Overview
Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in the bone marrow, leading to bone destruction and marrow failure. MM is most frequently diagnosed among people aged 65 to 74 years, with the median age being 69 years.1 The American Cancer Society has estimated 35,730 new MM cases and an estimated 12,590 deaths in the United States in 2023.2 The NCCN Multiple Myeloma Panel members have developed guidelines for the management of various plasma cell neoplasms including monoclonal gammopathy of clinical significance, solitary plasmacytoma, smoldering myeloma, MM, polyneuropathy, organomegaly, Endocrinopathy, monoclonal plasma cell disorder, skin changes syndrome, systemic light chain amyloidosis, and Waldenström macroglobulinemia. This manuscript focuses only on management of relapsed/refractory MM. For the complete NCCN Guidelines for Multiple Myeloma, please visit nccn.org.
Therapy for Previously Treated MM
A variety of therapies are available for previously treated or relapsed/refractory MM. The choice of appropriate therapy for a specific patient depends on the context of clinical relapse such as prior treatment and duration of response.
The therapeutic options for previously treated MM include systemic therapy; autologous hematopoietic cell transplantation (HCT) for eligible patients who did not receive HCT as part of their initial treatment; or clinical trial. For those who underwent autologous HCT as part of initial treatment and had a durable response or stable disease, consideration may be given to a second transplantation at the time of relapse/disease progression.
As a general principle, if the relapse occurs at >6 months after completion of the initial primary therapy, patients may be retreated with the same primary regimen. This, however, does not apply to HCT for which a longer remission would be needed to justify another transplant.
Preferred Regimens for Previously Treated Multiple Myeloma: After 1 to 3 Prior Therapies
For patients who are still sensitive to bortezomib and/or lenalidomide, any of the regimens listed below may be appropriate. Since, however, bortezomib-containing or lenalidomide-containing regimens are often given as induction therapy, and it is likely that at relapse the disease is refractory to these agents, especially if relapse is well within 6 months of primary treatment completion, other combinations are preferred.
The NCCN MM Panel has provided a list of regimens for bortezomib-refractory and lenalidomide-refractory disease after 1 to 3 prior therapies.
Preferred Regimens for Bortezomib- or Lenalidomide-Refractory Disease
Daratumumab/Carfilzomib/Dexamethasone
A phase Ib, open-label, nonrandomized, multicenter trial first studied this regimen in patients (n=82) with relapsed or refractory MM. At a median follow-up of 16 months, the overall response rate (ORR) was 84%. In the overall treatment population, although the median progression-free survival (PFS) was not reached, the 12-month and 18-month PFS rates were 74% and 66%, respectively.3 In a multicenter, open-label phase III trial (CANDOR), the addition of daratumumab to carfilzomib plus dexamethasone showed deeper responses and improved PFS.4 This response has been shown to be maintained with longer follow-up analyses of about 27 months. PFS was 28.6 months in the daratumumab group versus 15.2 months in the carfilzomib alone group (hazard ratio [HR], 0.59; 95 CI, 0.45–0.78; P<.0001).5 Based on the previously cited data and the FDA approval, the panel has included this regimen as a category 1, preferred option for patients with relapsed or refractory MM.
Isatuximab-irfc/Carfilzomib/Dexamethasone
A prospective, randomized, open label, phase III study (IKEMA) examined the utility of isatuximab/carfilzomib/dexamethasone versus carfilzomib/dexamethasone in 302 patients with relapsed/refractory MM who had received 1 to 3 prior lines of therapy (median, 2 prior lines of therapy). Treatment was continued until disease progression or unacceptable toxicity, with the primary endpoint being PFS. Median PFS was 35.7 months in the isatuximab/carfilzomib/dexamethasone group versus a median PFS of 19.15 months in the carfilzomib/dexamethasone group (HR, 0.53; 99% CI, 0.32–0.89, P=.0007). Grade 3 or higher treatment-related adverse events occurred in 77% of patients in the isatuximab group versus 67% of patients in the control group.6 Based on this data, the NCCN panel has included isatuximab-irfc/carfilzomib/dexamethasone as a category 1, preferred regimen option for relapsed or refractory MM.
Carfilzomib/Pomalidomide/Dexamethasone
A phase II trial investigated carfilzomib/pomalidomide/dexamethasone followed by continuous pomalidomide/dexamethasone as second line therapy for relapsed/refractory MM in patients who experienced progression during lenalidomide maintenance therapy. Patients who were eligible for transplant and had not received it previously received HCT. On this regimen, 75% of patients had a very good partial response (VGPR), and 37% displayed complete response (CR). At 40-months of follow up, the median PFS was 26 months for patients who received therapy with HCT, and 17 months for patients who received carfilzomib/pomalidomide/dexamethasone therapy without HCT. The median overall survival (OS) was 67 months, with the most common grade 3 and 4 adverse events related to treatment including hematologic toxicity (41%), cardiovascular (6%) and respiratory (3%) events, and infections (17%).7 Based on these data, the NCCN panel has included carfilzomib/pomalidomide/dexamethasone as a preferred regimen option for relapsed or refractory MM.
Daratumumab/Pomalidomide/Dexamethasone
The combination of daratumumab/pomalidomide/dexamethasone was evaluated in an open-label, multicenter, phase Ib study (MMY1001). This study included patients (n=103 patients) who had received at least 2 prior lines of therapy (excluding daratumumab or pomalidomide).8 At a median follow-up of 13.1 months, the ORR was 60%. The median PFS and OS were 8.8 and 17.5 months, respectively, and estimated survival at 1 year was 66%.8 Toxicities reported were similar to those seen in other trials of pomalidomide and daratumumab, except for increase in neutropenia.8
The open-label phase III APOLLO trial randomly assigned patients with relapsed/refractory disease and at least one previous line of therapy (n=304) to receive pomalidomide/dexamethasone or daratumumab/pomalidomide/dexamethasone. With a median follow up time of 16.9 months, a statistically significant improvement was seen in the primary endpoint of PFS for the added daratumumab group (12.4 vs 6.9 months; P=.0018). Serious adverse events occurred in 50% of patients in the daratumumab group compared with 39% of patients in the pomalidomide/dexamethasone group, the most common being pneumonia and lower respiratory tract infections.9
The MM-014 study evaluated 112 patients with relapsed/refractory MM who had previously been treated with lenalidomide and assigned them to a regimen containing daratumumab/pomalidomide/dexamethasone. The primary endpoint was ORR, which was achieved in 77.7% of patients in a median follow up of 17.2 months (median PFS was not reached at time of follow up). The most common adverse event of grade 3 or higher was infection, which developed in 31.3% of patients (13.4% with grade 3 or higher pneumonia).10
Based on the previously cited data, the NCCN panel has included daratumumab/pomalidomide/dexamethasone as a treatment option for patients with relapsed/refractory MM who have received one prior therapy including an immunomodulator (IMiD) and a proteasome inhibitor (PI).
Isatuximab-irfc/pomalidomide/dexamethasone
In an open-label, multicenter, phase III trial (ICARIA-MM), patients (n=307) with MM who had received at least 2 lines of prior therapy, including lenalidomide and a PI were randomized to receive pomalidomide/dexamethasone with or without isatuximab-irfc.11 After a median follow-up of 12 months, a higher ORR (60% vs 35%) and improved PFS (median, 11.5 vs 6.5 months; HR, 0.6; 95% CI, 0.44–0.81) were reported in the isatuximab-irfc/pomalidomide/dexamethasone arm. In a prespecified subgroup analysis of this study, the addition of isatuximab-irfc showed improved ORR and PFS in patients with renal impairment.12
The NCCN MM Panel has included isatuximab-irfc/pomalidomide/dexamethasone as a category 1, preferred option for the treatment of patients with relapsed/refractory MM after 2 prior therapies including lenalidomide and a PI.
