 17 months; HR 0.59; 95% CI 0.37-0.93).

Toxicity – In the patients treated with EPd on the ELOQUENT-3 trial, adverse events resulted in treatment discontinuation in 18 percent [44,45]. There were no deaths attributed to toxicity. When compared with Pd, EPd resulted in similar rates of grade 3 or 4 adverse events (60 versus 62 percent) and adverse events leading to treatment discontinuation (18 versus 24 percent). Infection rates were similar between the treatment groups (70 versus 66 percent). Second primary malignancies developed in four patients assigned to EPd and two patients assigned to Pd.

The most common nonhematologic toxicities of any grade were nasopharyngitis (25 percent), diarrhea (25 percent), constipation (23 percent); hyperglycemia (22 percent); pyrexia and respiratory tract infection (20 percent each); fatigue, edema, and bone pain (18 percent each); insomnia and bronchitis (17 percent); muscle spasms (15 percent each); asthenia (13 percent); hypokalemia (12 percent); and rash, cataract, and pneumonia (10 percent each).

The most common grade 3 or 4 nonhematologic toxicities were hyperglycemia and cataract (8 percent each).

Refractory to lenalidomide and daratumumab — For patients with MM refractory to both lenalidomide and daratumumab, we offer the combination carfilzomib, pomalidomide, and dexamethasone (KPd); bortezomib, pomalidomide, and dexamethasone (VPd); bortezomib, cyclophosphamide, and dexamethasone (VCd, also called CyBorD) (table 4); or selinexor, bortezomib, and dexamethasone (SVd) (algorithm 1).

Patients who experience disease progression on or within 60 days of receiving standard doses of lenalidomide and daratumumab are considered to be refractory to both agents. Of note, a patient who progresses on once-monthly daratumumab may respond to daratumumab when the agent is administered once weekly.  

We have limited data addressing whether MM that is refractory to one anti-CD38 monoclonal antibody will respond to another. Although preliminary reports of some trials have described responses to isatuximab-based combinations following daratumumab, in one small phase 2 study, no patients with MM refractory to daratumumab responded to single-agent isatuximab [46]. As such, we presume that MM refractory to one anti-CD38 monoclonal antibody is refractory to other anti-CD38 monoclonal antibodies.

Carfilzomib, pomalidomide, dexamethasone (KPd)

Clinical use Carfilzomib, pomalidomide, and dexamethasone (KPd) is a preferred treatment for patients with relapsed MM refractory to lenalidomide and daratumumab, regardless of bortezomib sensitivity (algorithm 1). This includes patients progressing on or within 60 days of daratumumab, lenalidomide, and dexamethasone (DRd).

KPd is an off-label combination for the treatment of MM. Phase 1/2 studies have used once-weekly [47] or twice-weekly [48] dosing of carfilzomib. We typically prefer once-weekly dosing. Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – KPd has been evaluated in phase 1/2 multicenter dose escalation trials that enrolled patients refractory to lenalidomide [47-49]. In these trials, responses were seen in approximately 50 to 60 percent of patients on the maximum tolerated dose (MTD), and responses were similar regardless of whether or not the patient was refractory to bortezomib. While no randomized trials have evaluated KPd, randomized trials have demonstrated a clinical benefit from the use of carfilzomib and pomalidomide in other combinations used to treat relapsed MM (eg, KRd versus Rd, VPd versus Vd) [9-12,28-30].

A multicenter phase 1/2 study (NCT02185820) evaluated once-weekly KPd in 57 patients who had received one to three prior therapies and were refractory to lenalidomide [47]. Responses were observed in 29 of 47 patients (62 percent) who received the MTD of carfilzomib (27 mg/m2), with a median time to partial response of two months. After a median follow-up of 13 months, the median PFS was 10.3 months and did not differ by bortezomib sensitivity. Median OS was not reached, and OS at one year was 67 percent.

Another multicenter phase 1/2 study (NCT01464034) evaluated twice-weekly KPd in 32 patients refractory to lenalidomide [48]. Patients had received a median of six prior therapies and 91 percent were refractory to bortezomib. The ORR was 50 percent (16 percent VGPR, 34 percent PR). After a median follow-up of 26 months, median PFS was 7.2 months (95% CI 3-9 months) and median OS was 21 months.  

Toxicity – The most common adverse events described in the two phase 1/2 studies were as follows:

With once-weekly KPd (NCT02185820): Most common nonhematologic adverse events of any grade included infection (43 percent); fever (34 percent); neuropathy and fatigue (23 percent each); hypertension, dermatologic, gastrointestinal (15 percent each); cardiac (6 percent); and renal failure (4 percent) [47]. Most common grade 3 or 4 nonhematologic adverse events were infections (11 percent), vascular events (9 percent), cardiac events (4 percent), and fatigue (4 percent). There were no treatment-related deaths.  

