Update in treatment of Symptomatic newly
Diagnosed Transplant Eligible Multiple
Nahla A M Hamed*
Professor of Clinical Hematology, Hematology Department, Faculty of Medicine, Alexandria University, Egypt
Submission: December 09, 2019; Published: January 22, 2020
*Corresponding Address: Nahla A M Hamed, Professor of Clinical Hematology, Hematology Department, Faculty of Medicine, Alexandria University, Egypt
How to cite this article: Nahla A M Hamed. Update in treatment of Symptomatic newly Diagnosed Transplant Eligible Multiple Myeloma Patients. Canc Therapy & Oncol Int J. 2020; 15(3): 555913. DOI:10.19080/CTOIJ.2020.15.555913
The updated criteria for multiple myeloma (MM) diagnosis requires evidence of either 10% or more clonal plasma cells in bone marrow examination or a biopsy-proven plasmacytoma in addition to the presence of one or more myeloma defining events (MDE). MDE consists of established CRAB features (hypercalcemia, renal failure, anemia, or lytic bone lesions) as well as 3 specific biomarkers: clonal bone marrow plasma cells ≥60%, serum free light chain (FLC) ratio ≥100 (provided involved FLC level is ≥100 mg/L), and more than one focal lesion on MRI .
The levels of monoclonal (M) proteins and FLC in blood are assessed routinely to confirm active disease . The M protein is considered measurable if it is ≥1 g/dL in the serum. The serum FLC assay is particularly useful in patients who lack a measurable M protein, provided that the FLC ratio is abnormal and the involved FLC level is ≥100 mg/L .
ii.The evaluation of M-protein in urine is less widespread across clinical practice . The M protein is considered measurable if it is ≥200 mg/day in the urine .
iii. Routine bone marrow assessment (aspirate or biopsy) remains key in the establishment of MM diagnosis in clinical practice, as reflected in the updated International Myeloma Working Group (IMWG) diagnostic criteria .
The creatinine clearance test or estimated glomerular filtration rate (calculated using either the Modification of Diet in Renal Disease [MDRD] study or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equations) are also performed at diagnosis to assess renal function .
Skeletal surveys using X ray do not reveal lytic bone disease until 70% of the bone has decalcified . Whole body low dose computed tomography (CT) or magnetic resonance imaging (MRI) is now recommended by the European Myeloma Network (EMN) and the IMWG as standard for the detection of lytic or focal lesions. Both are more sensitive than conventional skeletal survey using X ray for detecting bone disease . MRI of the spine and pelvis are particularly valuable for detection of focal lesions and may be used if whole body imaging is not available .
vi. Whole body MRI is also effective for bone marrow evaluation
vii. PET-CTs help in recognizing extramedullary disease, an
aggressive phenotype of high-risk myeloma .
The risk status for all patients should be assessed at the
time of diagnosis using the R-ISS. The R-ISS incorporates the
original ISS (serum B2M and serum albumin), serum LDH as well
as chromosomal abnormalities (CAs) detected by plasma cell–
specific interphase FISH. R-ISS stage I is ISS stage I with normal
LDH and standard-risk CA. R-ISS stage II is neither stage I nor
stage III. R-ISS stage III is stage III ISS (B2M ≥ 5.5 mg/dL) with
high LDH and/or high-risk CA (del17p, t[4;14], t[14;16]) . In
addition to these CAs included in staging, t(14;20), a gain of 1q
associated with del(1p), and a non hyperdiploid karyotype are
considered high-risk features. Greater than or equal to three
cytogenetic abnormalities confer ultra-high risk per the IMWG.
Gene expression profiling has allowed characterization of gene
signatures that also identify high-risk patients with a worse
prognosis, but clinical availability of such testing is limited .