Ixazomib/Pomalidomide/Dexamethasone
In the phase I/II Alliance A061202 study (n=29), patients with lenalidomide/PI refractory MM were treated with ixazomib/pomalidomide/dexamethasone- with 51.7% of patients having a PR or better, a median PFS of 4.4 months, a median response duration of 16.8 months, and a median OS of 34.3 months. Common adverse events included hematologic toxicity, and gastrointestinal events.13
Another phase I/II study examined the safety and efficacy of ixazomib/pomalidomide/dexamethasone in patients who had multiple prior therapies, were refractory to lenalidomide alone, or were refractory to lenalidomide and bortezomib, or lenalidomide, bortezomib, and carfilzomib.14 The ORRs were 33% and 40% with 2 different doses of ixazomib.14
Considering promising preliminary response rates, especially in patients whose disease was refractory to both lenalidomide and a PI, the NCCN Panel has included ixazomib/pomalidomide/dexamethasone as a treatment option for patients with relapsed/refractory MM who have received at least 2 prior therapies including an IMiD and a PI and have shown disease progression on or within 60 days of completion of the last therapy.
Additional Preferred Regimens for Bortezomib-Refractory Disease
In addition to the regimens listed in the previous section, the following 2 lenalidomide-containing regimens may be used for lenalidomide-sensitive or naïve and bortezomib-refractory disease.
Daratumumab/Lenalidomide/Dexamethasone
In a multicenter, open-label phase III trial (POLLUX), patients (n=569) with relapsed/refractory MM were randomized to receive lenalidomide/dexamethasone with or without daratumumab until disease progression or unacceptable toxicity.15
After a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone was associated with better PFS and ORR compared with lenalidomide/dexamethasone alone. After a median follow-up of 25.4 months, a subsequent analysis reported that the higher ORR (92.9% vs 76.4%, P<.001), and PFS (83% vs 60% at 12 months; 68% vs 41% at 24 months; HR, 0.41; 95% CI, 0.31–0.53) was maintained in those who had received daratumumab.15
The most common adverse events of grade 3 or 4 in patients treated with the daratumumab regimen versus lenalidomide/dexamethasone were neutropenia (51.9% vs 37.0%), thrombocytopenia (12.7% vs 13.5%), and anemia (12.4% vs 19.6%). Daratumumab-associated infusion-related reactions (mostly grade 1 or 2) were reported in 47.7% of patients.
With an extended follow-up of 3.5 years, the improvements in PFS and ORR continued to be maintained in patients treated with the daratumumab regimen (PFS, 16.7 vs 7.1 months; HR, 0.31; 95%; CI, 0.25–0.40; P<.0001). In a subgroup of patients with one prior line of therapy, the median PFS was 27.0 months with daratumumab versus 7.9 months with daratumumab and lenalidomide (HR, 0.22; 95% CI, 0.15–0.32; P<.0001). The ORR rates for patients with one prior line of therapy for those receiving the daratumumab-regimen was 92% compared with 74% in those receiving daratumumab/dexamethasone.16
Based on the above data, the NCCN MM Panel has added daratumumab/lenalidomide/dexamethasone as a category 1, preferred option for the treatment of patients with relapsed/refractory MM.
Carfilzomib/Lenalidomide/Dexamethasone
The randomized, multicenter, phase III ASPIRE trial, studied the combination of lenalidomide and dexamethasone with or without carfilzomib in patients (n=792) with relapsed/refractory MM who had received 1 to 3 prior lines of therapy. The primary endpoint of the study was PFS. The results showed that the addition of carfilzomib to lenalidomide and dexamethasone significantly improved PFS by 8.7 months (26.3 months for the carfilzomib arm vs 17.6 months for lenalidomide and low-dose dexamethasone; HR for progression or death, 0.69; 95% CI, 0.57–0.83; P=.0001). The median duration of treatment was longer in the carfilzomib group (88.0 vs 57 weeks). The incidence of peripheral neuropathy was nearly identical in both arms (17%). Nonhematologic adverse effects (≥ grade 3) that were higher in the carfilzomib group compared with lenalidomide and dexamethasone included dyspnea (2.8% vs 1.8%), cardiac failure (3.8% vs 1.8%), and hypertension (4.3% vs 1.8%). There were fewer discontinuations due to side effects in the carfilzomib arm (15.3% vs 17.7%). Patients in the carfilzomib arm reported superior health-related quality of life than those who received lenalidomide and dexamethasone alone.17
Based on the previously stated data, the NCCN MM Panel has included the combination of carfilzomib with lenalidomide and dexamethasone as a category 1, preferred option for patients with relapsed/refractory MM.
Additional Preferred Regimens for Lenalidomide-Refractory Disease
In addition to the regimens listed in the section for bortezomib- and lenalidomide refractory disease, the following bortezomib-containing regimens may be used for bortezomib-sensitive or -naïve and lenalidomide-refractory disease.
Daratumumab/Bortezomib/Dexamethasone
A phase III trial showed that adding daratumumab to bortezomib and dexamethasone markedly improved outcomes for patients with recurrent/refractory MM.18 Patients (n=498) were randomized to receive daratumumab/bortezomib/dexamethasone or bortezomib/dexamethasone. The ORR in the daratumumab arm was 82.9% compared with 63.2% in the control arm (P<.001).18 The rates of VGPR and CR were double in the daratumumab arm compared with the control arm (59.2% vs 29.1%; P<.001 and 19.2% vs 9.0%; P=.001, respectively). The 12-month estimated rate of PFS was significantly higher in the daratumumab arm compared with the control arm (60.7% vs 26.9%).18 The most common grade 3 or 4 adverse events reported in the daratumumab and control groups were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively).18 Grade 1 or 2 infusion-related reactions associated with daratumumab were reported in 45.3% of the patients in the daratumumab group and grade 3 in 8.6% of the patients. These infusion-related reaction rates are consistent with findings from previous trials of daratumumab.19,20
After a median follow-up of 40 months, patients receiving the daratumumab containing regimen demonstrated a 69% reduction in the risk of disease progression or death (median PFS, 16.7 vs 7.1 months; HR, 0.31; 95% CI, 0.25–0.40; P<.0001), and showed significantly better ORR (85% vs 63%; P<.0001).21 Patients who received one prior line of therapy demonstrated the greatest benefit with daratumumab (median PFS, 27.0 vs 7.9 months; HR, 0.22; 95% CI, 0.15–0.32; P<.0001).
Based on the previously noted phase III data, the NCCN Panel has added daratumumab/bortezomib/dexamethasone as a category 1, preferred option for the treatment of patients with relapsed/refractory MM.