With twice-weekly KPd (NCT01464034): Most common nonhematologic adverse events of any grade included fatigue (47 percent); creatinine elevation (38 percent); constipation, neuropathy, and muscle spasm (19 percent each); and diarrhea, rash, and hypocalcemia (16 percent each) [48]. Grade 3 or greater adverse events included one patient each with congestive heart failure, fluid overload, muscle weakness, maculopapular rash, and dyspnea, and three patients with acute renal failure. There were two treatment-related deaths (pulmonary embolism and pneumonia).  

Bortezomib, cyclophosphamide, dexamethasone (VCd)

Clinical useBortezomib, cyclophosphamide, and dexamethasone (VCd (table 4), also called CyBorD) is an important treatment option for patients with relapsed MM refractory to lenalidomide and daratumumab (algorithm 1). Both bortezomib and cyclophosphamide are approved in the United States and Europe for the treatment of MM. Details of the VCd regimen are provided in the table (table 4).

Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – Three randomized trials compared VCd versus other regimens in patients with previously untreated MM. A randomized phase 2 trial (EVOLUTION) evaluating bortezomib and dexamethasone in combination with lenalidomide (VRd), cyclophosphamide (VCd), or both (VDCR) reported ORR rates of 73, 68, and 80 percent, respectively [50]. In an open-label phase 3 trial that enrolled 155 patients in first relapse, VCd and lenalidomide, cyclophosphamide, and dexamethasone (RCd) resulted in similar PFS (median 16 versus 19 months) and OS (48 versus 51 percent at three years), but a different toxicity profile (VCd resulted in less neutropenia and thrombocytopenia, but more infections) [51]. In a multicenter phase 3 trial (IFM2013-04) comparing VCD versus bortezomib, thalidomide, and dexamethasone (VTD), VCD resulted in a lower ORR (83 versus 92 percent) and more hematologic toxicity but less neurologic toxicity [52]. There were five deaths during induction, three in the VCD arm (infections and disease progression) and two in the VTD arm (infection, pulmonary embolism). (See "Multiple myeloma: Initial treatment".)

A phase 2 trial evaluated a different regimen of bortezomib, dexamethasone, and continuous low-dose cyclophosphamide in 50 patients with relapsed MM yielded ORRs and CR rates of 66 and 16 percent, respectively [53].

Toxicity – In patients treated with VCd in the EVOLUTION trial, adverse events resulted in treatment discontinuation in 12 percent [50].

Grade 3 or 4 hematologic toxicities included neutropenia (30 percent), lymphopenia (12 percent), and thrombocytopenia (12 percent).

The most common grade 3 or 4 nonhematologic toxicities were neuropathy (9 percent), fatigue (3 percent), and diarrhea (3 percent).

Selinexor, bortezomib, dexamethasone (SVd)

Clinical useSelinexor, bortezomib, and dexamethasone is another option for patients with MM refractory to lenalidomide and daratumumab (algorithm 1). It is approved in the United States for MM following at least one prior therapy [54].

Specific administration considerations are discussed separately (table 2). (See "Multiple myeloma: Administration considerations for common therapies".)

Efficacy – The combination of once-weekly SVd was compared with twice-weekly bortezomib plus dexamethasone (Vd) in a multicenter, open label, phase 3 trial (BOSTON) of 402 patients with relapsed or refractory MM (median age 67 years, 48 percent with high-risk cytogenetics, 76 percent with prior proteasome inhibitor exposure) [55,56]. Both arms used subcutaneous bortezomib. Planned total doses of bortezomib and dexamethasone were lower in the SVd arm. Once-weekly SVd resulted in a higher ORR (76 versus 62 percent), and prolonged PFS (median 14 versus 9.5 months; HR 0.70). Crossover was allowed at progression and OS data are immature.

Toxicity – In patients treated with SVd in the BOSTON trial, adverse events lead to treatment discontinuation in 21 percent and there were 12 deaths (6 percent) due to adverse events (leading causes pneumonia and sepsis).

When compared with twice-weekly Vd, weekly SVd resulted in less peripheral neuropathy (32 versus 47 percent), and more cytopenias, infections, gastrointestinal toxicity, fatigue, and cataracts.

SVd resulted in higher rates of grade 3 or 4 thrombocytopenia (39 versus 17 percent), anemia (16 versus 10 percent), and neutropenia (9 versus 3 percent).

The most common grade 3 or 4 nonhematologic toxicities with SVd were fatigue (13 percent), pneumonia (12 percent), and cataracts (9 percent).