If one or more of MDE are detected in NDMM patients start
of therapy is immediately required . Induction regimens have
proven efficacious in fit NDMM patients (<65 years of age in a
good performance status or <70 years of age in good clinical
condition) . Induction therapy should include the first in class
proteasome inhibitor bortezomib combined with dexamethasone
(VD) and a third drug preferably an immunomodulatory agent like
thalidomide or lenalidomide. Cyclophosphamide or doxorubicin
may be an alternative option . The treatment goal should be
to induce the deepest possible remission . Typical treatment
consists of approximately 3–4 cycles of induction therapy prior
to stem cell harvest . After harvest, patients can undergo
high-dose chemotherapy with frontline autologous stem cell
transplantation as initial consolidation therapy . Alternatively,
patients can resume induction therapy delaying ASCT until first
relapse . Maintenance therapy should be considered as part of
the treatment plan in MM patients due to the known short PFS on
no maintenance therapy .
Currently three-drug regimens such as: bortezomib,
thalidomide, and dexamethasone (VTd); bortezomib, lenalidomide,
and dexamethasone (VRd); bortezomib, cyclophosphamide,
and dexamethasone (VCd) ; bortezomib, doxorubicin, and
dexamethasone (PAD); and carfilzomib, lenalidomide, and
dexamethasone (KRd); have all shown improved efficacy
compared with two-drug combinations . VCD is a preferred
primary treatment option especially in patients with acute renal
insufficiency . Cyclophosphamide is an acceptable substitute
if an immunomodulatory drug is not immediately available, until
it becomes available . In patients presenting with plasma
cell leukemia or multiple extramedullary plasmacytomas, initial
therapy of VDT-PACE (bortezomib, dexamethasone, thalidomide,
cisplatin, doxorubicin, cyclophosphamide, and etoposide)
is preferred followed by ASCT and then maintenance with a
bortezomib-based regimen .
Evaluation of response to therapy is based on the revised
IMWG uniform response criteria . All response categories
require two consecutive assessments made at any time before
starting any new therapy . The M protein level (by SPEP) and
serum FLC assay were monitored every month while on therapy
. The largest incremental decrease in paraprotein levels is
observed following the first cycle of therapy and then, a less
steep decline is observed . Urine protein electrophoresis is
recommended at least once every 3–6 months, to follow the urine
M protein level as well as to detect other renal complications
that may result in albuminuria . Minimal residual disease
(MRD) tests should be initiated at the time of suspected complete
response based on the revised IMWG uniform response criteria
. There is no need for two consecutive assessments for MRD
but information on MRD after each treatment stage is required
. Positron emission tomography (PET)-CT may be useful in
determining treatment response (imaging MRD negative status)
and disease progression .
The depth of response to induction therapy in NDMM is highly
prognostic . Very small incremental decreases in paraprotein
are seen beyond three to four cycles of therapy. Therefore, it is
recommended that three to four cycles of induction therapy
be administered in those planned to proceed to autologous
Agents associated with stem-cell toxicity should be avoided
in patients who are potential candidates for SCT. Melphalan and/
or prolonged immunomodulatory drugs exposure such as 
lenalidomide beyond four to six cycles may compromise stemcell
yield. Some of the deleterious effects from alkylator and
lenalidomide exposure can be overcome by either combination
of growth factor and chemotherapy or growth factor and CXCR4
antagonist (plerixafor) . Ample stem-cell collection (sufficient
for at least 2 transplants) should be considered up front, due to
concern for limited ability for future stem-cell collection after
prolonged treatment exposure .
Eligibility for ASCT is usually based on chronological age,
performance state and comorbidities . The level of minimal
response required to proceed to SCT is not established for patients
receiving induction therapy. Patients should be referred for SCT
independent of depth of response .
High dose melphalan / ASCT is performed  ideally within
6-8 weeks of finishing induction. High dose melphalan (200 mg/
m2) is the standard conditioning regimen for ASCT in multiple
myeloma . Melphalan doses may be attenuated for age, frailty,
obesity, or renal function. Several studies have used dose-reduced
melphalan (70 to 140 mg/m2) in older adults . When ASCT is
given as part of the planned frontline treatment, ~22% to 44%
patients achieve CR, with median time to progression and OS of
18 to 24 months and 4 to 6 years, respectively with a treatmentrelated
mortality of ~2% .
Delayed SCT may be used as consolidation at first relapse for
those not choosing to proceed to transplant initially  provided
that stem cells are harvested early in the disease course .