Pomalidomide/Bortezomib/Dexamethasone
A phase III open-label, multicenter, randomized, trial (OPTIMISMM) evaluated pomalidomide/bortezomib/dexamethasone (n=281) versus bortezomib/dexamethasone in patients (n=278) with relapsed or refractory MM who previously received lenalidomide.22 After a median follow-up of 15.9 months, a significantly improved PFS was seen in the pomalidomide arm (median, 11.20 vs 7.10 months; HR, 0.61; 95% CI, 0.49–0.77; P<.0001). The most common grade 3/4 treatment-related adverse events in the pomalidomide arm reported in this trial were neutropenia, infections, and thrombocytopenia.22 A posthoc subgroup analysis of the OPTIMISSM trial evaluated outcomes in 226 patients at first relapse that had only received one prior line of therapy. Analyses were conducted by lenalidomide-refractory status, prior bortezomib exposure, and prior HCT. Statistically significant improvements in PFS were seen in both lenalidomide-refractory (17.8 vs 9.5 months; P=.0276) and lenalidomide–nonrefractory (22.0 vs 12.0 months; P=.0491) patients. Statistically significant improvements in PFS were also seen in patients who had received prior bortezomib (17.8 vs 12 months), and patients with (22 vs 13.8 months) and without (16.5 vs 9.5 months) prior HCT.23
Based on these data, the NCCN Guidelines Panel has included pomalidomide/bortezomib/dexamethasone as a category 1, preferred option for the treatment of patients with relapsed/refractory MM.
Selinexor/Bortezomib/Dexamethasone
An ongoing phase III, randomized open label trial (BOSTON) compared selinexor/bortezomib/dexamethasone with bortezomib/dexamethasone in patients with previously treated MM (1–3 prior lines of therapy, including PIs). Four hundred two patients were randomized to the selinexor/bortezomib/dexamethasone and 206 to the bortezomib/dexamethasone group. After a median follow-up duration of 13.2 months in the selinexor/bortezomib/dexamethasone group, the median PFS was 13.93 months compared with a median follow up duration of 16.5 months and median PFS of 9.46 months in the bortezomib/dexamethasone group (HR, 0.70; 95% CI, 0.53–0.93; P=.0075). The most frequent adverse events of grade 3–4 that were more common in the selinexor/bortezomib/dexamethasone group were thrombocytopenia (39% vs 17%), fatigue (13% vs 1%), and anemia (16% vs 10%).24
Based on the previously cited data, the NCCN Guidelines Panel has included once weekly selinexor in combination with bortezomib and dexamethasone as a category 1, other recommended regimen option for previously treated MM.
Elotuzumab/Pomalidomide/Dexamethasone
In a phase II study, patients (n=117) with refractory/relapsed MM and refractory to lenalidomide and a PI were randomized to receive pomalidomide/dexamethasone or elotuzumab/pomalidomide/dexamethasone.25 After a follow-up of 9.1 months, the median PFS and ORR were both more than double with elotuzumab (PFS, 10.3 vs 4.7 months; ORR, 53% vs 26%).25 Median OS was also significantly improved with elotuzumab/pomalidomide/dexamethasone compared with pomalidomide/dexamethasone (29.8 vs 17.4 months; HR, 0.59; 95% CI, 0.37–0.93; P=.0217).26
The NCCN Guidelines Panel has included the combination of pomalidomide/dexamethasone/elotuzumab as an option for patients who have received ≥2 prior therapies including an IMiD and a PI.
Other Recommended Regimens for Relapse After One to Three Prior Therapies
Carfilzomib (Twice Weekly)/Dexamethasone
The results of the phase III ENDEAVOR trial in patients with relapsed/refractory MM treated with multiple prior lines of therapy showed a 2-fold improvement in median PFS with carfilzomib/dexamethasone compared with bortezomib/dexamethasone (18.7 vs 9.4 months; HR, 0.53; P<.0001).27 ORR was 77% in the carfilzomib group versus 63% in the bortezomib group; rates of CR or better were 13% and 6% and rates of VGPR were 42% and 22%, respectively. The median duration of response was 21.3 months in the carfilzomib group and 10.4 months in the bortezomib group. Adverse events (grade 3 or higher) in the carfilzomib arm compared with the bortezomib arm included hypertension (6% vs 3%), anemia (12% vs 9%), thrombocytopenia (10% vs 14%), and dyspnea (5% vs 2%). Rate of grade ≥2 peripheral neuropathy was 6% in the carfilzomib group and 32% in the bortezomib group.27
The OS analysis showed that those treated with carfilzomib/dexamethasone lived 7.6 months longer (median OS was 47.6 months in the carfilzomib group vs 40 months in the bortezomib group; HR, 0.791 [95% CI, 0.648–0.964]; P=.010).28 The most frequent grade 3 or worse adverse events in the carfilzomib arm compared with the bortezomib arm included hypertension (15% vs 3%), anemia (16% vs 10%), dyspnea (6% vs 2%), decreased lymphocyte count (6% vs 2%), diarrhea (4% vs 9%), and peripheral neuropathy (1% vs 6%).28 Rates of thrombocytopenia, pneumonia, and fatigue were similar in both groups.28
Based on these phase III data, the NCCN MM Guidelines Panel has included the combination of carfilzomib (twice weekly) and dexamethasone as a category 1, preferred option for patients with relapsed/refractory MM.
Elotuzumab/Lenalidomide/Dexamethasone
The FDA has approved elotuzumab in combination with lenalidomide and dexamethasone for the treatment of patients with MM who have received 1 to 3 prior therapies. This is based on the results of the phase III trial, ELOQUENT-2. The trial randomized 646 patients (1:1) to receive either elotuzumab in combination with lenalidomide and dexamethasone or lenalidomide and dexamethasone alone.29
The rates of PFS at the end of 1 and 2 years were higher for those receiving the elotuzumab-containing regimen (68% at 1 year and 41% at 2 years) compared with those receiving lenalidomide and dexamethasone alone (57% at 1 year and 27% at 2 years).29 Median PFS in the group receiving the elotuzumab-containing regimen was 19.4 months versus 14.9 months in those receiving lenalidomide and dexamethasone alone (HR for progression or death in the elotuzumab group, 0.70; 95% CI, 0.57–0.85; P<.001) indicating a relative reduction of 30% in the risk of disease progression or death.29 Common grade 3 or 4 adverse events in both arms of the trial were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients.29
Consistent with these findings, a subset analysis of 3-year follow-up reported a reduced risk of progression by 27% with the elotuzumab/lenalidomide/dexamethasone combination compared with lenalidomide/dexamethasone.30
The final results of the ELOQUENT-2 study have demonstrated that the addition of elotuzumab to lenalidomide/dexamethasone improved OS in patients with MM who received 1 to 3 prior lines of therapy (48.3 vs 39.6 months).31
Based on the above data and FDA approval the NCCN Panel has included elotuzumab in combination with lenalidomide and dexamethasone as a category 1 option for previously treated MM.