SPECIAL POPULATIONS

Frail patients — When possible, we prefer three-drug regimens over two-drug regimens. Indeed, many older adults were included in the trials that evaluated three-drug regimens and demonstrated superiority over two-drug regimens. However, two-drug regimens are an acceptable alternative for frail patients who are unable to tolerate three-drug regimens.

Single-agent therapy is used occasionally in frail patients who are unable to tolerate steroids, or in patients who have been well controlled on three-drug or two-drug regimens with a goal of reducing the intensity of therapy in order to minimize side effects.

Two-drug regimens include:

Ixazomib plus dexamethasone (Id) – In a phase 2 trial of ixazomib plus dexamethasone in 70 patients with relapsed MM not refractory to bortezomib, approximately 43 percent achieved a partial response (PR) or better [57]. The median event-free survival (EFS) was 8.4 months.

Carfilzomib plus dexamethasone (Kd) – In a multicenter, phase 3 trial (ENDEAVOR) comparing carfilzomib plus dexamethasone versus bortezomib plus dexamethasone in patients with MM relapsed after one to three prior therapies, Kd improved overall response rate (ORR; 77 versus 63 percent), progression-free survival (PFS; median 19 versus 9 months; HR 0.53, 95% CI 0.44-0.65) and overall survival (OS; median 48 versus 39 months; HR 0.76, 95% CI 0.63-0.92) [58-62].

Kd also resulted in fewer dose reductions due to an adverse event (23 versus 48 percent); lower rates of all-grade peripheral neuropathy (19 versus 52 percent) and constipation (15 versus 27 percent); higher rates of dyspnea (29 versus 13 percent), pyrexia (28 versus 14 percent), cough (25 versus 14 percent), hypertension (25 versus 9 percent), and cardiac failure (8 versus 3 percent).

Bortezomib plus dexamethasone (Vd) – In one study of bortezomib plus dexamethasone, the response rate was 66 percent in relapsed disease with a median time to progression of 9.5 months [63]. Similar ORRs are seen in patients with an initial PR or better with bortezomib therapy who undergo repeat treatment with bortezomib at progression [64,65].

Common adverse effects with bortezomib include anorexia, nausea and vomiting, peripheral neuropathy, cutaneous reactions, neutropenia, and thrombocytopenia [66,67].

Kd was superior to Vd in the ENDEAVOR study as noted above, but Vd may be preferred to Kd in a frail, elderly patient with a history of significant cardiovascular disease.

Pomalidomide plus dexamethasone (Pd)Pomalidomide plus dexamethasone results in a response rate of approximately 60 percent in relapsed disease [68], and approximately 30 percent in patients with lenalidomide-refractory disease [69-73]. Randomized trials have shown improved survival with Pd when compared with high-dose dexamethasone alone and higher response rates when compared with pomalidomide alone [71,74]. The duration of response ranged from 4 to 10 months in these multiply relapsed patients.

Data regarding safety also come from a phase 3b study of Pd in patients with multiply relapsed or refractory MM [75]. Pomalidomide dose interruption, dose reduction, and discontinuation were observed in 66, 22, and 6 percent of patients, respectively. There were 15 deaths due to toxicity (2 percent). The most common severe (grade 3/4/5) toxicities were neutropenia (50 percent with 5.3 percent neutropenic fever), anemia (33 percent), infections (30 percent, including pneumonia in 13 percent), and thrombocytopenia (24 percent).

Patients with moderate to severe renal impairment were excluded from these randomized trials; however, a small phase 2 trial of Pd suggested that this regimen is safe and effective in patients with moderate to severe renal insufficiency, including in those requiring dialysis [76].

Lenalidomide plus dexamethasone (Rd) – In two large randomized phase 3 studies (MM-009 and MM-010) that compared lenalidomide plus dexamethasone versus dexamethasone plus placebo in relapsed or refractory MM, Rd improved response rates and time to progression [77-79].

The most common severe (grade 3/4) toxicities seen in patients treated with Rd include neutropenia (30 to 40 percent), anemia (9 to 13 percent), thrombocytopenia (12 to 15 percent), and venous thromboembolism (11 percent). Nonhematologic toxicities of fatigue (55 percent), insomnia (20 percent), diarrhea (21 percent), constipation (24 percent), muscle cramps (24 percent), and infections (20 percent) have been reported but were usually not severe [80].

Aggressive disease — Treatment of patients who relapse or progress on therapy with major complications (eg, acute renal failure, extramedullary disease) is individualized.

Aggressive relapses may benefit from more aggressive treatment regimens that incorporate several new agents. As an example, a patient with aggressive progression on bortezomib, lenalidomide, and dexamethasone may be treated with daratumumab, carfilzomib, pomalidomide, and dexamethasone (Dara-KPd). A clinical trial evaluating Dara-KPD is ongoing and will provide insight on the efficacy and safety of the combination (NCT04176718).    

