5 – Optimizing drug-based treatment at relapse
In 1999 the activity of single-agent thalidomide was reported in refractory MM  and followed by many phase II studies confirming this initial observation. However, prolonged use of thalidomide is associated with an increased risk for severe side effects, particularly irreversible peripheral neuropathy . The initial observations with thalidomide stimulated the search for more potent and less toxic thalidomide analogues. A few years later, lenalidomide was approved in relapsed MM based on two multicenter, randomized trials (MM-009, MM-010) comparing the combination of lenalidomide 25 mg/day for 21 days/month plus high-dose dexamethasone (Len/Dex) with dexamethasone (Dex) alone [20,21]. Compared with Dex, Len/Dex significantly improved response rates, time to progression, and overall survival. With standard doses of Len/Dex, a partial response or better could be reached in 60% of patients having previously received one to three treatment lines, with a median time to progression of 11 months.
Additional analyses of these pivotal studies have shown that Len/Dex has the highest clinical benefit when it is given until disease progression or in first versus later relapse [22,23]. Lenalidomide is usually well tolerated with mild myelosuppression, asthenia, muscle cramps, skin eruptions or chronic diarrhea caused by malabsorption of bile salts reported as the most common adverse events [24,25]. Over the years, dexamethasone doses have been reduced to once weekly administration (further referred to as Rd regimen) with similar efficacy but significantly less toxicity .
An Rd-based regimen is currently the preferred treatment choice for myeloma patients relapsing after a bortezomib-based regimen. During the last few years several studies have explored the benefit of the addition of a third agent to the Rd backbone in relapsed MM. These can include low-dose cyclophosphamide  or bortezomib, but more recently a major breakthrough has been achieved by combining Rd with the second-generation proteasome inhibitors carfilzomib (KRd) , ixazomib (IRd) , and the monoclonal antibodies daratumumab (DRd)  or elotuzomab (ERd) . These four studies have been conducted in similar patient groups (after 1 to 3 previous lines of treatment) and have proven a significant prolongation of the PFS and response rates in favor of the lenalidomide-based triplet. Although some of these regimens seem to be more potent than others, a priority listing on depth of response and response duration only would narrow the clinical decision making. The combination of Rd plus daratumumab seems to be associated with the deepest response rates with even a significant percentage of patients reaching minimal residual disease (MRD) negativity, an observation for the first time reported in relapsed MM. The availability of these highly active Rd-based regimens for relapsed MM provides opportunities but also creates more complexity in the therapeutic decision making. For example the use of continuous Rd at diagnosis should be balanced in the perspective of more active Rd-based ‘triplets’ at relapse. Drug availability in addition to disease characteristics, age, comorbidities, patient preference and hospital capacity are important factors to be taken into consideration when making the therapeutic choice of an Rd-based triplet at relapse. It is beyond doubt that the registration of some of these Rd-based triplets for first-line treatment within a few years will alter again the therapeutic choice at relapse.
Pomalidomide is a third generation IMiD and, as for thalidomide and lenalidomide, there is synergistic activity with dexamethasone. Pomalidomide 4 mg/day 21 days/month with weekly dexamethasone (Pom/dex) is registered for MM patients who have failed treatment with a proteasome inhibitor and IMiD . In this patient group, clinically meaningful responses can be obtained, that can further be enhanced by addition of a third drug like cyclophosphamide of clarithromycin. Studies of pomalidomide with monoclonal antibodies like daratumumab or isatuximab are ongoing. The side effect profile of pomalidomide is comparable with lenalidomide although the myelosuppressive effect is more pronounced, particularly during the first treatment cycles. All patients receiving IMiD-based combinations should receive thromboprophylaxis for the whole duration of their treatment .
The phase III APEX trial resulted in approval of bortezomib for MM patients relapsing after first-line treatment . As with lenalidomide, bortezomib at a dose of 1.3 mg/m2 is administered together with dexamethasone where the most commonly used regimen is administration of dexamethasone on the day of bortezomib and the day after (Vd regimen). Over the years, bortezomib has gradually moved from salvage treatment for relapsed refractory patients, to earlier relapses, and has become a standard regimen for first line treatment in both transplant candidates and elderly myeloma patients. Moreover, the switch from intravenous to subcutaneous administration , and from bi-weekly to weekly in more vulnerable subgroups  has contributed significantly to a better management of side effects such as peripheral neuropathy. However, further response improvement of the Vd regimen can be obtained by adding a third drug to bortezomib plus dexamethasone. This third drug can either be chemotherapy such as (pegylated) doxorubicin (PAD) , cyclophosphamide (VCD) , or an immunomodulatory drug such as thalidomide (VTD)  or lenalidomide (VRD) . According to the number of previous treatment lines, response durations between 6 and 18 months have been reported with these regimens without serious toxicities, with the exception of significant peripheral neuropathy with VTD. Most recently the addition of daratumumab (DVd) significantly improved response rates and prolonged PFS compared with Vd without adding more toxicity to the regimen .
The success of bortezomib has also stimulated the development of second-generation proteasome inhibitors. Carfilzomib is an irreversible proteasome inhibitor with fewer off-target activities and without significant neurotoxicity. As discussed previously the addition of carfilzomib to Rd (KRd) significantly prolonged depth and duration of response compared to Rd. A direct head-to-head comparative study between Vd and carfilzomib plus dexamethasone (Kd), (ENDEAVOR) revealed a significant superiority of Kd over Vd in terms of response rates, PFS and OS . Oral proteasome inhibitors like ixazomib in combination with Rd have the advantage of being fully oral regimens .
Finally, combinations of bortezomib with histone deacetylase inhibitors such as panobinostat  have been evaluated prospectively. Although this combination increased the PFS, there were significant additional toxicities with that particular dosing regimen.
Other therapeutic options
In the era of targeted therapy many interesting new agents are emerging in the field of MM. Based on their success in many other malignancies, monoclonal antibodies (MoAb) were long awaited in MM. Elotuzumab, an anti-CS1 antibody, has no single agent activity and is currently licensed in combination with Rd . In contrast, monotherapy with the anti-CD38 MoAb daratumumab can induce a partial response or better in more than 30% of heavily pretreated MM patients . Interestingly, even patients with minimal response or stable disease benefited from this treatment based on their OS results. Other compounds in different phases of clinical development include the bcl-2 antagonist venetoclax that might become the first targeted treatment for patients carrying the t(11;14) in their plasma cells  and selinexor , an XPO-1 antagonist explored in patients refractory to all other registered treatment options. Cell-based therapy with chimeric antigen receptor (CAR) T-cells is in early phase development in many hematological malignancies including MM and is expected to change the therapeutic landscape at relapse in the following years . Finally, one should not forget conventional chemotherapy such as monotherapy with agents like bendamustine, or combination regimens such as DCEP  or DT-PACE . However, the latter regimens are associated with profound myelosuppression and response durations in relapsed and refractory MM have not been proven to be durable.
All topics within this chapter
1. General considerations
2. Immediate treatment initiation or watchful waiting
3. To switch or re-treat
4. Role of allogeneic transplantation
5. Optimizing drug-based treatment at relapse
6. Supportive care
Chapter 1 – Pathophysiology
Chapter 2 – Diagnosis and staging
Chapter 3 – Treatment of transplant-eligible patients
Chapter 4 – Pathophysiology
Chapter 5 – Treatment of relapsed multiple myeloma
Chapter 6 – Bone disease