Ixazomib/Lenalidomide/Dexamethasone
A double-blind, randomized, placebo-controlled, phase III TOURMALINE MM1 trial randomized 722 patients with relapsed and/or refractory MM to a combination of ixazomib plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone (control group). This trial was designed based on the promising results of a phase I/II study (discussed under “Other Recommended Primary Therapy Regimens for Transplant Candidates,” available online, in these NCCN Guidelines, at NCCN.org).32
The results of the TOURMALINE MM1 trial show a significant improvement in PFS with the ixazomib-containing regimen. After a median follow-up of almost 15 months, a 35% improvement in PFS was seen in the group treated with the ixazomib regimen compared with the control group (HR, 0.74; P=.01).33 Median PFS was 20.6 months in the ixazomib-treated group versus 14.7 months in the group receiving lenalidomide and dexamethasone alone. In the ixazomib-treated group versus the control group, the ORR (78% vs 72%, P=.035) and CR (11.7% vs 6.6%, P=.019) were also improved. Of note, patients with high-risk cytogenetics enrolled in the trial receiving ixazomib had a similar HR for PFS as the entire study population (HR, 0.596 and 0.543, respectively).33 Grade ≥3 adverse events were reported in 74% and 69% of patients in the ixazomib-treated and control groups, respectively. These included anemia (9% with ixazomib/lenalidomide/dexamethasone vs 13% with lenalidomide/dexamethasone), thrombocytopenia (19% vs 9%), and neutropenia (23% vs 24%).33 The addition of the ixazomib/lenalidomide/dexamethasone group had a slightly higher rate of peripheral neuropathy compared with lenalidomide/dexamethasone (27% vs 22%).
Based on the results of the phase III TOURMALINE MM1 trial33 the panel has included ixazomib/lenalidomide/dexamethasone as a category 1, preferred regimen option for previously treated MM after 1 to 3 prior therapies.
Bortezomib/Cyclophosphamide/Dexamethasone
The effects of adding an alkylating agent (such as cyclophosphamide) and a novel agent (such as lenalidomide or bortezomib) to dexamethasone have been investigated for patients with relapsed/refractory MM. The combination of bortezomib, dexamethasone, and cyclophosphamide was found to be effective in patients with relapsed/refractory MM with an acceptable toxicity profile.34,35 The NCCN MM Panel members have included bortezomib/cyclophosphamide/dexamethasone as an other recommended regimen for relapsed/refractory MM after 1 to 3 prior therapies.
Bortezomib/Lenalidomide/Dexamethasone
Data from preclinical studies showed lenalidomide sensitizes myeloma cells to bortezomib and dexamethasone. The results of phase I and phase II studies show that bortezomib/lenalidomide/dexamethasone is well tolerated and active, with durable responses in heavily pretreated patients with relapsed and/or refractory MM, including patients who have had prior lenalidomide, bortezomib, thalidomide, and HCT.36,37 After a median follow-up of 44 months, the median PFS was 9.5 months and median OS was 30 months (95% CI, 24–37).37 The NCCN MM Panel members have included bortezomib/lenalidomide/dexamethasone as other recommended regimen for relapsed/refractory MM after 1 to 3 prior therapies.
Carfilzomib/Cyclophosphamide/Dexamethasone
Carfilzomib/cyclophosphamide/dexamethasone has been shown to be well tolerated with the toxicity profile of carfilzomib being similar to that seen in other trials.38
A phase II trial (MUKfive) compared the safety and toxicity of carfilzomib/cyclophosphamide/dexamethasone with bortezomib/cyclophosphamide/dexamethasone in patients with relapsed/refractory MM, who had received one prior regimen.38 A higher proportion of patients receiving carfilzomib experienced VGPR or better, and it was noninferior to bortezomib. Carfilzomib/cyclophosphamide/dexamethasone was well tolerated, with the toxicity profile of carfilzomib being similar to that seen in other trials.38 This study also included a maintenance phase and demonstrated a median PFS of 11.9 versus 5.6 months in favor of carfilzomib maintenance versus observation.
Another phase II trial compared treatment with cyclophosphamide plus carfilzomib and dexamethasone to treatment with carfilzomib and dexamethasone in patients (n=197) with relapsed/refractory MM after 1 to 3 prior lines.39 After a median follow-up of 37 months, median PFS was 19.1 with the 3-drug regimen compared with 16.6 months with the 2-drug regimen (P=.577).39 The combination of cyclophosphamide with carfilzomib and dexamethasone did not improve outcomes significantly compared with carfilzomib and dexamethasone alone in the overall population. However, in a subgroup analysis of the lenalidomide-refractory population, the addition of cyclophosphamide to carfilzomib and dexamethasone resulted in a PFS benefit of 18.4 versus 11.3 months (HR, 1.7; 95% CI, 1.1–2.7; P=.043).39
The panel has included carfilzomib/cyclophosphamide/dexamethasone as treatment as an other recommended regimen for relapsed/refractory MM after 1 to 3 prior therapies.
Daratumumab/Cyclophosphamide/Bortezomib/Dexamethasone
In the LYRA study,40 among the small cohort of patients with relapsed MM (n=14), after 4 cycles of induction therapy, ORR was 12.3% and VGPR or better was seen in 57.1% of patients.40 The ORR after 4 induction cycles was 71.4%. The median PFS was 13.3 months (95% CI, 6.8–13.3). At 12‐months, the OS rate was 54.5% (95% CI, 8.6%–86.1%).40
Based on this, the NCCN Guidelines Panel has included daratumumab/bortezomib/cyclophosphamide/dexamethasone as a treatment option for relapsed/refractory MM.
Elotuzumab/Bortezomib/Dexamethasone
Numerous randomized trials have shown that 3-drug combinations are consistently more effective than 2-drug combinations for the treatment of MM. A phase II trial studied the effect of the addition of elotuzumab to bortezomib/dexamethasone in patients with relapsed/refractory MM.41
Interim analysis results showed a 28% reduction in risk of disease progression or death for patients in the elotuzumab-containing triple-drug arm compared with patients treated with bortezomib/dexamethasone (HR, 0.72; 70% CI, 0.59–0.88). Median PFS was significantly higher in the elotuzumab-containing arm (9.7 vs 6.9 months). After 2 years the addition of elotuzumab continued to show an efficacy benefit compared with bortezomib/dexamethasone alone with a 24% relative risk reduction in PFS (HR, 0.76; 70% CI, 0.63–0.91).41
Based on these phase II trial data, the panel has included elotuzumab/bortezomib/dexamethasone as an other recommended regimen for relapsed/refractory MM after 1 to 3 prior therapies.
Ixazomib/Cyclophosphamide/Dexamethasone
This regimen has been shown to be tolerable and efficacious in newly diagnosed patients.42,43 A phase II study evaluated this regimen in the relapsed/refractory setting in patients with a median age of 63.5 years and found that it is well tolerated. At a median follow-up of 15.2 months in the phase II study, median PFS was 14.2 months. The PFS trend with this regimen was better in patients aged 65 and older compared with those younger than 65 years (median, 18.7 vs 12.0 months; HR 0.62; P=.14).44 The NCCN Guidelines Panel has included this all oral regimen under the list of “other recommended regimens” for relapsed/refractory MM.
Lenalidomide/Cyclophosphamide/Dexamethasone
A retrospective analysis to assess the efficacy of lenalidomide in combination with cyclophosphamide and dexamethasone showed that this regimen is effective in heavily pretreated patients with manageable adverse effects.45 The NCCN Guidelines Panel has included cyclophosphamide/lenalidomide/dexamethasone treatment as an other recommended regimen for relapsed/refractory MM after 1 to 3 prior therapies.