The treatment of extramedullary relapse is discussed separately. (See "Multiple myeloma: Overview of management", section on 'Extramedullary relapse'.)

Resource-poor settings — Access to preferred three-drug regimens is limited in certain areas of the world by age restrictions or resource limitations. Patients in such settings can still benefit from the use of treatment regimens that are based on alkylating agents (eg, melphalan or cyclophosphamide) and/or first generation immunomodulatory agents (eg, thalidomide). Details regarding the use of these regimens and guidance regarding the choice of regimen are provided separately. (See "Multiple myeloma: Management in resource-limited settings".)

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.)

Basics topics (see "Patient education: Multiple myeloma (The Basics)")

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

General principles – There are many approved treatment combinations for patients with relapsed and/or refractory multiple myeloma (MM). Most patients experience serial relapses over time and will ultimately receive most if not all available agents at some point during their disease course. A preferred order for their use has not been established. Accompanying tables provide active drugs by class (table 5) and major toxicities of selected treatment regimens (table 2). General principles for treatment are provided separately. (See "Multiple myeloma: Overview of management", section on 'Relapsed or refractory disease'.)

We typically suggest a three-drug regimen that includes a monoclonal antibody rather than one that does not (Grade 2B). An exception would be for patients refractory to both lenalidomide and daratumumab, in whom a monoclonal antibody is unlikely to be effective. Although direct comparisons between these combinations have not been conducted, network meta-analyses that incorporated both direct and indirect comparisons identified monoclonal antibody-containing three-drug combinations among the most active regimens in relapsed MM.

Assess drug sensitivity – The choice of therapy for relapsed MM is influenced significantly by prior therapies received, response to those therapies, and likelihood of the disease being refractory to specific agents. In general, refractory disease is defined as progressing on or within 60 days of receiving standard doses of a specific therapy. It's important to consider that patients progressing on a low dose of an agent being administered in the context of maintenance therapy may still be sensitive to the same agent given at standard doses. (See 'Assess drug sensitivity' above.)

Lenalidomide sensitive For most patients with lenalidomide-sensitive MM in first or second relapse, we suggest a lenalidomide-containing three-drug regimen rather than regimens that do not contain lenalidomide (Grade 2C). This includes patients who experience a biochemical relapse off lenalidomide, or while on low doses of single-agent lenalidomide (eg, 10 mg daily) administered as maintenance. This approach maximizes the benefit of lenalidomide-based treatment regimens and is supported by numerous phase 3 trials that have found it to be effective and well tolerated.

Daratumumab, lenalidomide, and dexamethasone (DRd) (table 1) is one such option. Other options include carfilzomib, lenalidomide, and dexamethasone (KRd); ixazomib, lenalidomide, and dexamethasone (IRd) (table 3); and elotuzumab, lenalidomide, and dexamethasone (ERd). (See 'Daratumumab, bortezomib, dexamethasone (DVd)' above.)

Lenalidomide refractory – Treatment of lenalidomide-refractory disease is individualized based on response to prior therapy and expected toxicities (algorithm 1).

Refractory to lenalidomide alone – For patients with MM refractory to lenalidomide alone, we offer daratumumab, bortezomib, and dexamethasone (DVd); daratumumab, pomalidomide, and dexamethasone (DPd); isatuximab, pomalidomide, and dexamethasone (IsaPd); or bortezomib, pomalidomide, and dexamethasone (VPd). (See 'Daratumumab, bortezomib, dexamethasone (DVd)' above.)

Refractory to lenalidomide and bortezomib – For patients with MM refractory to both lenalidomide and bortezomib, we offer either daratumumab, carfilzomib, and dexamethasone (DKd) or isatuximab, carfilzomib, and dexamethasone (IsaKd). Other options in this context are DPd, IsaPd, and elotuzumab, pomalidomide, and dexamethasone (EPd). (See 'Daratumumab, carfilzomib, dexamethasone (DKd)' above and 'Isatuximab, carfilzomib, dexamethasone (IsaKd)' above.)

Refractory to lenalidomide and daratumumab – For patients with MM refractory to both lenalidomide and daratumumab, we offer the combination carfilzomib, pomalidomide, and dexamethasone (KPd); VPd; bortezomib, cyclophosphamide, and dexamethasone (VCd, also called CyBorD) (table 4); or selinexor, bortezomib, and dexamethasone (SVd). (See 'Carfilzomib, pomalidomide, dexamethasone (KPd)' above.)

Administration considerations – All of these medications have associated risks and complex administration schedules, which are discussed in more detail separately. (See "Multiple myeloma: Administration considerations for common therapies".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Robert A Kyle, MD to earlier versions of this topic review.

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Topic 121127 Version 58.0

References

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