Several retrospective studies and consensus guidelines suggest
that salvage SCT can be a safe and potentially beneficial option,
particularly in patients with remission duration of 18 months
or more following first ASCT . The IFM 2009 trial reported
notable improved PFS and response rate (measured as both CRs
and MRD negativity at 1 × 10−4) in patients who received upfront
ASCT compared with those who deferred transplant. Although
there were no differences in OS at 4 years, and there were more
treatment-related adverse effects in the upfront ASCT arm, there
was a substantial population (21%) of patients in the delayed arm
that had refractory disease and are ineligible for transplant at
time of relapse .
Tandem or double ASCT: a planned second course of high dose
therapy and SCT within 6 months of the first course . The role
of tandem ASCT remains controversial . Tandem ASCT may be
beneficial in patients with high-risk cytogenetic abnormalities
; advanced ISS  or those with a suboptimal response to first
transplant . Those patients who did not achieve a CR or VGPR
within 3 months after the first transplant appeared to benefit the
most from a second transplant .
An allogeneic SCT can be performed after prior myeloablative
or non myeloablative therapy. Non myeloablative allogeneic
transplant (mini transplant) is not adequate and is usually done
following maximal tumor control through adequate induction
therapy or an autologous SCT. The NCCN guidelines consider
myeloablative allogeneic SCT an accepted option, preferably in a
clinical trial in:
i) Patients whose disease responds to primary therapy;
ii) Patients with primary PD; or
iii) Patients with PD after an initial autologous SCT .
Consolidation therapy is recommended now, later, or never?
Consolidation therapy is not routinely recommended but
may be considered in the context of a clinical trial. Consolidation
therapy for at least two cycles may be considered for patient’s
ineligible or unwilling to consider maintenance therapy .
Lenalidomide maintenance therapy should be routinely
offered to standard-risk patients starting at approximately day
90 to 110 at 10 to 15 mg daily until progression. The optimal
duration or depth of response has not been defined. A minimum
of 2 years of maintenance therapy irrespective of response is
associated with improved PFS. The goal-directed group (stopping
lenalidomide once CR was achieved) received less lenalidomide
and was associated with early relapse. Survival benefit has not
been clearly shown in patients with ISS stage III disease, those
with adverse risk cytogenetics such as t(4;14) or deletion 17p,
those with elevated LDH, or those with low creatinine clearance
Bortezomib maintenance every 2 weeks may be considered
for patients intolerant of or unable to receive lenalidomide. PI
with or without lenalidomide may be considered in high-risk
patients, especially if bortezomib was part of the initial induction
therapy, as this may be associated with improved survival .
Evidence is emerging for use of other agents such as ixazomib
as maintenance therapy .
Absence of MRD is evidenced ideally by undetectable
myeloma cells at levels less than or equal to 1 × 10−6 . Skeletal
involvement in myeloma has heterogeneous nature. MRD flow only represents sampling from the pelvic bone, and the disease may be
active in other areas of involvement (vertebral bones, skull, long
bones, etc.). Patients may be MRD negative by flow cytometry and
still positive on PET-CTs. Therefore, PET-CTs are becoming more
important . Absence of MRD correlates strongly with PFS and
OS . Beyond the prognostic implications of being MRD negative
or positive, escalation or de-escalation of therapy based on MRD
assay results is not recommended . The only caveat would be
an ultrahigh-risk patient who becomes MRD .
Achievement of MRD negativity rates, in the 30-60% range in
ASCT-ineligible and –eligible patients respectively, will hopefully
translate in the coming years into furtherly extended PFS and OS
and are likely to offer a chance of cure to a fraction of standard risk
NDMM . There is insufficient evidence to make modifications to
maintenance therapy based on depth of response, including MRD
status. Future clinical trials will address whether the MRD status
of patients can be used to guide maintenance therapy .
In the ASCT setting, exploration of novel maintenance
strategies as well as better platforms are needed to continue to
improve outcomes and to give patients with high risk myeloma
a better good quality of life, with a minimum burden of therapy.
The role of MRD status in guiding therapy needs to be studied in