Pomalidomide/Cyclophosphamide/Dexamethasone
A phase II study compared the combination of pomalidomide/cyclophosphamide/dexamethasone to pomalidomide/dexamethasone in patients (n=70) with relapsed/refractory MM who had received more than two prior therapies.46
The triple-drug combination significantly improved the ORR (≥PR, 64.7% vs 38.9%; P=.0355). The median PFS reported was 9.5 versus 4.4 months. No significant differences were seen in adverse event reports between the treatment arms; grade 3 and 4 anemia, neutropenia, and thrombocytopenia, respectively, were reported in 11%, 31%, and 6% of patients treated with pomalidomide/dexamethasone and 24%, 52%, and 15% of patients treated with the triplet regimen.46 Similar results were reported by a single-center retrospective study of patients (n=20) with relapsed/refractory MM who received pomalidomide/cyclophosphamide/dexamethasone until transplant or disease.47 Response to the triple-drug regimen was 63%, with nearly half of patients (42%) after 1 cycle with a median time to response of 3 cycles. One-year median PFS was 80.7%, and 65% of patients were relapse-free.47
Based on these phase II trial data, the NCCN Guidelines Panel has included pomalidomide/cyclophosphamide/dexamethasone as other recommended treatment option for patients with relapsed/refractory MM who have received 2 prior therapies, including an IMiD and a PI and disease progression on/within 60 days of completion of last therapy.
Regimens Useful in Certain Circumstances for Previously Treated MM – Early Relapse (1 to 3 Prior Therapies)
Bortezomib/Liposomal Doxorubicin/Dexamethasone
Bortezomib with liposomal doxorubicin (PLD) was approved by the FDA as a treatment option for patients with MM who have not previously received bortezomib and have received at least one prior therapy. The approval was based on a priority review of data from an international phase III trial (n=646) showing that use of the combination significantly extended the median time to disease progression compared with bortezomib alone (9.3 vs 6.5 months).48 Median duration of response was increased from 7.0 to 10.2 months with the combination therapy. Based on these results, the NCCN MM Panel considers bortezomib with the PLD regimen as a category 1 option that is useful in certain circumstances for patients with relapsed/refractory MM.
Bortezomib/Dexamethasone
The addition of dexamethasone to bortezomib in patients with relapsed/refractory MM who had PD during bortezomib monotherapy resulted in improvement of response in 18%–34% of patients.49–51 The NCCN MM Panel members have included the bortezomib and dexamethasone regimen as an option that is useful in certain circumstances for patients with relapsed/refractory MM (category 1).
Lenalidomide/Dexamethasone
Lenalidomide combined with dexamethasone received approval from the FDA as a treatment option for patients with MM who had received at least one prior treatment. This was based on the results of 2 studies with a total of 692 patients randomized to receive dexamethasone either with or without lenalidomide. The primary efficacy endpoint in both studies was time to progression (TTP). A preplanned interim analysis of both studies reported that the median TTP was significantly longer in the lenalidomide arm compared with the control group.52,53 The updated clinical data from the pivotal North American phase III trial (MM-009) in 353 previously treated patients with MM reported increased OS and median time to disease progression in patients receiving lenalidomide plus dexamethasone compared with patients receiving dexamethasone plus placebo.53 Similar results were seen in the international trial MM-010.52 Patients in both of these trials had been heavily treated before enrollment. Many had 3 or more prior lines of therapies with other agents and more than 50% of patients had undergone HCT.52,53 Most adverse events and grade 3/4 adverse events were more frequent in patients with MM who received the combination of lenalidomide/dexamethasone compared with placebo and dexamethasone. Thrombocytopenia (61.5%) and neutropenia (58.8%) were the most frequently reported adverse events observed. The NCCN MM Panel now considers this regimen as a category 1 option that is useful in certain circumstances for patients with relapsed/refractory MM.
Carfilzomib/Cyclophosphamide/Thalidomide/Dexamethasone
The results of the phase I/II trial showed that this 4-drug regimen is efficacious with an ORR of 91%, with 59% experiencing VGPR or greater after 4 cycles in patients with MM.54 The PFS and OS at 24 months (median, 17.5 months) were 76% and 96%, respectively.54 This regimen has now been included under the list of regimens “useful in certain circumstances” for relapsed/refractory MM.
Carfilzomib (Weekly)/Dexamethasone
In the phase III A.R.R.O.W. trial, patients (n=578) with relapsed and refractory MM previously treated with 2 or 3 treatments, including PI and IMiD were randomly assigned (1:1) to receive carfilzomib once a week (70 mg/m2) or twice a week (27 mg/m2). All patients received dexamethasone. The media PFS was higher in the once weekly (11.2 months) compared with those who received twice weekly carfilzomib (7.6 months; HR 0.69, 95% CI 0.54-0.83; P=.0029). The overall safety was comparable between the two groups.55 The NCCN panel has included this combination on the list of regimens “useful in certain circumstances” for relapsed/refractory MM.
Selinexor/daratumumab/dexamethasone
A phase Ib/II trial assessed the safety and efficacy of adding daratumumab to selinexor dexamethasone. Patients (n=34) enrolled in the trial had received 3 or more prior lines of therapy, including a PI and an IMiD. In daratumumab-naïve patients, the ORR was 73%, with 11 VGPR and 11 PR. The median PFS was 12.5 months. This regimen has been included under the list of regimens useful in certain circumstances for relapsed/refractory MM.
Selinexor/Carfilzomib/Dexamethasone
In a study of 32 patients who had received a median of 4 prior therapies were assigned to receive once weekly selinexor, carfilzomib, and dexamethasone. The ORR was 78% with a median PFS of 15 months. The most common grade 3 or higher treatment-related adverse events were thrombocytopenia (47%), nausea (6%), anemia (19%), and fatigue (9%).56
Another analysis of a subset of this patient population that had triple-class refractory MM also showed an ORR of 66.7% with a median PFS of 13.8 months and median OS of 33 months.57
This regimen has now been included under the list of regimens “useful in certain circumstances” for relapsed/refractory MM.
Venetoclax/Dexamethasone With or Without Daratumumab or PI for t(11;14) Patients
A phase I study of patients (n=66) with relapsed/refractory MM who received a median of 5 prior lines of therapy studied venetoclax monotherapy and reported an ORR in 21% of patients, with the response rate higher in patients (n=30) with t(11;14) compared with those without t(11:14) (40% vs 6%).58 Similar higher response rates have been found in patients with t(11:14) in real-world experience as well.59 An open-label phase I/II study examined venetoclax/dexamethasone in heavily pretreated t(11;14) patients. In this phase II part of the study, patients had received a median of 5 prior lines of therapy. At a median follow-up of 9.2 months, the ORR was 48%, with a median TTP of 10.8 months.60
Several prospective trials have reported on the efficacy and tolerability of venetoclax/dexamethasone–containing combination regimens in relapsed t(11;14) MM. A phase I study found that venetoclax/dexamethasone in combination with daratumumab with or without bortezomib produced high rates of durable responses in patients with relapsed or refractory MM with t(11;14) translocation.61
In patients with no prior treatment with carfilzomib, venetoclax/dexamethasone plus carfilzomib was found to be safe and efficacious, especially in those with t(11;14) translocations.62 This finding has been supported by case studies.63
The NCCN Guidelines Panel included venetoclax/dexamethasone with or without daratumumab or a PI as options for patients with t(11:14) translocation.
Pomalidomide/Dexamethasone
Pomalidomide, like lenalidomide, is an analogue of thalidomide. It possesses potent immunomodulatory and significant antimyeloma properties.64
A phase III, multicenter, randomized, open-label study (MM-003) conducted in Europe compared the efficacy and safety of pomalidomide and low-dose dexamethasone (n=302) versus high-dose dexamethasone (n=153) in patients with relapsed MM refractory to both lenalidomide and bortezomib.65 After a median follow-up of 10 months, PFS, the primary endpoint of the study, was significantly longer in patients who received pomalidomide and low-dose dexamethasone compared with those who received high-dose dexamethasone (4 vs 1.9 months; HR, 0.45; P<.0001).65 The median OS was also significantly longer in the patients who received pomalidomide and low-dose dexamethasone (12.7 vs 8.1 months; HR, 0.74; P=.0285).65 The most common hematologic grade 3 and 4 adverse effects found to be higher with the low-dose dexamethasone compared with the high-dose dexamethasone were neutropenia and pneumonia.65 Other phase III studies of pomalidomide plus low-dose dexamethasone in combination with other agents (eg, bortezomib) are currently ongoing (ClinicalTrials.gov identifier: NCT01734928).
A European multicenter, single-arm, open-label, phase IIIb trial evaluated the safety and efficacy of pomalidomide and low-dose dexamethasone in a large patient population (n=604).66 The median PFS reported was 4.2 months and OS was 11.9 months. Whether the patients received prior lenalidomide or bortezomib, the PFS, OS, and ORR reported were similar.66 The results of this trial are consistent with those observed in the pivotal MM-003 trial.65
In addition, several complementary phase II studies have been published evaluating the use of pomalidomide and dexamethasone in patients with MM relapsed/refractory to lenalidomide and/or bortezomib. A phase II study investigated 2 different dose regimens of pomalidomide and dexamethasone in 84 patients with advanced MM. Pomalidomide (4 mg) was given orally on days 1 to 21 or continuously over a 28-day cycle, and dexamethasone (40 mg) was given orally once weekly.67 ORR was 35% and 34% for patients in the 21-day and 28-day groups, respectively. With a median follow-up of 23 months, median duration of response, PFS, and OS were 7.3, 4.6, and 14.9 months across both groups, respectively. All patients experienced similar adverse events in both groups. The adverse events were primarily due to myelosuppression.67 Another phase II trial evaluated 2 doses of pomalidomide, 2 or 4 mg/day with dexamethasone 40 mg weekly in heavily pretreated patients (n=35).68 The ORR in the 2-mg cohort was 49% versus 43% in the 4-mg cohort. OS at 6 months was 78% and 67% in the 2- and 4-mg cohort, respectively. Myelosuppression was the most common toxicity.68
The FDA has approved pomalidomide for patients with MM who have received at least 2 prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. The FDA-recommended dose and schedule of pomalidomide is 4 mg orally on days 1 to 21 of repeated 28-day cycles, with cycles repeated until disease progression along with the recommendation to monitor patients for hematologic toxicities, especially neutropenia.
Based on these data, the panel has included pomalidomide plus dexamethasone as a therapeutic option in patients who have received at least 2 prior therapies, including an IMiD and a PI, and have demonstrated disease progression on or within 60 days of completion of the last therapy (category 1).
Selinexor/Pomalidomide/Dexamethasone
An abstract presented at the 2021 ASCO Annual Meeting presented data from an ongoing phase I/II clinical trial that contains one arm evaluating the regimen of selinexor/pomalidomide/dexamethasone (ClinicalTrials.gov identifier: NCT02343042). Sixty-five patients were enrolled initially in phase I with a median of 3 prior lines of therapy. After determining a recommended phase II dose, it was administered to 20 patients. Among these patients, the ORR was 65% and the median PFS was not reached in a median follow up of 3.9 months.69 Based on these data, the NCCN Guidelines Panel has included selinexor/pomalidomide/dexamethasone as a therapeutic option in patients who have received at least 2 prior therapies, including an IMiD and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy (category 1).
Daratumumab
Daratumumab is a human immunoglobulin G kappa monoclonal antibody that targets the CD38 surface protein on myeloma cells.19 In a phase I/II study, patients who had received more than 3 lines of therapy including an IMiD and a PI or were double refractory to PI and IMiD were randomized to 2 different doses of daratumumab (8 mg/kg vs 16 mg/kg). Findings from 106 patients who received 16 mg/kg noted an ORR of 29.2% in 31 patients (3 stringent CR [sCR], 10 VGPR, and 18 PR). The median duration of response was 7.4 months and median TTP was 3.7 months. The estimated 1-year OS rate was 65%.20 Adverse events reported were fatigue (39.6%), anemia (33.0%), nausea (29.2%), and thrombocytopenia (25.5%). Grade 1 and 2 infusion-related reactions were seen in 42.5% of patients, mainly during first infusion. No patients discontinued the study due to infusion-related reactions.20
Based on the noted phase II results and FDA approval, the panel has added daratumumab as an option for the treatment of patients with MM who have received at least 3 prior lines of therapy including a PI and an IMiD or who are double refractory to a PI and IMiD.
DCEP and VTD-PACE for Aggressive MM
Patients with an aggressive relapse may need multidrug combinations such as DCEP,70–72 TD-PACE (thalidomide, dexamethasone, cisplatin, doxorubicin, high-dose cyclophosphamide, and etoposide),73,74 and VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide)75–77 for effective disease control.
Preferred Regimens for Relapse After 4 Prior Therapies
Currently there are 3 bispecific antibodies (elranatamab-bcmm, talquetamab-tgvs, and teclistamab-cqyv) and 2 CAR T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) approved by the FDA and included as preferred options by the NCCN Guidelines Panel for relapsed/refractory MM after at least 4 prior therapies including an anti-CD38 monoclonal antibody, a PI, and an IMiD.
Bispecific Antibodies
Elranatamab-bcmm
Elranatamab-bcmm is a bispecific T-cell engager that binds CD3 on T cells and to B-cell maturation antigen (BCMA) on myeloma cells. In the phase II, MagnetisMM-3 trial, patients with relapsed/refractory MM received subcutaneous elranatamab once weekly.78 The primary population in whom the efficacy was seen were patients (n=123) without prior BCMA-directed therapy. The findings indicated an ORR of 61.0% (75/123) and 35.0% greater than or equal to CR. Fifty responders switched to biweekly dosing, and 40 of those (80.0%) improved or maintained their response for ≥6 months. Common adverse events reported were infections, cytokine release syndrome, anemia, and neutropenia. With biweekly dosing, grade 3–4 adverse events decreased from 58.6% to 46.6%.78
Talquetamab-tgvs
Talquetamab is a T cell–redirecting bispecific antibody targeting both GPRC5D and CD3 on T cells. In the single-arm, open-label, multicenter trial, MMY1001 (MonumenTAL-1) patients (n=187) who had previously received at least 4 prior systemic therapies received talquetamab-tgvs subcutaneously weekly or talquetamab-tgvs biweekly until disease progression or unacceptable toxicity.79 The most common adverse reactions reported with weekly and biweekly dosing were cytokine release syndrome (in 77% and 80% of the patients, respectively), skin-related events (in 67% and 70%), and dysgeusia (in 63% and 57%).79
Teclistamab-cqyv
Teclistamab-cqyv, similar to elranatamab-bcmm, is a bispecific T-cell engager that binds to CD3 on T cells and BCMA on myeloma cells. A phase I/II study examined the T cell–redirecting bispecific antibody teclistamab-cqyv in 165 patients who had triple class refractory disease, with a median of 5 prior lines of therapy.80 After a median follow up of 14.1 months, the ORR was 63%, and 39.4% of patients demonstrated a CR or better. The median PFS was 11.3 months, with a median response duration of 18.4 months. Common adverse events included cytokine release syndrome in 72.1% of patients (0.6% grade 3) and grade 3 or 4 hematologic toxicity including neutropenia (64.2%), anemia (37%), and thrombocytopenia (21.2%). Infections were also common, with grade 3 or 4 infection occurring in 44.8% of patients.
CAR T-Cell Therapies
Idecabtagene vicleucel
Idecabtagene vicleucel is a BCMA-directed CAR T-cell therapy. In a phase II study (n=128) patients with relapsed and refractory MM who had received at least 3 prior regimens (including a PI, an IMiD, and an anti-CD38 antibody) received idecabtagene vicleucel. Patients had received a median of 6 previous regimens for MM and 94% had received HCT. In this population of heavily pretreated patients, after a median 13 months follow up, 73% of patients demonstrated response, with 33% having a CR or better. The median time to response was 1 month and median time to a CR or better was 2.8 months. High response rates (>50%) were found in several examined subgroups including older patients, patients with high-risk cytogenetic abnormalities, pentarefractory disease, and high tumor burden. Adverse events at grade 3 or 4 were common and included neutropenia (91%), anemia (70%), and thrombocytopenia (63%). Twenty-eight patients were retreated with idecabtagene vicleucel after disease progression and 21% showed a second response. Grade 3 or 4 adverse events were common and were reported in 99% of patients. The most common adverse events were related to hematologic toxicity such as neutropenia (89%), anemia (60%), and thrombocytopenia (52%). Infections (69%) and cytokine release syndrome (84%) were also common treatment-related adverse events, although the incidence of grade 3 or higher cytokine release syndrome was lower (5%).81 The NCCN Guidelines Panel has included idecabtagene vicleucel as an option for patients who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a PI, and an IMiD.
Ciltacabtagene Autoleucel
Ciltacabtagene autoleucel is another BCMA-directed CAR T-cell therapy. The CARTITUDE-1 trial (n=97) was an open label phase Ib/II study with the goal of assessing the safety and efficacy of ciltacabtagene autoleucel in patients with relapsed or refractory MM who had received 3 or more previous lines of therapy (including an IMiD, PI, and anti-CD38 antibody).82 The median amount of prior therapies was 6. After a median 12.4 months of follow up, the ORR was 97%, with 67% of patients achieving sCR. The PFS rate was 77% with an 89% OS rate. Adverse events included neutropenia in 95% of patients and anemia in 68%. Other common adverse events included thrombocytopenia (60%), leukopenia (61%), and lymphopenia (50%). Cytokine release syndrome also occurred in 95% of patients. There were 6 deaths due to treatment-related adverse events.82 A follow-up analysis at 18 months showed that responses were durable; 18-month PFS and OS rates were 66.0% and 80.9% respectively, with no new observed safety signals.83
Other Recommended Regimens for Relapse After 3 Prior Therapies
Bendamustine
In a trial by Knop et al,84 31 patients who had experienced relapse after autologous transplantation were enrolled to receive increasing doses of bendamustine. The ORR was 55%, with a median PFS of 26 weeks for all patients and 36 weeks for patients who received higher doses of bendamustine (90–100 mg/m2). The toxicity was mild and mainly hematologic. A retrospective analysis of 39 patients has reported that bendamustine is effective and tolerable in patients with advanced progressive MM, with an ORR of 36%.85
The ECOG studied treatment with high-dose cyclophosphamide in patients with poor-risk features who had disease that was refractory to prior chemotherapy.86 The ORR reported was 43% (29% response rate in patients refractory to prior therapy with cyclophosphamide).86 Bendamustine is currently a treatment option for relapsed/refractory MM.
Bendamustine/Bortezomib/Dexamethasone
A phase II study evaluated bendamustine/bortezomib/dexamethasone administered over six 28-day cycles and then every 56 days for 6 more cycles in patients (n=75; median age 68 years) with relapsed/refractory MM treated with multiple prior therapies and not refractory to bortezomib. The PR rate was 71.5% (16% CR, 18.5% VGPR, 37% partial remission). At 12-month follow-up, median TTP was 16.5 months, and 1-year OS was 78%.87
Bendamustine/Carfilzomib/Dexamethasone
A multicenter trial evaluated combination therapy with bendamustine/carfilzomib/and dexamethasone in 63 patients with relapsed/refractory MM (with ≥2 lines of prior therapy). Fifty-two percent of patients experienced a PR or better and 32% experienced a VGPR or better. After a median follow up of 22 months, the median PFS was 11.6 months with a median OS of 30.4 months. The most common adverse events of grade 3 or higher included lymphopenia (29%), neutropenia (25%), and thrombocytopenia (22%).88 The NCCN Guidelines Panel has included carfilzomib in combination with bendamustine and dexamethasone as a treatment option for relapsed/refractory MM.
Bendamustine/Lenalidomide/Dexamethasone
A multicenter phase I/II trial investigated the combination of bendamustine, lenalidomide, and dexamethasone as treatment for patients (n=29) with relapsed/refractory MM.89 PR was seen in 52% (n=13) of patients, with VGPR in 24% (n=6) of patients. The median PFS in the trial was 6.1 months (95% CI, 3.7–9.4 months), and the 1-year PFS rate was 20% (95% CI, 6%–41%).89 The panel has included lenalidomide in combination with bendamustine and dexamethasone as a treatment option for relapsed/refractory MM.
High-Dose or Fractionated Cyclophosphamide
Studies have reported that high-dose cyclophosphamide or hyperfractionated cyclophosphamide is efficacious particularly in patients needing immediate disease control who have received multiple prior treatments.90,91 Therefore the NCCN Guidelines Panel has included high dose or fractionated cyclophosphamide as an option for relapsed/refractory MM.
Selinexor/Dexamethasone
Selinexor in combination with dexamethasone was studied in a phase IIb trial (STORM) in patients with relapsed/refractory MM.92 The patients in the trial had multiple prior therapies and were refractory to IMIDs (lenalidomide and pomalidomide), PIs (bortezomib and carfilzomib), and the CD38 antibody daratumumab. A total of 122 patients were included in the intent-to-treat population. PR or better was observed in 26% of patients (95% CI, 19%–35% with sCR in 2%, VGPR in 5%, and PR in 20% of patients.
The most common adverse events reported during treatment were thrombocytopenia in 73% of the patients, fatigue in 73%, nausea in 72%, and anemia in 67%.
Based on these results, the NCCN MM Panel has included selinexor/dexamethasone under other recommended options for patients with relapsed/refractory MM who have received at least 4 prior therapies and whose disease is refractory to at least 2 PI, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.56
Regimens Useful in Certain Circumstances for Relapse After 4 Prior Therapies
Belantamab Mafodotin-blmf
Belantamab mafodotin-blmf is a BCMA antibody, conjugated to a microtubule disrupting agent—monomethyl auristatin—via a stable, protease resistant linker. It is the first in its class. In the open-label phase II trial (DREAMM-2), belantamab mafodotin was evaluated in patients whose MM was refractory to multiple agents. Responses were seen in approximately one-third of patients.93 The most common grade 3/4 adverse events in the safety population were keratopathy, thrombocytopenia, and anemia.93
In November 2022, it was announced that belantamab mafodotin-blmf is being withdrawn because it did not meet the primary end point of having a superior PFS compared with pomalidomide/dexamethasone in the DREAMM-3 trial (HR, 1.03; 95% CI, 0.72–1.47). The PFS with belantamab mafodotin-blmf was 11.2 months compared with 7 months for pomalidomide plus dexamethasone; however, this was not statistically significant. Since that time, patients already receiving belantamab mafodotin-blmf and those enrolled on the FDA Risk Evaluation and Mitigation Strategy program have been able to continue to receive the drug through a compassionate use program. Other trials with belantamab mafodotin-blmf are ongoing. The NCCN Guidelines Panel has included this as an option useful in certain circumstance for those after 4 prior therapies (including a PI, an IMiD, and an anti-CD38 monoclonal antibody).
Supportive Care for MM
Important advances have been made in adjunctive treatment/supportive care of patients with MM. This involves careful patient education about the probable side effects of each drug, the drug combinations being used, and the supportive care measures required. Supportive care can be categorized into those measures required for all patients and those that address specific drugs.
Bony manifestations in the form of diffuse osteopenia and/or osteolytic lesions develop in 85% of patients with MM. Related complications are the major cause of limitations in quality of life and performance status in patients with MM. A large, double-blind, randomized trial has shown that monthly use of intravenous pamidronate (a bisphosphonate) can decrease pain and bone-related complications, improve performance status, and, importantly, preserve quality of life in patients with Durie-Salmon stage III MM and at least 1 lytic lesion.94,95 Zoledronic acid has equivalent benefits.96 Results from the study conducted by Zervas et al97 show a 9.5-fold greater risk for the development of osteonecrosis of the jaw (ONJ) with zoledronic acid compared with pamidronate. Patients who are on bisphosphonates should have their renal function monitored. They should undergo a dental examination before starting bisphosphonate therapy and should be monitored for ONJ.
The Medical Research Council Myeloma IX study examined effects of zoledronic acid versus clodronate (a bisphosphonate not currently FDA approved) in patients with MM initiating chemotherapy regardless of bone disease. The patients were randomized to receive zoledronic acid (n=981) or clodronic acid (n=979). Zoledronic acid was reported to reduce mortality and significantly improve PFS.98 Patients on clodronate and zoledronic acid had similar occurrence of acute renal failure and treatment-related serious adverse events. Zoledronic acid was associated with higher rates of ONJ than was clodronic acid.99 An extended follow-up (median, 5.9 years) of the Medical Research Council Myeloma IX showed significant improvement in OS (52 vs 46 months; HR, 0.86; P=.01) compared with clodronic acid.100 The long-term rates of ONJ were also observed to be higher with zoledronic acid compared with clodronate (3.7% vs 0.5%; P=.0001).100
A recent meta-analysis of 20 randomized controlled trials comparing bisphosphonates with either placebo or a different bisphosphonate as a comparator concluded that adding bisphosphonates to the treatment of MM reduces vertebral fractures and probably reduces pain.101 It did not find a particular bisphosphonate to be superior to another.101 In a multicenter trial (CALGB 70604), patients with MM or bone metastases from a solid malignancy were randomly assigned to zoledronic acid either monthly or every 3 months for 2 years.102 The rates of skeletal-related events were similar in both arms. Among the 278 patients with MM, rates of skeletal-related events were 26% in those receiving monthly versus 21% in those receiving treatment every 3 months.102
A large, placebo-controlled, randomized trial compared denosumab with zoledronic acid in patients (n=1,718) with newly diagnosed MM with bone lesions. Time to first skeletal-related event and OS were similar in both arms. The denosumab arm had lower rates of renal toxicity and higher rates of hypocalcemia. ONJ was slightly higher in the denosumab arm (3% vs 2%) but not statistically significant.103
The NCCN Guidelines for MM recommend bisphosphonates (category 1) or denosumab for all patients receiving therapy for symptomatic MM regardless of documented bone disease. Denosumab is preferred by the NCCN MM Panel in patients with renal disease. The panel recommends a baseline dental examination and monitoring for ONJ in all patients receiving a bone-modifying agent and monitoring for renal dysfunction with use of bisphosphonate therapy. With respect to duration of therapy, the panel also recommends continuing bone-targeting treatment (bisphosphonates or denosumab) for up to 2 years; continuing beyond 2 years should be based on clinical judgement. The frequency of dosing (monthly vs every 3 months) would depend on the individual patient criteria and response to therapy.
Excess bone resorption from bone disease can lead to excessive release of calcium into the blood, contributing to hypercalcemia. Symptoms include polyuria and gastrointestinal disturbances, with progressive dehydration and decreases in glomerular filtration rate. Hypercalcemia should be treated with hydration, bisphosphonates, denosumab,103 steroids, and/or calcitonin. Among the bisphosphonates (zoledronic acid, pamidronate, and ibandronate), the NCCN MM Panel members prefer zoledronic acid for treatment of hypercalcemia.96,104,105
The panel has provided general principles of palliative radiation therapy for patients with MM. Careful planning of the radiation field and radiation technique is important to minimize toxicity to the spinal cord, brain, bone marrow, and adjacent organs at risk because patients with MM may be treated multiple times during the disease course. The panel has noted that initiation of systemic therapy should not be delayed for radiation therapy and can often be given concurrently and that patients should be carefully monitored for toxicities.106,107 Low-dose radiation therapy (8 Gy × 1 fraction) or 20 to 30 Gy in 5 to 10 total fractions can be used as palliative treatment for uncontrolled pain, for impending pathologic fracture, or for impending cord compression. Moderately fractionated courses of 20 to 25 Gy in 8 to 10 fractions are generally preferred over higher doses (30 Gy) absent extenuating circumstances (eg, severe symptomatic cord compression) to limit unnecessary toxicity and reduce risk of future treatment of adjacent or overlapping organs at risk (eg, spinal cord).108 For radiation therapy dose constraint suggestions regarding bone marrow and other organs at risk, see NCCN Guidelines for Hodgkin Lymphoma (available at NCCN.org).
Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity.109 Institutions differ in their use of plasmapheresis for adjunctive treatment of renal dysfunction.
Erythropoietin therapy may be considered for patients with anemia, especially those with renal failure. Measuring endogenous erythropoietin levels may also be helpful in treatment planning110,111 (see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections, available at NCCN.org). Daratumumab can interfere with cross-matching and red blood cell antibody screening. The NCCN MM Panel recommends performing type and screen before receiving daratumumab to inform future matching.
The highest risk for venous thromboembolism (VTE) is in the first 6 months after a new diagnosis of MM. The NCCN MM Panel has outlined management of VTE, risk stratification, and VTE prophylaxis in a separate section in the NCCN Guidelines for MM (available at NCCN.org), and VTE prophylaxis is administered to all patients, assuming there are no contraindications to anticoagulation agents or antiplatelets (see NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease, available at NCCN.org).
To prevent infections in patients with MM, the panel recommends referring to the NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections (available at NCCN.org) and the CDC recommendations for Use of COVID-19 Vaccines in the United States. In the most recent update, the NCCN MM Guidelines Panel has outlined recommendations for prophylaxis and management of infections in patients undergoing treatment with CAR T-cell and bispecific antibody.
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
The complete NCCN Guidelines for Multiple Myeloma are not printed in this issue of JNCCN but can be accessed online at NCCN.org.
© 2023, National Comprehensive Cancer Network® (NCCN®). All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
Disclosures for the NCCN Multiple Myeloma Panel
At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.
Individual disclosures for the NCCN Multiple Myeloma Panel members can be found on page 1301. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
